The long-term clinical benefit and effectiveness of switching to once-daily quetiapine extended release in patients with schizophrenia.

OBJECTIVE: To evaluate the long-term clinical benefit and effectiveness of switching to once-daily quetiapine extended release (XR) from an oral antipsychotic in patients with schizophrenia. Reasons for switching included insufficient efficacy, tolerability, and/or non-acceptability. The primary endpoint was the percentage of patients achieving an improvement in Clinical Global Impression - Clinical Benefit (CGI-CB) scale scores. RESEARCH DESIGN AND METHODS: A 24-week, international, multicentre, open-label, prospective study ( www.clinicaltrials.gov : NCT00640601). After a 7-14 day enrolment period (depending whether prior antipsychotic mono- or combination therapy), all patients received quetiapine XR 300 mg once daily (day 1), 600 mg/day (day 2), 600-800 mg/day (day 3) and 400-800 mg/day thereafter, with down-titration and discontinuation of prior antipsychotic by day 4. RESULTS: A total of 62% of patients completed the study and 56.9% (LOCF, ITT) achieved a significant improvement in CGI-CB (95% CI [0.51, 0.63]; p = 0.02). Switches due to insufficient efficacy showed a significant improvement (60%, 95% CI [0.51, 0.68]; p = 0.02), compared to 54.4% ([0.44, 0.64]; p = 0.38) and 52.4% ([0.36, 0.68]; p = 0.76) of switches due to insufficient tolerability and non-acceptability respectively (both p = ns). Patients previously on olanzapine and quetiapine IR showed a significant improvement in CGI-CB (62.6% [p = 0.02] and 61.2% [p = 0.04], respectively). Somnolence (18.0%) and dizziness (14.6%) were the main adverse events. Anticholinergic use decreased from 7.1 to 2.7%. Overall mean weight gain was 0.4 kg; 12.9% of patients experienced a weight gain of ≥7% and 15% experienced a clinically relevant shift in triglycerides from baseline. CONCLUSIONS: A majority of patients switched from other antipsychotics to quetiapine XR experienced clinical benefit. This was supported by all other efficacy outcomes regardless of the reason for switching. Safety data confirmed quetiapine XR was safe and well tolerated. The open-label design and lack of a placebo group represent limitations.

[A new program of social rehabilitation PRACS (Program of Reinforcing Autonomy and Social Capacities)]. / Un nouveau programme de Réhabilitation Sociale PRACS (Programme de Renforcement de l'Autonomie et des Capacités Sociales).

Schizophrenia is a widespread and severe disease in spite of an efficient pharmaco-therapy. The Programme for the Reinforcement of Autonomy and Social Skills (PRASS) we have devised is a new psycho-educational programme inspired from such techniques as psycho-education, cognitive remediation and cognitive behavioural therapy. The principle of the programme consists in increasing patients'awareness of the concrete problems of everyday life with a view to helping them to achieve personalized projects. Therefore, PRASS is composed of four units corresponding to daily situations: (1) dealing with money, (2) dealing with time, (3) developing communication skills and leisure and (4) introducing oneself. This programme is based on the principle of group sessions (learning social skills) and individual sessions (projects elaboration). The validation study of this programme has shown its efficiency, especially in that it brings more autonomy to the patients.

Quetiapine as an adjunctive pharmacotherapy for the treatment of non-remitting generalized anxiety disorder: a flexible-dose, open-label pilot trial.

BACKGROUND: Generalized anxiety disorder (GAD) is a chronic disorder associated with significant morbidity and disability. Traditional therapies are associated with poor levels of remission, and often result in troublesome side effects. METHODS: This was a 12-week, open-label, flexible-dose study to assess the efficacy and tolerability of quetiapine as an adjunctive treatment to traditional medication. 40 outpatients with GAD who had not achieved remission following at least 8 weeks of an adequate dose of traditional therapy were enrolled. The primary endpoint was the mean change from pre-treatment to week 12 in the Hamilton Anxiety Rating Scale (HAM-A) total scores. Secondary endpoints included: the proportion of patients achieving remission (HAM-A total score of < or =10 at week 12), Clinical Global Impressions-Severity of Illness (CGI-S), Clinical Global Impressions-Global Improvement (CGI-I), Pittsburgh Sleep Quality Index (PSQI) and Penn State Worry Questionnaire (PSWQ). RESULTS: Adjunctive quetiapine (mean dose 386mg/day at week 12) significantly reduced the HAM-A total scores from pre-treatment (29.8+/-9.0) to week 12 (9.0+/-10.2) (-20.6; p<0.001). The HAM-A remission rate was 72.1% at week 12. Adjunctive quetiapine resulted in a significant reduction in all efficacy measures by study end. Quetiapine was well tolerated: the most common adverse event (AE) was sedation, with no incidence of serious AEs and no clinically significant changes in vital signs, weight (mean gain 0.5kg at week 12) or laboratory assessments. CONCLUSION: The results of this small pilot trial suggest that quetiapine adjunctive to traditional therapy may be a useful treatment in patients with GAD or treatment-resistant GAD, and warrant further investigation.

