Transmembrane pH-driven Na+ permeability of fluorinated phospholipid-based membranes.

The permeability to the H+/Na+ exchange of fluorinated phospholipid-based membranes has been evaluated by measuring the dissipation rate of a liposomal transmembrane pH gradient in the presence of Na+. The fluorinated liposomes are made from fluorocarbon/hydrocarbon or fluorocarbon/fluorocarbon double-chain ether-connected glycerophosphocholines or amido-connected phosphocholines deriving from diaminopropanol or serine. The fluorocarbon/hydrocarbon mixed-chain phospholipids, as compared to the fluorocarbon/fluorocarbon ones, form membranes that are substantially more able to maintain a transmembrane pH gradient in the presence of NA+ and display a lower Na+ permeability. However, these membranes are more permeable to the H+/Na/ exchange than conventional DSPC (1,2-distearoylphosphatidylcholine) ones. Our results indicate a detrimental impact of the membrane fluorination degree on H+/Na+ permeability: the lower the fluorination degree of the membrane, the lower its H+/Na+ permeability. Concerning structure/permeability relationships, it appears that the replacement of the ester connecting bond in their fluorinated phosphatidylcholine analogues for an ether or amide one lowers the transmembrane H+/Na+ exchange.

[Repeat evaluation of impulsiveness in a cohort of 155 patients with obsessive-compulsive disorder: 12 months prospective follow-up]. / Evaluation répétée de l'impulsivité dans une cohorte de 155 patients souffrant d'un trouble obsessionnel-compulsif: suivi prospecif de 12 mois.

UNLABELLED: Relationships between OCD and impulsivity are currently under research. METHOD: In the phase 3 of the national study on OCD, 155 patients suffering from an OCD (DSM III-R criteria, score on NIMH-OC > or = 7) had entered a naturalistic follow-up of 12 months duration. Impulsivity was assessed by using the BDS (Behavioral Dyscontrol Scale, offautoquestionnaire of 24 items) at day 0, 6th and 12th months and a semi-structured interview for Obsessive-Compulsive Related Syndrome and Behaviors Spectrum, as defined by Hollander (DSM III-R criteria). RESULTS: Impulsivity was more intense in females (mean score on BDS 35.6 vs 31.9, p = 0.06), in patients with personal history of anxiety-depression (36.3 vs 32.3, p = 0.04) and suicidal behavior (38.3 vs 33.2, p = 0.06) and familial history of OCD (37.1 vs 33.0, p = 0.07). Moreover, syndromal typology of obsessions or compulsions did not seem to influence impulsivity. In contrast, presence of co-existing OC Related Syndrome was significantly linked to higher impulsivity score, especially with "Intermittent Explosive Syndrome" (mean score = 40.1 vs 30.8, p < 10(-4), "Compulsive Buying" (38.5 vs 32.4, p = 0.005), "Hypochondriasis" (36.7 vs 32.1, p = 0.02), "Dysmorphophobia" (37.1 vs 32.4, p = 0.02) and "Depersonnalization" (37.7 vs 32.9, p = 0.05). Paradoxically, impulsivity was augmented in patients with important to severe slowness syndrome (38.3 vs 31.8, p = 0.001). This mixed association between slowness and impulsivity can be an excellent testimony of "Dyscontrol" phenomenon. In 130 patients who had received an anti-obsessional pharmacologic treatment during 12 months follow-up, impulsivity score was gradually reduced from day 0 (mean score = 34.1) at M6 (24.8-22% reduction) and at M12 (20.1-36% reduction). After one year of follow-up, a decreased by > or = 50% of impulsivity score was observed in 42% of obsessional patients. Finally, the response rate of OCD to pharmacotherapy seemed to be modulated by the dimensions of impulsivity and slowness. In fact, the best results after 6 months of treatment were observed in the sub-groups presenting high level of "impulsivity" (62-66% were responders) versus 39% in the sub-group with important to severe slowness.

Phase behavior of fluorocarbon di-O-alkyl-glycerophosphocholines and glycerophosphoethanolamines and long-term shelf stability of fluorinated liposomes.

