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Introduction OPTIMIZE evaluated the efficacy, safety and treatment satisfaction of insulin glargine 300 U/mL once daily (Gla-300 OD) in people with type 1 diabetes mellitus (T1DM) previously uncontrolled on basal insulin twice daily (BID) as part of basal–bolus therapy. Methods OPTIMIZE was a 28-week, prospective, interventional, single-arm phase 4 trial in adults with T1DM. At baseline, basal insulin BID treatment was switched to Gla-300 OD titrated to a fasting self-monitored blood glucose target of 4.4–7.2 mmol/L (80–130 mg/dL). The primary endpoint was the mean glycated haemoglobin (HbA1c) change from baseline to week 24. Secondary endpoints included self-monitored blood glucose, fasting-plasma glucose, hypoglycaemia and patient-reported outcomes including the Diabetes Treatment Satisfaction Questionnaire status version (DTSQs). Results Switching to Gla-300 OD significantly improved mean HbA1c (8.54% at baseline and 8.27% at week 24 [last observation carried forward, N = 94, p

Introduction Chronic Hypersensitivity Pneumonitis (cHP) is a fibrotic interstitial lung disease (ILD) resulting from repeated exposure to an offending antigen. Prognostication in cHP remains challenging, and the relationship between comorbidities and survival has yet to be characterized. The aim of this study was to describe the relationship between comorbid conditions and survival in patients with cHP. Methods The prospective database from a tertiary referral centre for ILD was reviewed for patient-reported comorbidities, their frequency, and relationship with survival in cHP patients. Comorbidities were assessed by direct questioning of the patient at the baseline visit and by a standardized questionnaire for the diagnosis of interstitial lung diseases. During the follow-up examinations, patients were asked about newly diagnosed comorbidities. Results Two hundred eleven patients with cHP were identified (mean age 63 years, 53% male, mean FVC 73%), with mean follow-up of 32 months. The mean number of comorbidities was 3 (10% had 0, 59% 1–3 and 31% ≥4 comorbidities). Most frequent comorbidities groups were cardiovascular (65%) and respiratory (26%), most common comorbidities were hypertension (56%), gastro-esophageal reflux disease (GERD) (24%), diabetes (20%) and coronary heart disease (18%). In general, deceased patients had more comorbidities than survivors (p = 0.005), yet there was no association between the absolute number of comorbidities and survival. Pulmonary hypertension (30.8% versus 5.7%, p = 0.001;), diastolic dysfunction (26.9% versus 6.4%, p = 0.004) and cerebrovascular disease were more frequent in non-survivors (23.1% versus 7.6%, p = 0.026). Lung cancer was not observed, and neither GERD nor antacid drugs were associated with outcome (p = 0.357 and p = 0.961, respectively). Conclusions Comorbidities are common in cHP are associated with survival. Further work should determine whether interventions for these specific comorbidities can positively affect survival.

Introduction MAGE was a Multicenter, single-Arm, observational 6-month (plus 6-month extension) study that aimed to assess treatment satisfaction, efficacy, and safety of insulin Glargine 300 U/mL (Gla-300) in people with type 2 diabetes (T2DM) receiving basal-bolus insulin in a rEal-world setting. Materials and methods Participants were at least 18 years old, with T2DM for more than 1 year, HbA1c 7.0–10.0%. The primary endpoint was change in Diabetes Treatment Satisfaction Questionnaire status version (DTSQs) total score (baseline to month 6). Secondary endpoints included reasons for starting Gla-300, changes in the DTSQ change version (DTSQc) total score, Hypoglycemia Fear Survey-II (HFS-II) total behavior and worry scores at months 6 and 12, HbA1c changes at months 3, 6, 9, and 12, and safety. Results MAGE included 87 adults (mean T2DM duration 17 years). The primary endpoint of DTSQs mean (standard deviation) total score improvement at month 6 was achieved (2.80 [5.46] points; p

Background A vaccine (HB-101) consisting of 2 nonreplicating lymphocytic choriomeningitis virus (LCMV) vectors expressing the human cytomegalovirus antigens glycoprotein B (gB) and the 65-kD phosphoprotein (pp65), respectively, is in development to prevent cytomegalovirus infection. Methods HB-101 was tested in cytomegalovirus-naive, healthy adults in a randomized, double-blind, placebo-controlled, dose-escalation Phase I trial. Fifty-four subjects received low, medium, or high dose of HB-101 or placebo by intramuscular administration at Month 0, 1, and 3. Safety and immunogenicity were the respective primary and secondary endpoints. Subjects were followed for 12 months after the initial immunization. Results Vaccination was associated with transient mild to moderate adverse events. HB-101 administration induced dose-dependent gB- and pp65-specific cellular responses, dominated by pp65-specific CD8 T cells, a high fraction of which were polyfunctional. Two administrations were sufficient to elicit dose-dependent gB-binding and cytomegalovirus-neutralizing antibodies (Abs). Cytomegalovirus-specific immune responses were boosted after each administration. Only 1 of 42 vaccine recipients mounted a transient LCMV vector-neutralizing Ab response. Conclusions HB-101 was well tolerated and induced cytomegalovirus-specific polyfunctional CD8 T-cell and neutralizing Ab responses in the majority of subjects. Lack of vector-neutralizing Ab responses should facilitate booster vaccinations. These results justify further clinical evaluation of this vaccine candidate.

Fear of hypoglycemia and treatment satisfaction both influence therapy adherence. MAGE was a 6-month multicenter, prospective, single-arm, observational study with a 6-month extension conducted in Belgium, mainly assessing patient satisfaction with Gla-300 in people ≥18 years, with T2DM for ≥1 year, HbA1c 7.0-10.0%, receiving a basal-bolus insulin regimen for ≥6 months ± oral antidiabetic therapy, and naïve to Gla-300. Primary objective: change of ≥2 points in Diabetes Treatment Satisfaction Questionnaire Status Version (DTSQs) total score (TS) from baseline (BL) to month 6. Secondary objectives included change in: HbA1c, other DTSQs scores, and hypoglycemia fear scale II (HFS-II). The intent-to-treat population comprised 87 patients (Table). Primary endpoint was achieved; DTSQs TS increased by 2.80 (SD: 5.46; p0.05); however, more patients reached HbA1c Treatment satisfaction and fear of hypoglycemia significantly improved after switching to Gla-300 in people with T2DM on basal-bolus insulin therapy in a real-life setting. Disclosure A.A. Verhaegen: Advisory Panel; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck & Co., Inc., Sanofi. Speaker's Bureau; Self; Mylan, Novo Nordisk Inc. A. Scheen: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Sanofi, Servier. Research Support; Self; AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Sanofi, Servier. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Sanofi, Servier. K.C. Alexandre: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. J. Bruhwyler: Other Relationship; Self; Sanofi. I.M. Colin: None. Funding Sanofi