Impacts of agriculture on the parasite communities of northern leopard frogs (Rana pipiens) in southern Quebec, Canada.

Given that numerous amphibians are suffering population declines, it is becoming increasingly important to examine the relationship between disease and environmental disturbance. Indeed, while many studies relate anthropogenic activity to changes in the parasitism of snails and fishes, little is known of the impact on the parasites of amphibians, particularly from agriculture. For 2 years, the parasite communities of metamorphic northern leopard frogs from 7 agricultural wetlands were compared with those from 2 reference wetlands to study differences in parasite community diversity and abundance of various species under pristine conditions and 3 categories of disturbance: only agricultural landscape, only pesticides, and agricultural landscape with pesticides. Agricultural (and urban) area was negatively related to species richness, and associated with the near absence of adult parasites and species that infect birds or mammals. We suggest that agriculture and urbanization may hinder parasite transmission to frogs by limiting access of other vertebrate hosts of their parasites to wetlands. The only parasite found at all localities was an unidentified echinostome infecting the kidneys. This parasite dominated communities in localities surrounded by the most agricultural land, suggesting generalist parasites may persist in disrupted habitats. Community composition was associated with dissolved organic carbon and conductivity, but few links were found with pesticides. Pollution effects may be masked by a strong impact of land use on parasite transmission.

Safety and pharmacokinetics of paracetamol following intravenous administration of 5 g during the first 24 h with a 2-g starting dose.

Intravenous (i.v.) paracetamol is used as 1-g infusions with a maximal daily dose of 4 g/day. However, a higher initial analgesic dose could be of interest in the immediate postoperative period when the pain is maximal. The purpose of the present study was to determine in healthy subjects the safety and the pharmacokinetics of i.v. paracetamol, starting with a 2-g dose, followed by 1-g doses every 6 h, leading to a total of 5 g the first 24 h. This was an open-label, single-sequence study. The paracetamol pharmacokinetic profile was assessed in 26 subjects after both the 2-g starting dose and the 1-g doses. Safety, especially hepatotoxicity, was evaluated up to 72 h after the initial 2-g dose. Following the first 15-min i.v. administration of paracetamol 2 g, plasma concentrations ranged from 67.9+/-21.8 mug/ml (peak plasma concentration (C(max)) at the end of infusion) to 6.2+/-2.3 mug/ml (trough plasma concentration (C(min)) measured just before the next infusion) without any C(max) in the toxic range for any subject. After the repeated 1-g infusions, the plasma concentrations were approximately 35% lower than that measured after 2 g, showing the absence of accumulation. No clinical adverse events related to the drug administration nor clinically relevant changes in laboratory parameters, including biochemical signs of hepatotoxicity, were reported. After i.v. administration of paracetamol 2-g starting dose and 5 g during the first 24 h, the pharmacokinetics of paracetamol remain unchanged, with concentrations far below the toxic threshold. Overall, these results demonstrate that the i.v. administration of a 2-g starting dose of paracetamol, followed by three i.v. administrations of 1 g during the first 24 h is safe in healthy subjects.

[The influence of memory disorders on self-evaluation of subjective quality of life among schizophrenic patients]. / Inluence des troubles mnéstique sur l'auto-évaluation de la qualité de vie subjective des patients schizophrènes.