This paper is devoted to the morphological characterization, by freeze-fracture electron microscopy, and to the thermotropic phase behavior, by differential scanning calorimetry and X-ray diffraction of the aqueous dispersions of various fluorocarbon/fluorocarbon or mixed fluorocarbon/hydrocarbon 1,2- or 1,3-di-O-alkyl-glycerophosphocholines (PC) and 1,2-di-O-alkyl-glycerophosphoethanolamines (PE). The fluorinated PCs form classical lamellar phases and liposomes while an interdigitated lamellar phase has been evidenced for a hydrocarbon 1,3-analog. The fluorinated PEs display a lamellar to hexagonal phase transition which occurs almost simultaneously with the gel-to-fluid lamellar phase transition. The impact of each of the structural features [ether vs ester chemical junction connecting the hydrophobic chains on glycerol, their position (1,2- vs 1,3 isomers), number and length of the perfluoroalkylated chains, length of the fluorinated tail and hydrocarbon spacer, PC vs PE polar head] of the fluorinated phospholipids on the phase transition thermodynamic parameters (Tc, delta H, delta S) is discussed. Most of the liposomes formed from the fluorinated ether-PCs display a remarkable long-term shelf stability: they can be thermally sterilized and stored at room temperature for several months without any significant modification of their size and size distribution.

Membrane permeability and stability in buffer and in human serum of fluorinated di-O-alkylglycerophosphocholine-based liposomes.

The stability (with respect to encapsulated carboxyfluorescein release) of liposomes made from various fluorocarbon 1,2-or 1,3-di-O-alkylglycerophosphocholines (ether-connected) and their membrane permeability have been investigated in buffer and in human serum. Membranes and liposomes, whether formulated with fluorocarbon/fluorocarbon or mixed fluorocarbon/hydrocarbon, 1,2- or 1,3-di-O-alkylglycerophospholipids, display lower permeability coefficients and are able to retain more efficiently encapsulated CF, even when incubated in human serum, than any of their conventional counterparts. These fluorinated liposomes are as stable as the first generation of liposomes formulated with their fluorocarbon ester-connected 1,2-di-O-acylglycerophosphocholine analogs. These results further confirm that a fluorinated intramembranar layer reduces the permeability of membranes (more significantly when they are in a fluid state), protects them from the destabilizing effects of serum components and increases even the stability of the fluorinated liposomes whose membranes are in the gel state when incubated in human serum. The impact of the modular structure of the fluorinated phospholipids (number of fluorocarbon chains, ether vs. ester bond, 1,2- vs. 1,3-isomer, etc...) and structure/permeability/ stability relationships are also presented.

Structure and interactive properties of highly fluorinated phospholipid bilayers.

Because liposomes containing fluoroalkylated phospholipids are being developed for in vivo drug delivery, the structure and interactive properties of several fluoroalkylated glycerophosphocholines (PCs) were investigated by x-ray diffraction/osmotic stress, dipole potential, and hydrophobic ion binding measurements. The lipids included PCs with highly fluorinated tails on both alkyl chains and PCs with one hydrocarbon chain and one fluoroalkylated chain. Electron density profiles showed high electron density peaks in the center of the bilayer corresponding to the fluorine atoms. The height and width of these high density peaks varied systematically, depending on the number of fluorines and their position on the alkyl chains, and on whether the bilayer was in the gel or liquid crystalline phase. Wide-angle diffraction showed that in both gel and liquid crystalline bilayers the distance between adjacent alkyl chains was greater in fluoroalkylated PCs than in analogous hydrocarbon PCs. For interbilayer separations of less than about 8 A, pressure-distance relations for fluoroalkylated PCs were similar to those previously obtained from PC bilayers with hydrocarbon chains. However, for bilayer separations greater than 8A, the total repulsive pressure depended on whether the fluoroalkylated PC was in a gel or liquid-crystalline phase. We argue that these pressure-distance relations contain contributions from both hydration and entropic repulsive pressures. Dipole potentials ranged from -680 mV for PCs with both chains fluoroalkylated to -180 mV for PCs with one chain fluoroalkylated, compared to +415 mV for egg PC. The change in dipole potential as a function of subphase concentration of tetraphenyl-boron was much larger for egg PC than for fluorinated PC monolayers, indicating that the fluorine atoms modified the binding of this hydrophobic anion. Thus, compared to conventional liposomes, liposomes made from fluoroalkylated PCs have different binding properties, which may be relevant to their use as drug carriers.