The 28-week, prospective, multicenter, open-label OPTIMIZE study, conducted in Belgium (presented at ADA 2018) and Canada, evaluated treatment optimization with once-daily (OD) Gla-300 in combination with a prandial insulin analog in adults with T1DM previously uncontrolled (HbA1c 8-10%) on twice-daily (BID) BI as part of basal-bolus therapy. The intent-to-treat and safety populations comprised 94 patients (53.2% women; 51.1% from Belgium); mean (SD) age 49.4 (13.1) years and BMI 27.8 (4.7) kg/m². Prior to the study, 45.7% received insulin glargine 100 U/mL and 52.1% insulin detemir. There was a statistically significant reduction in HbA1c from baseline to month 6 (p In this clinically challenging population, better overall treatment satisfaction and improvement in HbA1c, without increase in the rate of hypoglycemia, was achieved on switching from BID to OD Gla-300 plus prandial insulin. Disclosure C. Mathieu: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S, Roche Diabetes Care, Sanofi. Speaker's Bureau; Self; AstraZeneca, Novartis AG, Novo Nordisk A/S, Sanofi. P. Stella: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. J. Bruhwyler: Other Relationship; Self; Sanofi. K.C. Alexandre: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. Funding Sanofi (EudraCT 2015-001186-46)

Human papillomaviruses (HPVs) are well known for being linked to the development of cervical cancers, most of them being caused by the high-risk (HR) oncogenic genotypes, mainly 16 and 18. The efficacy of 2LPAPI® (Labo’Life), a micro-immunotherapy homeopathic drug, has been evaluated in HR-HPV infected women (n = 18), in a private gynecology practice, by comparing them to an untreated control group (n = 18). Patients were 20 to 45 years old and had cytology with Atypical Squamous Cells of Undetermined Significance (ASCUS) or Low grade Superficial Intra Lesions/ Cervical Intraepithelial Neoplasia Grade I (LSIL/CINI). Patients freely chose to be treated with the drug or not. Those deciding not to take the drug remained untreated and were followed as a control group. The drug was taken at the regimen of one capsule per day during 6 months. HR-HPV and cytology were evaluated at 6 and 12 months. After 12 months, HR-HPV was cleared in 78% of the patients taking the drug versus 44% in those not taking it (p = 0.086). In patients over 25 years, HR-HPV clearance in the treated group was significantly higher (81.3%) than in the control group (20%) (p = 0.004). The difference in the regression of the lesion grades almost reached statistical significance (p = 0.053). This follow-up confirms that the micro-immunotherapy drug 2LPAPI® is a safe and effective therapeutic approach to treat HR-HPV cervical lesions in women over 25 years.

Introduction: Chronic Hypersensitivity Pneumonitis (cHP) is an interstitial fibrotic lung disease (ILD) resulting from long-term exposure to an offending antigen. Outcome prediction in cHP is still challenging and the impact of comorbid conditions, already established in other chronic ILDs, is unknown in cHP. We therefore aimed to assess the prognostic impact of comorbidities in cHP. Methods: The database of a tertiary referral centre for ILD was reviewed for comorbidities, their frequency and impact on survival in cHP patients Results: 211 patients with cHP were identified (mean age 63 years, 53% male, FVC mean 73%), mean follow up was 32 months. The mean number of comorbidities was 3. 10% had 0, 58% 1–3 and 31% ≥4 comorbidities. Most frequent comorbidities groups were cardiovascular (65%) and respiratory (26%), most common comorbidities were hypertension (56%), GERD (24%), diabetes (20%) and coronary heart disease (18%). In general, deceased patients had significantly more comorbidities than survivors (p=0.005), yet there was no significant association of the absolute number of comorbidities to survival. The following comorbidities were significantly associated with impaired survival: pulmonary hypertension (n=20, p=0.002), diabetes (n=43, p=0.002) and diastolic dysfunction (n=21, p=0.016). Lung cancer did not occur and GERD and antacid drugs did not affect survival in HP (p=0.357 and p=0.961, respectively). In general, there was no meaningful impact of drug treatment of comorbidities on the course of HP. Conclusion: Comorbidities are common in cHP and some significantly impact survival. Yet, the effect of treatment of these conditions is still unclear and has to be investigated further.

The 28-week, prospective, multicenter, open-label OPTIMIZE study, conducted in Belgium and Canada, evaluated treatment optimization with once-daily (OD) Gla-300 in combination with a prandial rapid-acting insulin analog in adults with T1DM previously uncontrolled (HbA1c 8-10%) on twice-daily (BID) basal insulin as part of basal-bolus therapy. The intent-to-treat (ITT) and safety populations of the Belgian cohort comprised 48 patients (52.1% women); mean (SD) age 51.7 (12.8) years and mean (SD) body mass index 28.2 (4.9) kg/m². Prior to the study, 37.5% were on insulin glargine 100 U/mL and 62.5% were on insulin detemir. There was a statistically significant reduction in HbA1c from baseline to month 6 (primary endpoint, p Switching from a BID basal insulin analog to OD Gla-300 in this challenging T1DM population was associated with a statistically significant improvement in HbA1c levels and better overall treatment satisfaction. Disclosure C. Mathieu: Research Support; Self; Novo Nordisk A/S. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Advisory Panel; Self; Sanofi. Research Support; Self; Merck Sharp & Dohme Corp.. Speaker's Bureau; Self; Merck Sharp & Dohme Corp.. Advisory Panel; Self; Merck Sharp & Dohme Corp.. Research Support; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; Novartis AG. Speaker's Bureau; Self; Novartis AG. Advisory Panel; Self; Novartis AG, Bristol-Myers Squibb Company. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; AstraZeneca, Pfizer Inc., Janssen Pharmaceuticals, Inc., Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Hanmi Pharmaceutical. Research Support; Self; Roche Diagnostics Corporation. Advisory Panel; Self; Roche Diagnostics Corporation. Research Support; Self; Medtronic. Advisory Panel; Self; Medtronic, MannKind Corporation. Research Support; Self; Intrexon. Advisory Panel; Self; Intrexon, Dianax, UCB, Inc.. Research Support; Self; Abbott. P. Stella: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. J. Bruhwyler: Other Relationship; Self; Sanofi. K. Alexandre: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi.