INTRODUCTION: For the past few years, in the field of psychiatric disorders, measurements of subjective quality of life are integrated as an important criterion of judgment. The use of standardized questionnaires, based on the patients point of view has become widespread. However, in schizophrenic patients, cognitive impairement, and notably memory, is often advanced as a limit to the use of the self-reported questionnaires. METHODS: In this preliminary study, we investigated in 53 schizophrenic patients, the impact of memory impairment, specifically the episodic memory, on quality of life, taking into account confounding socio-demographic and clinical factors. The memory was assessed using the BEM 84. The patient's subjective quality of life was assessed by the self-reported questionnaire S-QoL. RESULTS: No correlation was found between memory efficiency and quality of life level: patients with severe and non-severe impairment scored all the S-QoL domains similarly. DISCUSSION: However, the majority of schizophrenic patients could be considered as deficient on a wide assortment of neuropsychological evaluations, in particular in the attention and executive functions. The influence of the whole cognitive impairment of life must be confirmed.

Effects of agricultural pesticides on the immune system of Xenopus laevis and Rana pipiens.

Over the last 30 years, there have been mass declines in diverse geographic locations among amphibian populations. Multiple causes have been suggested to explain this decline. Among these, environmental pollution is gaining attention. Indeed, some chemicals of environmental concern are known to alter the immune system. Given that amphibians are frequently exposed to agricultural pesticides, it is possible that these pollutants alter their immune system and render them more susceptible to different pathogens. In this study, we exposed two frog species, Xenopus laevis and Rana pipiens, for a short period of time to a mixture of pesticides (atrazine, metribuzine, endosulfan, lindane, aldicarb and dieldrin) representative in terms of composition and concentrations to what it is found in the environment of the southwest region of the province of Quebec. The pesticides were known to be present in surface water of many tributaries of the St. Lawrence River (Quebec, Canada). Our results demonstrate that the mixture of pesticides could alter the cellularity and phagocytic activity of X. laevis and the lymphocyte proliferation of R. pipiens. Taken together, these results indicate that agricultural pesticides can alter some aspects of the immune response in frogs and could contribute to their global decline by rendering them more susceptible to certain infections.

Bioequivalence study comparing a new paracetamol solution for injection and propacetamol after single intravenous infusion in healthy subjects.

OBJECTIVES: A new, ready-to-use solution for injection of paracetamol (Perfalgan 10 mg/ml) without previous reconstitution has been developed. The aim of the study was to determine the serum concentration profiles of paracetamol after 15 min infusion of Perfalgan 0.5 g and 1 g doses and to demonstrate the bioequivalence between Perfalgan 1 g dose and a marketed reference formulation for injection, propacetamol 2 g (Pro-Dafalgan 2 g) equivalent to 1 g of paracetamol. The secondary objective was to evaluate local tolerance, and clinical and biological safety. METHODS: The study was performed in 24 healthy, male volunteers, according to an open-label, randomized, single-dose, 3-period crossover design, with a 1-week washout period between the doses. Blood samples were taken prior to each administration and at 18 time points within the 24-hour period following the beginning of each infusion. Serum concentrations of paracetamol were determined by validated high-performance liquid chromatography with UV detection. From serum concentration-time data, a non-compartmental pharmacokinetic analysis was performed to calculate Cmax, tmax, AUC(inf), t(1/2), MRT, Cl(T) and Vd. Log-transformed AUC(inf) and Cmax were tested for bioequivalence. The local pain intensity at infusion site was assessed using a 4-point categorical scale from 0 (none) to 3 (severe). The clinical and biological safety was evaluated by physical examination with measurements of vital signs and ECG and laboratory tests including hematology and biochemistry. RESULTS: After infusion of 0.5 g and I g of the new paracetamol solution, C(max) and AUC(inf) increased proportionally with dosage. After dose correction to 1 g of paracetamol, the mean (+/- SD) Cmax ratio was 0.98 +/- 0.24 and 0.94 +/- 0.08 for AUC ratio. Identical t(max) was observed for the 2 paracetamol dosages and 90% confidence intervals for t(1/2), MRT, Cl(T) and V(d) were within the acceptable interval 0.8-1.25. The calculated 90% confidence intervals of the new solution (Perfalgan 1 g) to marketed solution (propacetamol 2 g) ratios were 1.11-1.31 (point estimate 1.20) for C(max) and 1.10-1.16 (point estimate 1.13) for AUC(inf). These values were within the acceptable bioequivalence intervals of 0.75 to 1.33 for Cmax and 0.80-1.25 for AUC(inf). Application site disorders were the most frequently observed adverse events but local pain at infusion site was less reported by subjects after Perfalgan (2%) compared to propacetamol (20%). The clinical and biological safety was good and equivalent for the 3 treatments. CONCLUSION: After administration of paracetamol solution for injection 0.5 g and 1 g, the pharmacokinetics of paracetamol is linear. All results indicate that 1 g of paracetamol administered as Perfalgan 10 mg/ml is bioequivalent to propacetamol 2 g with a better local safety.