[Prevalence of obsessive-compulsive disorders in a large French patient population in psychiatric consultation]. / Prévalence des troubles obsessionnels-compulsifs dans une large population française de patients consultant en psychiatrie.

Recent epidemiologic studies were conducted in general population, showing high rate prevalence of obsessive-compulsive disorder (OCD) (2-3%). Although more investigation of OCD prevalence in clinical population is still warranted. The prevalence of DSM III-R diagnosis of OCD and obsessive-compulsive syndromes (OCS) is reported in 4 364, 16-70 year old new consecutive patients, consulting in out-patient psychiatry. Point prevalence rates of 9.2% were recorded for OCD and 17% for OCS. Significantly different from non obsessional patients, it was observed in OCD and OCS patients more male representation (41% vs 37%, p = 0.007), a younger current age (36 y vs 39 y, p < 10(-4)) and age of disorder onset, higher rate of celibat (31.5% vs 28.6%) and lesser of separated or widowed (9.4% vs 16.2%, p = 0.003), more anxiety and depression comorbidity (50% vs 39%, p < 10(-4), a higher suicidal risk (17% vs 14%, p = 0.04--especially in OCS patients: 18.3%), more chronicity (mean current episode duration: 14.8 months vs 11.2 m., p < 10(-4)) and higher rate of global functioning impairment (score at GAF: 53.9 vs 57.9, p < 10(-4)). The results of the french survey confirmed the high prevalence of OCD and OCS in patients seeking psychiatric treatment. OCS (or subclinical OCD) seem to form a valid group (high rates of comorbidity and suicidal attempts) which need to be recognized and to receive adequate treatment.

The cost of treatment dropout in depression. A cost-benefit analysis of fluoxetine vs. tricyclics.

In this study, we tried to estimate the economic potential benefit of the use of fluoxetine (PROZACR 20 mg, Lilly) versus tricyclic antidepressants (TCAs) in depression of mild to moderate intensity. Fluoxetine has demonstrated, in controlled studies, significantly lower rates of side-effects and treatment dropout than TCAs while showing similar efficacy. Treatment dropout, especially at an early stage of the therapy, can have profound consequences, including excessive lengthening of the depressive episode, symptomatic relapse, increase of repeated days out of work, even suicides or suicide attempts. We estimated the expected cost of treatment dropout using a Delphi expert panel. We then computed the economic benefit of fluoxetine by combining the dropout cost and the differential rate of total treatment dropout between fluoxetine and TCAs, as found in clinical trials. We thus showed that a 8 week fluoxetine could be beneficial to society provided society values a year of human life above a threshold varying from French Francs 23.800 to FF8.600 (respectively, about US$4500 and 1600) depending on the type of depression. As these values are extremely low compared to those found in the literature, we concluded that an apparently costly innovation such as fluoxetine may induce short-term financial savings for society.

[Work loss and depression. Impact of fluoxetine]. / Arrêt de travail et dépression. Impact de la fluoxétine.

The goal of our study was to explore the impact of various antidepressant drugs on the relative risk of work loss in depressed patients. 1,852 depressed patients (DSM III-R) were observed using a "cross-sectional" design. Patients were included into five groups: patients without antidepressant treatment, patients treated with one of the main antidepressant drugs in France (amineptine amitriptyline, clomipramine and fluoxetine). Primary variables were the depression intensity (Hamilton scores) and job status (work loss). The other parameters (clinical, demographic, economic, therapeutic) were used as potentially predicting variables. Data have been collected through a network of 295 physicians (GP, Psychiatrists). The main socio-demographic characteristics of treated and untreated depressive patients, either working or absent from work, were predominantly female and city dwellers. A significant difference was found between working patients and work loss in terms of professional characteristics, i.e. type of employment (p < 0.001), type of employer (p < 0.05), level of responsibility (p < 0.01) and type of remuneration (p < 0.01). We found a positive correlation between depression severity and the risk of work loss (R2 = 0.86, p < 0.001). This risk was significantly lower with fluoxetine compared to other treatments. Pooling these data with data from clinical trials led to a saving of 2.4 days (vs clomipramine) to 4.7 days (vs amitriptyline) (p < 0.05, respectively) of work loss per patient for a 8-week treatment period.