Context: Since the discovery of toll-like receptor 3 (TLR3), no specific tools have been developed to modulate its activity in upper respiratory tract viral infections (URTIs). ContafluTM (antibodies to TLR3 cytoplasmic fragment) is the first specific TLR3 modulator that showed efficacy in a mouse model of influenza. Objective: To evaluate the efficacy of Contaflu in URTI. Methods: A double-blind randomized placebo-controlled trial in adults with self-reported URTI (the ESTUAR trial) was conducted in 2012/2013 in Belgium. Adult outpatients started a 7-day treatment course with oral tablets of Contaflu or placebo within 36 h after onset of at least one of 4 typical symptoms of URTI. Patients were examined twice by their general practitioners, on days 2-3 and 10-14 after start of treatment. The primary endpoint was the overall severity of URTI calculated as the sum of Wisconsin Upper Respiratory Symptom Survey (WURSS-21) scores over the follow-up. Independent Student’s t test was used to compare the disease severity between groups. Results: A total of 243 patients were enrolled by 32 investigators (121 Contaflu, 122 placebo); 92% of cases matched ICD codes J00 or J06. Most patients had very mild (41.8%) or mild (18.2%) URTI symptoms. In the ITT cohort, neither primary nor secondary outcome measures (duration of URTI, day-to-day and overall functional impairments) showed statistically significant differences between groups. The rate of adverse events was similar in both groups. In patients with moderate to severe URTI symptoms, Contaflu tended to reduce the overall disease severity, daily symptoms, and to improve the functional state. Due to the small size of the corresponding subgroups, Contaflu efficacy on daily scores was statistically significant (p < 0.05) only 1, 2, and 5 days after start of treatment. Conclusion: Contaflu was ineffective in mild URTI and showed efficacy in moderate to severe URTI cases.

SummaryBackgroundThe efficacy and safety of extrafine beclomethasone dipropionate 100 μg/formoterol 6 μg (BDP/F HFA) pressurized metered dose inhaler (pMDI) in patients with moderate-to-severe persistent asthma, has been demonstrated in randomised controlled trials (RCTs). The aim of this prospective observational study was to assess real-life effectiveness in terms of asthma control in smoking (most of the time excluded from RCTs) and non-smoking asthmatics.MethodsAdult patients with persistent asthma, in whom treatment with an inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) combination is indicated, were included. Pulmonary function (FEV1%pred or PEF absolute value), Asthma Control Questionnaire (ACQ) and asthma control according to GINA criteria were measured at baseline as well as 2–8 months and >8–14 months after treatment initiation with BDP/F HFA.ResultsOverall, 619 patients were enrolled by 97 investigators. In the effectiveness cohort (N = 568), at baseline, smoking asthmatics (N = 123) had higher ACQ6 (p

Prolonged-release molsidomine 16 mg once daily) QD (has proved effective in the short-term treatment of patients with stable angina. The purpose of this multicenter study was to assess its long-term tolerability and clinical effectiveness. A total of 320 patients with stable angina were treated for 1 year with molsidomine 16 mg QD administered open label as monotherapy or add-on therapy, when beta blockers and/or calcium antagonists were prescribed concomitantly) in 128 patients, ie, 40% of cases), depending on the severity of disease and/or local therapeutic policies. In all, 293 patients (91.6%) completed the study. The proportion of patients who reported drug-related adverse events (AEs) was 9.1%, which is not significantly different (P=.13) from the 5.9% observed during previous short-term (2-4 wk) treatment. Headache accounted for 80.6% of all drug-related AEs and required discontinuation of the drug in one quarter of patients who reported the symptom (ie, 1.9% of the 320 patients involved in the study). No serious drug-related AEs occurred during the study. Tolerability to molsidomine, evaluated with use of a visual analog scale (VAS), improved by 20% from beginning to end of 1-year follow-up. Two-by-two Bonferroni's comparisons were significant at the .05 level between the 2-month assessment and assessments performed at 8, 10, and 12 months. No age-time interaction was noted (P=.82). Heart rate, blood pressure, electrocardiogram, and blood parameters showed no statistically significant or clinically relevant changes during the study. Compliance with treatment was satisfactory throughout the follow-up period. There was no significant change in the weekly frequency of anginal attacks and consumption of short-acting nitroderivatives during the 1-year study (P=.07 and P=.12,respectively), but their frequency was significantly (ie, approximately 50%) lower than during a preceding short-term treatment period (P.0001 and P=.014, respectively). Subjective clinical status, evaluated through an appropriate VAS, improved by 38% from start to end of 1-year follow-up. Bonferroni's comparisons between baseline and subsequent 2-month evaluations were all significant at the .05 level. No age-time interaction could be seen for frequency of anginal attacks and consumption of short-acting nitroderivatives, nor for clinical status )P=.10, P=.11, and P=.51, respectively). Neither tolerability to molsidomine nor effectiveness of the drug was biased by concomitant antianginal therapies, insofar as none of these parameters showed a significant treatment type (ie, molsidomine administered as monotherapy or add-on therapy)-time interaction (VAS for tolerability: P=.44; angina: P=.39; nitroderivatives: P=.72; VAS for clinical status: P=.62). Molsidomine 16 mg QD administered for 1 y to patients with stable angina was well tolerated and remained effective during the entire treatment period, independent of age and concomitant antianginal therapy.

Antipsychotic therapy is frequently associated with several side effects such as hyperprolactinemia. The influence of a putative antipsychotic JL 13 on prolactin release was assessed after intraperitoneal injection in gentled male rats in comparison with clozapine and haloperidol. A total of 30 or 150 min after administration, whole blood was collected for preparing serum samples. Prolactin was quantified by radioimmunoassay method. At 30 min, JL 13 like clozapine, increased prolactin concentration only at the higher dose (30 mg/kg) while haloperidol at both tested doses induced a dramatic increase of prolactin concentration. At 150 min after injection, only haloperidol (0.3 mg/kg) significantly increased serum prolactin level. This minimal effect on prolactinemia reinforces the similarity of clozapine and JL 13 regarding the atypical antipsychotic profile.