Exposure of leopard frogs to a pesticide mixture affects life history characteristics of the lungworm Rhabdias ranae.

We tested the hypothesis that exposure of leopard frogs ( Rana pipiens) to agricultural pesticides can affect the infection dynamics of a common parasite of ranid frogs, the lungworm Rhabdias ranae. After a 21-day exposure to sublethal concentrations of a pesticide mixture composed of atrazine, metribuzin, aldicarb, endosulfan, lindane and dieldrin, or to control solutions (water, dimethyl sulfoxide), parasite-free juvenile frogs were challenged with 30 infective larvae of R. ranae. Approximately 75% of the larvae penetrated the skin and survived in both exposed and control animals, suggesting that pesticides did not influence host recognition or penetration components of the transmission process. Rather, we found that the migration of R. ranae was significantly accelerated in hosts exposed to the highest concentrations of pesticides, leading to the establishment of twice as many adult worms in the lungs of frogs 21 days post-infection. Pesticide treatment did not influence the growth of lungworms but our results indicate that they matured and reproduced earlier in pesticide-exposed frogs compared to control animals. Such alterations in life history characteristics that enhance parasite transmission may lead to an increase in virulence. Supporting evidence shows that certain components of the frog immune response were significantly suppressed after exposure to the pesticide mixture. This suggests that the immune system of anurans exerts a control over lungworm migration and maturation and that agricultural contaminants can interfere with these control mechanisms. Our results also contribute to the ongoing debate regarding the role that anthropogenic factors could play in the perplexing disease-related die-offs of amphibians observed in several parts of the world.

Chronic myelocytic leukemia in a juvenile rhesus macaque (Macaca mulatta).

Myeloid neoplasia has been studied extensively in human beings but has not been reported in macaques. A 2-year-old female rhesus macaque that was experimentally exposed to lead as a neonate, was noted to have immature circulating myelocytic cells, including 1% blasts, and normocytic normochromic anemia on a blood sample obtained for monthly health monitoring. The animal was treated with hydroxyurea, blood transfusion, and recombinant human erythropoietin to reduce the leukocytosis and correct the anemia. The disease had a relatively indolent course for 3 months, when it progressed to blast crisis. After the onset of blast crisis, the animal was euthanized because of bleeding problems, anemia, and a progressive decline in her health. The animal was negative by serology, polymerase chain reaction (PCR) assays, and/or culture for simian retrovirus (SRV), simian T-lymphotropic virus type I (STLV-I), and simian immunodeficiency virus (SIV). PCR assay for the bcr-ABL chromosomal translocation using primers made for the human gene was negative. Serology for Epstein-Barr virus (EBV)-like viruses was positive for IgG directed against the viral nucleocapsid antigen, but epidemiologic factors make it unlikely that the leukemia was associated with EBV-induced viral transformation. Lead exposure has been associated with neoplasia in human beings, and the possible role of neonatal lead exposure in hematologic neoplasias deserves further scrutiny.

Occurrence of compounds estrogenic to freshwater mussels in surface waters in an urban area.

Estrogens play a major role in the sexual differentiation, gonad development, and oocyte growth of most oviparous organisms. They also stimulate vitellogenesis, the formation of high-density glycolipophosphoprotein that serves as an energy source for the developing embryo. Surface waters from the St. Lawrence River, obtained in the vicinity of an urban area (Montreal, Quebec, Canada), were studied with respect to their estrogenic potential to the freshwater mussel Elliptio complanata. Estrogenicity was measured in water extracts by means of a competitive assay of estradiol binding to cytosolic proteins and by the vitellin-inducing ability of mussel hemolymph following direct extract injection. Surface-water samples drawn downstream of a municipal outfall plume and in a river draining a large farming and agricultural area had high levels of total and fecal coliform bacteria. High levels of estrogen competitors were also found and were able to induce vitellins in injected mussels. Moreover, the estrogen-competing potential of the extracts was found to be significantly correlated with total and fecal coliform bacteria (R = 0.9, p < 0.01) and with the levels of vitellins in the hemolymph (R = 0.62, p = 0.03). The results indicate that water samples drawn from within the municipal effluent plume and from a river draining an agricultural area are estrogenic to freshwater mussels. Thus, the environmental inputs of estrogens are likely to be associated with human sewage and pesticide products.