Rationale: Neuroleptic or antipsychotic drugs are the mainstay of treating acute and chronic psychosis. However, their efficacy is offset by a wide array of side effects, especially extrapyramidal syndromes (EPS). In an attempt to develop novel antipsychotic agents, several animal models have been developed to characterize the profile of new chemical entities. Objective: To evaluate the behavioral characteristics of JL 13, a potentially unique antipsychotic agent, three separate studies across a wide dose range in Cebus monkeys were conducted and compared with two studies of oral and parenteral haloperidol. Methods: Twelve Cebus monkeys were tested with single i.m. doses of JL 13 (0.1–2.5 mg/kg), single p.o. doses (1.0–50.0 mg/kg), and 35 days of continuous p.o. (up to 25 mg/kg) treatments and were blindly evaluated. The same twelve monkeys were also tested with haloperidol i.m. (0.01–0.25 mg/kg) and nine of the monkeys also received haloperidol p.o. (0.1–5.0 mg/kg). Behaviors scored included sedation/arousal, locomotor activity, EPS of parkinsonism and dystonia, as well as reactivity. Results: JL 13 produced mild to moderate and dose-related increased sedation and decreased locomotor activity. Minimal decreases in eye blinking rates were also noted as a consequence of sedation. Mild dystonia and parkinsonian symptoms of slow movement developed at the highest dose tested of 50 mg/kg p.o. in only 6 of 12 monkeys. This is 50 times higher than oral doses of haloperidol that would be needed to produce similar EPS effects. Dose-related EPS of dystonia and bradykinesia occurred in relation to decreased locomotor activity and reactivity to stimuli with haloperidol i.m. and p.o., which are features characteristically seen with traditional neuroleptics. Conclusions: The behavioral effects of JL 13 in non-human primates suggest this compound is well tolerated and may have a favorable antipsychotic benefit/risk ratio in the clinic, especially if antipsychotic efficacy occurs at doses well below those that can cause EPS.

The chemical modification of clozapine (1) has permitted the finding of new analogues, e.g., olanzapine (2), quetiapine (3), 5-(4-methylpiperazin-1-yl)-8-chloropyrido[2,3-b] [1,5]benzoxazepine fumarate (9), with a clinical or psychopharmacological profile similar to that of clozapine. However, when developing new derivatives, the designers are discouraged by the development of clozapine-induced agranulocytosis. Different researchers have raised the role played by the oxidizability of the molecule in such a deleterious effect. In the present paper, we examined the oxidation profile (direct scavenging abilities, efficacy in inhibiting lipid peroxidation, and electrooxidation potential) of newly developed methoxy and trifluoromethylsulfonyloxy analogues related to clozapine, some of them being described as putative antipsychotic. The oxazepine derivative 7, unlike the other diazepine derivatives (6, 10-12), was not readily oxidized. Using a statistical predictive model for hematotoxicity previously described, 7 was found in the cluster of potentially nontoxic compounds while diazepine derivatives 6 and 10-12 were classified as potentially toxic compounds. Among these original compounds, 7, which presents a preclinical clozapine-like profile and a low sensitivity to oxidation, could be a promising antipsychotic candidate with low side effects. Considering the tricyclic derivatives examined so far, some elements of structure-oxidation relationship (SOR) might be pointed out. Regarding the nature of the tricyclic ring substituent, from the most to the least sensitive to oxidation, the sequence was as follows: HO > Cl > CH3O > CF3SO2O. The nature of the tricyclic ring influenced also the sensitivity to oxidation; the diazepine moiety appeared to be the most reactive ring compared to oxa- and thiazepine congeners. These parameters could be advantageously integrated in the early design of new safer clozapine-like analogues.

JL 13 (5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b]- [1,5]benzoxazepine fumarate) and JL 3 (10-(4-methylpiperazin-1- yl)pyrido[4,3-b][1,4]benzothiazepine), two pyridobenzazepine derivatives structurally related to clozapine, were selected for further development. Due to their structural similarity to clozapine, they are haunted by the spectre of clozapine-induced agranulocytosis. In a previous study, JL 13 was shown to be less sensitive to oxidation than clozapine. In the present paper, using an in vitro procedure, we report the effect of hypochlorous acid (HOCl), a major in vivo oxidant, on both drugs. It appears that the oxidations of JL 3 and JL 13, unlike clozapine, are very slow and little secondary product is formed. Moreover, in contrast to clozapine, the products that were formed are not reactive and thus do not react with glutathione or N-acetylcysteine. Thus, if, as postulated for clozapine, drug-induced agranulocytosis is due to a reactive metabolite formed by neutrophils or their precursors, JL 3 and JL 13 would not be expected to cause the same adverse reaction.

Using in vitro electrophysiological procedures, we confirm the inhibitory effect of 10-(4-methylpiperazin-1-yl)pyrido[4,3-b][1, 4]benzothiazepine (JL 3), on dorsal raphe serotonergic (IC(50)=14 microM) and noradrenergic neurons (IC(50)=4.5 microM). The effect on dorsal raphe neurons was reduced by N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl- cyclohexanecarboxamide (WAY-100635), suggesting the importance of 5-HT(1A) receptor stimulation. Yohimbine, and ritanserin, to a lesser extent, blocked the inhibitory effect of JL 3 on locus coeruleus neurons indicating that alpha(2)-adrenoceptors and 5-HT(2A) receptors may be implicated in the effects. Because of its negligible alpha(2)-adrenoceptor affinity, the effect of JL 3 on locus coeruleus neurons, would have to be indirect. JL 3 may interfere with the norepinephrine transporter site (IC(50)=0.34 microM). JL 3 tended to reinforce the hypertensive effect of norepinephrine, while it strongly inhibited the hypertensive effect of tyramine, further indicating an interaction at the norepinephrine transporter site level.

In an uncontrolled, open-label trial, 885 patients with painful osteoarticular conditions—(738 patients with nonarticular rheumatism, including 167 with painful spinal problems [cervical, dorsal, or low-back pain, or several of these problems combined] and 571 with soft-tissue rheumatism [194 with tendinitis and bursitis, 117 with painful shoulder, and 260 with minor traumas such as strains, sprains, and tears], and 147 patients with other painful conditions)—received nimesulide 100 mg twice daily (BID) for a maximum of 14 days. Patients had the opportunity to stop treatment after 7 days if symptoms were relieved. The efficacy and safety of nimesulide were assessed for all patients on an intent-to-treat basis. In addition, each subgroup of patients was assessed separately. After 7 days of treatment, a significant improvement in locomotor function and a significant reduction in pain, as well as significant reductions in swelling, heat, and redness, were observed in the entire group of patients as well as in each subgroup. The incidence of side effects (11.2%), mainly gastrointestinal (9.2%), was low compared with that described in the literature for nonsteroidal anti-inflammatory drugs (NSAIDs). At the end of the study, a significant percentage of patients and investigators estimated that, globally, both the efficacy and tolerability of nimesulide were satisfactory or excellent. Results of the present study suggest that nimesulide 100 mg BID is a safe and effective NSAID for the treatment of painful osteoarticular conditions, especially nonarticular rheumatism.

This multicenter, open-label, uncontrolled study included 98 patients with mild-to-moderate hypertension and assessed the efficacy of pinacidil alone or in combination with hydrochlorothiazide (HCTZ) for 135 days. The initial dosage of pinacidil was 12.5 mg twice daily. The dosage was increased to 25 mg twice daily if diastolic blood pressure remained > 90 mm Hg after 30 days. If blood pressure was still not controlled in 30 days, HCTZ 12.5 mg twice daily could be added. If target blood pressure was not reached after 30 days of combination therapy, the regimen was increased to pinacidil 25 mg twice daily plus HCTZ 12.5 mg twice daily. In addition, HCTZ could be added at any time if peripheral edema developed. Systolic and diastolic blood pressures decreased significantly after 30 days of treatment from 162.1 ± 14.1 mm Hg (mean ± SD) and 102.1 ± 5.0 mm Hg to 153.2 ± 14.9 mm Hg and 92.8 ± 9.0 mm Hg, respectively. Some additional benefit was observed during the following months of drug administration. Systolic and diastolic blood pressures were 140.5 ± 11.4 mm Hg and 84.3 ± 6.7 mm Hg, respectively, at the end of the study. At that time, 32 patients (32.7%) were receiving pinacidil only, 12.5 mg twice daily; 20 patients (20.4%) were receiving pinacidil 25 mg twice daily; and 46 patients (46.9%) were receiving pinacidil and HCTZ twice daily. HCTZ was added for incomplete blood pressure control in 15 patients (32.6%) and for peripheral edema in 31 patients (67.4%). The addition of HCTZ to pinacidil reduced the incidence of edema from 65.4% to 15.%. The results of this study suggest that pinacidil was associated with a significant reduction in systolic and diastolic blood pressures in patients with mild-to-moderate hypertension. The high incidence of peripheral edema was largely reduced by the addition of HCTZ.

A multicenter, randomized, double-blind, crossover, placebo-controlled study was conducted in 90 isosorbide dinitrate responders showing stable angina to compare the efficacy of molsidomine retard, 8 mg b.i.d., with that of molsidomine, 4 mg t.i.d., for 6 weeks. Total work performance (workload x min) was significantly improved, compared with baseline and placebo until 8 and 12 h after molsidomine and molsidomine retard administration, respectively. ST-segment depression decreased significantly under the two treatments at 60 W as well as at maximal exercise. The rate-pressure product (heart rate x systolic blood pressure) decreased and increased significantly at submaximal and maximal exercise level, respectively. All these effects remained significant after 6-week treatment, with only the ST segment showing a nonsignificant tendency to improvement at maximal work. The frequency of anginal attacks and of sublingual nitroderivative-tablets consumption decreased significantly with molsidomine, 4 mg, and molsidomine retard, 8 mg. However, overall results showed that the latter form reduces myocardial ischemia more efficiently at submaximal exercise level, has a more prolonged effect on exercise tolerance, and maintains it at a somewhat higher level after 6-week treatment.

The search for an improved clozapine-like compound has resulted in the selection of a new molecule: JL13 (5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5] benzoxazepine fumarate). Like clozapine, JL13 did not antagonize apomorphine-induced stereotypy and did not produce catalepsy but antagonized apomorphine-induced climbing in rodents (ID50 = 3.9 mg kg-1 s.c.). It was inactive against d-amphetamine-induced stereotypy but antagonized d-amphetamine-induced hyperactivity in the mouse (ID50 = 4.4 mg kg-1 i.p.). JL13, like clozapine, was able to antagonize (+/-)-DOI-induced head-twitches in the mouse (ID50 = 2.0 mg kg-1 i.p.). In the open-field test in the rat and forced swimming test in the mouse a high similarity was noted between the two drugs in the same range of doses. In a complex temporal regulation schedule in the dog, JL13 showed a high resemblance with clozapine without inducing sialorrhea, palpebral ptosis or any significant motor side effects. In rats trained to discriminate clozapine, JL13 (10 mg kg-1 i.p.) induced a high level of generalization (70%) to clozapine. In a drug discrimination procedure in the squirrel monkey, JL13 (3-10 mg kg-1 i.m.) produced a full substitution of clozapine. On the basis of these preclinical data, it is thus predicted that JL13 would be a promising atypical antipsychotic drug.

The oxidation behaviour of JL 13, a promising antipsychotic, was investigated in comparison with clozapine and loxapine, by measuring their direct "radical scavenging" abilities and their efficacies in inhibiting the lipid peroxidation. In the lipid peroxidation system, the reactivity of these compounds with free radicals produced by gamma-irradiation of linoleic acid may be presented as follows: JL 13 = loxapine < clozapine. In two enzymatic systems (HRP/GSH and HRP/H2O2/ GSH) which generate the thiyl free radicals, clozapine produces a strong enhancement of the thiyl-radical EPR signal intensity while JL 13 and loxapine exhibit no or minimal effect on this signal. The redox potential values for the three derivatives confirm the spectro-photometric and EPR results. Following this study, we show that JL 13, although presenting a preclinical clozapine-like profile, appears less sensitive to oxidation than clozapine.