Type 2 diabetes mellitus, hyperlipidemia, and extremity lesions in California mice (Peromyscus californicus) fed commercial mouse diets.

BACKGROUND AND PURPOSE: We characterized abnormalities of carbohydrate and lipid metabolism and determined whether those metabolic abnormalities are associated with extremity lesions in California mice (Peromyscus californicus). METHODS: Blood samples were evaluated for glucose, cholesterol, triglyceride, and insulin concentrations. Necropsy and histologic evaluation were done on selected mice, including staining pancreatic sections for insulin. Physical examinations also were performed. RESULTS: California mice were found to have Type 2 diabetes mellitus (T2DM). Sections of pancreas from diabetic and prediabetic mice had pathologic changes consistent with T2DM. After six months of feeding a low-fat diet, mice were normoglycemic, normotriglyceridemic, and normocholesterolemic. Some mice remained hyperinsulinemic. Traumatic lesions were not associated with T2DM. CONCLUSIONS: California mice develop diet-related T2DM when fed a diet containing 25.8% kcal from fat. California mice may be a useful animal model of human T2DM, and traumatic lesions result from housing California mice in multiple male groups.

High prevalence of gastric trichobezoars (hair balls) in Wistar-Kyoto rats fed a semi-purified diet.

Gastric trichobezoars (hair balls) are frequently found in rabbits but are rarely reported in rats. Several Wistar-Kyoto rats fed a semi-purified diet developed anorexia and abdominal tenderness. Proteolysis therapy with fresh papaya and commercially prepared enzyme was attempted in these rats but was not successful. The prevalence of trichobezoars at necropsy was 100%. We conclude that semi-purified diets contribute to trichobezoar formation in rats, but proteolysis therapy is not effective in dissolving the trichobezoars.

An open study of tolerability and pharmacokinetics of raclopride extended release capsules in psychiatric patients: a Canadian study.

The tolerability and pharmacokinetics of raclopride extended release (ER) capsules have been evaluated after a single oral dose and at steady state, with 3 different daily doses in 4 male patients requiring neuroleptic treatment. In this 3-week open study, the drug was administered to patients in increasing bid doses of 8 mg, 12 mg and 16 mg, respectively, for each 1-week treatment period, following a 1-week placebo washout. With this limited number of patients, assessments of clinical chemistry, hematology, cardiovascular variables and adverse symptoms suggest that raclopride is safe and well-tolerated in the group studied. The administration of repeated doses of raclopride showed linear pharmacokinetics based on parameter values which are either constant (effective elimination half-life, total plasma clearance, and dose-normalized area under the plasma concentration-time curve) or varying proportionally (trough plasma concentration, peak plasma concentration, average plasma concentration and the area under the plasma concentration-time curve for a dosage interval at steady state) with the doses. The linear 1-compartment open model with zero-order absorption was the most appropriate pharmacokinetic model describing the raclopride plasma concentration profile after a single 8 mg dose of raclopride ER capsules. The ER formulation reduced the fluctuation between peak and trough plasma drug concentrations which has been reported before with instant release dosage forms. In this study, the increase of plasma prolactin concentrations above the normal limit was transient and returned to normal levels. Although the plasma prolactin concentration tended to increase with the drug dose, no direct relationship between raclopride dose and prolactin plasma concentrations was found. The correlation of plasma prolactin response with the plasma raclopride concentration showed a low level of hysteresis.

[Determination of the concentrations of niflumic acid in the plasma and synovial tissue following repeated administration of capsules]. / Détermination des concentrations d'acide niflumique dans le plasma et le tissu synovial après administration répétée de gélules.

Niflumic acid was assayed in the plasma and synovial tissue of 12 adults about 10 hours following the end of a 1 g niflumic acid daily administration for 2 days; an arthroscopy of the knee had been carried out in these patients with various degenerative infections. The ratio of niflumic acid synovial concentrations to plasmatic concentrations was 1.27, showing the affinity of this drug for the synovial tissue.

Hepatic and gastric amebiasis in black and white colobus monkeys.

Three cases of hepatic amebiasis and one case of gastric amebiasis were diagnosed in black and white colobus monkeys during a 9-month period. The diagnosis was difficult because of the absence of trophozoites and cysts in the feces and because of few trophozoites found in many of the hepatic lesions. Indirect hemagglutination titers were diagnostic in 2 monkeys.