Citicoline is considered a promoter of neuronal repair. It has been shown in humans to be effective in the treatment of several cerebral pathologic conditions, including acute stroke. The aim of this open-label, uncontrolled study was to assess the efficacy and tolerability of citicoline in the treatment of patients suffering from acute cerebral infarction. Included in the trial, which lasted 10 to 14 days, were 123 patients who had an acute stroke within a maximum of 48 hours of the study. During the first 5 days, citicoline was administered intravenously (2 g per 24 hours). From day 6, it was administered intramuscularly (1 g per 24 hours). Patients were assessed using the Canadian Neurological (CAN) scale (patient alert or drowsy) and side effects were recorded at each visit. Each patient was always assessed by the same neurologist, who was aware of the treatment. The total score on the CAN scale showed a significant evolution over time. Post-hoc paired Student's t tests showed that this score had increased significantly after 3 days of citicoline administration and continued to increase to the end of treatment. An end-point analysis (value observed at the last available visit; n = 113) showed that the score decreased in 5.3% of patients and remained the same in 15.9% of patients. The score increased at least 1 point in 71.7% of patients, 3 points in 35.4% of patients, and 5 points in 12.4% of patients. Patients receiving aspirin concomitantly did not show a greater improvement in their neurologic state than patients receiving citicoline only. The frequency of patients showing side effects probably related to the medication was 7.4%. The results of this study are consistent with those already available, which show that citicoline is an effective and well-tolerated treatment for patients suffering from acute cerebral infarction.

This double-blind randomized pilot study aimed to compare the efficacy and the tolerability of pirlindole (150–225 mg/day), a reversible inhibitor of monoamine oxidase A, and mianserin (60–90 mg/day) in the treatment of major depression. Forty patients were included in the trial (20 pirlindole and 20 mianserin) and 38 patients (18 pirlindole and 20 mianserin) completed the whole study (28 days of administration). Both treatments exhibited highly significant improvements in the Hamilton Depression Rating Scale score (HDRS), the Hamilton Anxiety Rating Scale score (HARS) and the Beck auto-evaluation scale score (BECK) from day 7 up to day 28. The evolution of the HDRS score in the two groups did not differ significantly. The evolution of the HARS and BECK scores taken separately and the evolution of the combined total score (HDRS + HARS + BECK) significantly differed between the two groups, pirlindole producing a significantly higher decrease than mianserin in the two separate scores on day 28 and on days 21 and 28 in the case of the combined total score. Two patients experienced adverse reactions, one in the pirlindole group complained of sleep disturbances and one in the mianserin group suffered from dry mouth. The results of this study attest to the efficacy and tolerability of pirlindole in the treatment of depression. © 1997 John Wiley & Sons, Ltd.

JL3, 10-(4-methylpiperazin-1-yl)pyrido[4,3-b][1,4]benzothiazepine, has potent antidepressant-like activity in Porsolt's test in mice. Therefore, its influence on the electrical activity of central monoaminergic neurons was investigated in rats anaesthetized with chloral hydrate. JL3 induced a marked decrease of the firing rate of dorsal raphe serotonergic neurons (ID50 = 3.87 +/- 0.57 mg kg-1) and of locus coeruleus noradrenergic neurons (ID50 = 2.63 +/- 0.35 mg kg-1). The drug did not modify the electrical activity of A10 dopaminergic neurons. JL3 does not block amine uptake but it has affinity for 5-HT1A and 5-HT2 receptors. It is speculated that serotonergic mechanisms could play a role in the electrophysiological effects of JL3.

Dibenzoazepine derivatives have represented and still represent today an interesting and exciting field of investigation in medicinal chemistry. A slight modification of the tricyclic structure leads to a profound alteration of the activity profile. Indeed, clothiapine is a neuroleptic drug with strong pro­pensity to induce extrapyramidal side effects (EPS) while clozapine possesses an atypical neuroleptic profile and produces only minimal EPS. The action mechanisms of clozapine have not been completely elucidated. Although clozapine represents a great advance in the treatment of psychiatric disorders, the induction of dramatic toxic effects has stimulated the search for an alternative to clozapine. This challenge is currently the focus of the most active efforts in contemporary neuropharmacology. This review attempts to describe the development of atypical neuroleptic drugs through the diarylazepine series, a promising and modulable class of compounds.

In order to characterize the pharmacological profile of the different chemical classes of pyridobenzazepine derivatives, a series of N-methyl- piperazinopyrido[1,4]- and -[1,5]-benzoxa- and benzothiazepine deriva- tives were prepared. The affinities for D 2 , D 1 , 5-HT 2 , and choliner- gic (M) receptors were measured. In comparison to dibenzazepine refere- nce compounds, a strong decrease of the affinities was observed, less pronounced, however, for the substituted analogues. Oxazepine and thia- zepine analogues like clozapine (except 8-chloro-6-(4-methylpiperazin- 1-yl)pyrido[2,3-b][1,4]benzoxazepine (9) and 8-chloro-6-(4-methylpipe- razin-1-yl)pyrido[2,3-b][1,4]benzothiazepine (11)) were found to be in- active against apomorphine stereotypies. In the open-field test in rats, different molecules showed a high dishinibitory activity as observed with anxolytic drugs. Moreover, 8-chloro-5-(4-methylpiperazin-1-yl)py- rido[2,3-b][1,5]benzoxazepine (14) presented a clozapine-like profile that was confirmed in the behavioral model in dogs and showed most of the behavioral characteristics described for antipsychotic drugs. Its neurochemical profile, in particular the 5-HT 2 /D 2 ratio, was also compatible with atypical antipsychotic activity

The discovery of a new, safe, atypical antipsychotic remains an important challenge. To achieve this goal, a series of N-methylpiperazinopyrido[2,3-b] [1,4]- and -[1,5]- and -pyrido[4,3-b][1,4]- and -[1,5]- benzodiazepines were synthesized. The dopaminergic (D1, D2), serotonergic (5-HT2), and cholinergic (M) affinities, frequently remarked in the action mechanisms of antipsychotic drugs, were determined using their respective in vitro receptor binding assays. All affinities were reduced for each compound. Optimal substituents were found to be in the 2- or 8-position for the retention of affinities, while substitution at the 5-position by acyl or alkyl groups dramatically diminished binding affinities. Pyridobenzodiazepine derivatives, such as clozapine, were found to be inactive or only weakly effective against apomorphine-mediated stereotypes in rats. In an original and complex behavioral model developed in dogs and successfully used to differentiate distinct classes of psychotropic drugs and to discriminate between typical and atypical neuroleptic drugs, 8-chloro-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b] [1,4]benzodiazepine (9), 8-methyl-6-(4-methyl-1-piperazinyl)-11H-pyrido [2,3-b][1,4]benzodiazepine (12), and 5-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b][1,5]benzodiazepine (16) showed most of the behavioral characteristics previously described for neuroleptics. Their neurochemical profiles, particularly their 5-HT2/D2 pKi ratios, were compatible with an atypical antipsychotic effect. These compounds were selected for further investigation. The proposed modulations could lead to new possibilities for the pharmacochemistry of diarylazepines.

Classically, the D2 receptors formed the core of the dopamine hypothesis for schizophrenia. Recently, the dopamine D4 receptors have received particular attention in this context. This is due to the atypical antipsychotic, clozapine, which is effective in treating refractory schizophrenics without the side-effect profile of typical neuroleptics, and displays a ten-fold higher affinity for D4 compared to D2 or D3 receptors. Following various reports presenting the interest of D4 receptors in treating schizophrenia, multiple chemical developments were made. During the last five years, various structures were described with a high selectivity for D4 receptor subtype. Currently, although the first clinical report was very disappointing, the observation which support the idea that D4 might serve as a target for clozapine have significantly modified and extended the understanding of mechanism underlying atypical antipsychotic treatment of schizophrenia.

Benzodiazepines are the most widely prescribed class of psychotropes. The demonstration of specific, high affinity binding sites for benzodiazepines in mammalian brain has provided a basis for a radioreceptor assay (RRA) of these compounds in biological samples (fluids or tissues). The RRA permits the simultaneous measurement of the benzodiazepine molecules that bind to the receptor, providing a total estimate of all pharmacologically active forms of the drug, which is useful in drug monitoring and in the intensive care of patients. After a complete description of the methodological aspects of this technique, the results obtained in therapeutic monitoring and in toxicological analysis are reviewed, and the advantages and disadvantages of this method are examined.

Similar to other indigestible carbohydrates or dietary fibres, a consumption of too large quantities of inulin-type fructans may cause some digestive problems.To compare the digestive tolerance of inulin-type fructans, administered during 2 weeks, at different doses.Eighty-four healthy volunteers (aged 18-45 years, mean body mass index 25.1 kg/m2 and mean total fibre consumption 12 g) were included in a double-blind, placebo-controlled, randomized, cross-over study comparing Fibrulose F97 (5 and 20 g/day), Fibruline Instant (5, 10 and 20 g/day) and Fibruline XL (10 g/day) (degrees of polymerization respectively equal to 2-20, 2-60 with an average of 10, and 2-60 with an average20) to placebo. The study was decomposed into five 2-week periods: placebo run-in, treatment 1, placebo washout, treatment 2, placebo run-out. The following symptoms were assessed using visual analogue scales: flatulence, rumbling, bloating, abdominal pain, abdominal cramps, nausea, stool frequency and stool consistency. The primary variable was the mean difference between treatment and placebo in terms of tolerance (sum of the eight visual analogue scales).The three products tended to increase digestive symptoms whatever the dose but the change was mild (maximum, +19 mm on the 800-mm scale) and significant (P0.001) for Fibruline Instant at 20 g/day only. At 20 g/day, a statistically significant difference between Fibruline Instant and Fibrulose F97 was demonstrated (P=0.011). There was a dose-effect relationship both for Fibrulose F97 (P0.05) and Fibruline Instant (P=0.042). All the other tendencies were non-significant.The three different inulin-type fructans were very well tolerated.

The purpose of this study was to present a comparative and detailed picture of behavioral, physiological, and motor effects of some barbiturates, benzodiazepines, and neuroleptics, using an operant procedure of differential reinforcement of response duration (DRRD) in the dog. An increase in response rate with low doses of barbiturates and benzodiazepines is interpreted in terms of behavioral disinhibition, anxiolytic effect, and enhancement of motivation. The depressive effects noted with higher doses of benzodiazepines and barbiturates, as well as with all doses of neuroleptics, can be explained in different ways. For benzodiazepines and barbiturates, ataxic effects more than sedative or motivational effects are implicated. However, for neuroleptics, loss of motivation or "anhedonia" better explains the decrease in operant responding. Differences between the main classes of psychotropic drugs but also within a class between 1,4 benzodiazepines or 1,5 benzodiazepines, hypnotic or nonhypnotic benzodiazepines, and typical or atypical neuroleptics are highlighted and correlated with human observations.

Clozapine has a more marked affinity for the recently cloned dopamine D4 receptor than for the dopamine D2 receptor. In the search for a selective ligand for the dopamine D4 receptor, useful as a pharmacological tool or as a potent atypical antipsychotic, a pyridobenzodiazepine derivative bioisoster of clozapine, JL 18, 8-methyl-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine, was found to be the most dopamine D4-selective ligand belonging to the diarylazepinc class. Indeed, JL 18 binds to the dopamine D4 receptor with affinity up to 25 times superior to that for the dopamine D2 receptor and presents reduced affinities for other receptors.

Item does not contain fulltext A series of new pyridobenzodiazepines with variation of the basic side chain were synthesized and evaluated for their binding to D(4.2), D(2L), and 5-HT(2A) receptors in comparison with clozapine, haloperidol, and two parent compounds previously described, 8-chloro-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine (8) and 8-methyl-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine (9). In the piperazine series, replacing the N-methyl group by a N-phenyl moiety (15-17, 30-32) provided a dramatic decrease of affinity for all receptors (K(i) > 1000 nM). A N-cyclohexyl group (20, 35) restored some affinity. Compounds with a N-benzyl (18, 33) or N-phenethyl side chain (19, 34) had significant affinities at D(4.2) and 5-HT(2A) receptors. Homologation of the piperazine nucleus (29, 44) led to a significant decrease of the affinity at all receptors investigated. In the 4-aminopiperidine series, N-methyl derivatives (21, 36) possessed less affinity in comparison with the N-methylpiperazine analogues (8, 9) while the N-benzyl congeners (22, 37) showed similar affinities. The rigidification of piperidine nucleus as obtained in azabicyclo[3.2.1]octane derivatives (23, 38) involved a slight reduction of the affinity at D(4.2) and 5-HT(2A) receptors while the affinity at D(2L) receptors was dramatically increased. The introduction of N-substituted aminoalkylamines to replace N-methylpiperazine generally led to a significant decrease in the affinity for D(4.2) receptors but some of these molecules (24, 25, 41) presented a significant 5-HT(2A) binding affinity. The presence of a more flexible side chain induced an increased conformational freedom. Consequently, the preferential position of the distal nitrogen or its basicity in piperazine derivatives was greatly modified. 19 with a high D(4.2) and 5-HT(2A) affinity (K(i) = 40 and 103 nM, respectively) did not induce cataleptic phenomenon in the paw test in rats but significantly reduced the immobility time in Porsolt's test in mice suggesting antidepressant properties.

Some antipsychotic agents have been found to produce agranulocytosis and aplastic anemia. The oxidation phenomena and/or the formation of free radicals has been suggested to be causally related to various hematological disorders, e.g., agranulocytosis. Using five experimental conditions, we tested the oxidative potential of compounds with and without a history of hematological side effects, e.g., agranulocytosis and aplastic anemia. A statistical analysis was undertaken for each experimental condition and a multivariate analysis combining all results was performed. Two peroxidase-induced free radical models did not successfully discriminate between drugs with and without a history of causing hematologic problems (70%). The lipid peroxidation system provided even less satisfactory discrimination, with only 56.25% correct classification. However, an 87.5% correct classification was obtained when using the oxidation potentials of these drugs determined at pH 4.7 and at pH 7.4. A multivariate analysis taking into account the five variables provided 87.5% success in classification. The two clusters were better discriminated in terms of a "distance coefficient." In a second analysis, the putative antipsychotic pyridobenzodiazepine analogues (JL5, JL8, JL18, and JL25) were classified in the cluster of toxic compounds, while the oxa- and thiazepine analogues (JL2, JL3, and JL13) were classified as nontoxic compounds. On the other hand, a few metabolites of clozapine and fluperlapine were classified in the toxic compound group. The procedure described herein is, to our knowledge, the first which classifies molecules of different structures as well as different pharmacological profiles according to their hematotoxic potential. Such a procedure could be used to predict drug-induced hematological side effects.

1. Citicoline (cytidine (5') diphosphocholine) has been shown to reverse aging-induced memory deficits, scopolamine-induced amnesia and nucleus basalis magnocellularis lesion-induced learning impairment. 2. This study aimed to evaluate the effects of citicoline on learning and retrieval processes in a complex differential reinforcement of response duration schedule in normal dogs. 3. The effects of citicoline on a stabilized performance were also measured in order to be able to differentiate specific memory effects from non specific influences on the motor, neuro-vegetative and motivational systems. 4. The results demonstrate that citicoline can exert facilitatory effects on learning and memory but also on retrieval processes. The complete absence of effects on the stabilized performance and on the motor, neuro-vegetative and motivational systems constitutes arguments in favour of a selectivity of action on the memory processes.

The aim of this double-blind randomized study was to compare the efficacy and the tolerability of moclobemide (300-600 mg daily) and pirlindole (150-300 mg daily), two reversible inhibitors of MAO-A (RIMAs), in the treatment of depression. In total 116 patients were included in the trial, 111 patients (52 patients on pirlindole and 59 patients on moclobemide) were evaluable for efficacy and safety, and 77 patients completed the whole study (42 days of administration). Both treatments produced highly significant improvements in the Hamilton Depression Rating Scale (HDRS) score, the Hamilton Anxiety Rating Scale (HARS) score and the Montgomery-Asberg Rating Scale (MADRS) score from day 7 to day 42. The pattern of development of the three scores in the two groups did not differ significantly. After 42 days of treatment, an improvement of > or = 50% in the HDRS score was noted in 80% and 67% of patients in the pirlindole and moclobemide groups, respectively. A total of 30 (58%) patients on pirlindole and 33 (56%) patients on moclobemide experienced side-effects that were considered to be possibly or probably related to the medication. The differences between the two drugs were non-significant for all types of side-effect, with the exception of dry mouth and tachycardia, which were significantly more frequent with moclobemide.

The efficacy and safety of pirlindole (300 mg/day), a new reversible inhibitor of monoamine oxidase A, have been evaluated in a multicentre placebo-controlled double-blind randomized trial in 103 in-patients suffering from unipolar major depression (DSM-III-R 296.2, 296.3) over a 42-day period after a run-in placebo period of 6 days. Pirlindole produced a significantly greater decrease than placebo in the Hamilton depression score (from day 28), the Hamilton anxiety score (from day 28) and the Montgomery-Asberg depression score (on day 42). On day 42, the Hamilton depression score wasor = 7,or = 8 andor = 15, oror = 16 in 21%, 45% and 34%, respectively, in the placebo group compared to 72%, 24% and 3.4%, respectively, in the pirlindole group (P0.001). The differences between the two groups in terms of tolerance and safety were not statistically significant.

The clinical monitoring and intensive care of patients who have taken an overdose of a benzodiazepine require rapid and quantitative methods to assess benzodiazepine concentrations in biological fluids. A radioreceptor assay (RRA) permits the simultaneous measurement of the benzodiazepine molecules that bind to the receptor, providing a total estimate of all pharmacologically active forms of the drug(s) (parent drug and active metabolites). This study describes the development of an RRA for the determination of benzodiazepine compounds in serum using a lyophilized bovine brain cerebral cortex receptor preparation. The standard curves and the sensitivity of this RRA are determined for 20 different benzodiazepines and the specific antagonist flumazenil. The sensitivity ranges from 5 ng/mL for clonazepam to 3500 ng/mL for chlordiazepoxide. The IC50 values are significantly correlated (r = 0.81) with the lowest recommended therapeutic concentrations. The advantages and disadvantages of this RRA are discussed and compared with those of other chromatographic and immunological methods.

Numerous authors assign a mediatory role in respect of temporal regulation to collateral behaviour. Several hypotheses are proposed to account for these stereotyped activities: proprioceptive feedback, superstition or motor activities chain. They could intervene as compensatory mechanisms for the inhibition which is brought into play when there is temporal regulation and might only play a secondary role in marking out the time elapsed. The object of the research reported here is to evaluate the mediatory role of collateral behaviour in the dog, using a DRRD schedule. The DRRD schedule conditions the subject to hold a response for a fixed period and therefore restricts the repertoire of possible collateral activities and limits them spatially, thus adding a supplementary inhibitory charge to the temporal contingencies. The addition to this schedule of positive and negative external cues allows the measurement in respect of their compensatory role for the inhibitory mechanisms inherent in the temporal regulation.