The feasibility of using Internet support for the maintenance of weight loss.

This pilot study examined the acceptability and feasibility of conducting a weight loss maintenance intervention over the Internet. Obese adults participated in a 15-week behavioral weight control intervention and were then randomly assigned to one of the following three maintenance conditions: (a) in-person, therapist-led (TL); (b) Internet, therapist-led (I); and (c) control (C). Both maintenance interventions met biweekly for 22 weeks using the same program content. Results showed that TL participants were more likely to attend their meetings and feel more satisfied with their group assignment. However, there were no differences between the TL and I groups in overall attrition or number of peer support contacts made. There was also no significant difference in weight loss between the groups. Thus, the Internet may hold promise as a method for maintaining contact with patients to facilitate long-term behavior change.     

Nutritional intervention to prevent weight gain in patients commenced on olanzapine: a randomized controlled trial

OBJECTIVE: Olanzapine is the most commonly prescribed atypical antipsychotic medication in Australia. Research reports an average weight gain of between 4.5 and 7 kg in the 3 months following its commencement. Trying to minimize this weight gain in a population with an already high prevalence of obesity, mortality and morbidity is of clinical and social importance. This randomized controlled trial investigated the impact of individual nutrition education provided by a dietitian on weight gain in the 3 and 6 months following the commencement of olanzapine. METHOD: Fifty-one individuals (29 females, 22 males) who had started on olanzapine in the previous 3 months (mean length of 27 days +/- 20) were recruited through Peninsula Health Psychiatric Services and were randomly assigned to either the intervention (n = 29) or the control group (n = 22). Individuals in the intervention group received six 1 hour nutrition education sessions over a 3-month period. Weight, waist circumference, body mass index (BMI) and qualitative measures of exercise levels, quality of life, health and body image were collected at baseline at 3 and 6 months. RESULTS: After 3 months, the control group had gained significantly more weight than the treatment group (6.0 kg vs 2.0 kg, p < or = 0.002). Weight gain of more than 7% of initial weight occurred in 64% of the control group compared to 13% of the treatment group. The control group's BMI increased significantly more than the treatment group's (2 kg/m(2)vs 0.7 kg/m(2), p < or = 0.03). The treatment group reported significantly greater improvements in moderate exercise levels, quality of life, health and body image compared to the controls. At 6 months, the control group continued to show significantly more weight gain since baseline than the treatment group (9.9 kg vs 2.0 kg, p < or = 0.013) and consequently had significantly greater increases in BMI (3.2 kg/m(2)vs 0.8 kg/m(2), p < or = 0.017). CONCLUSION: Individual nutritional intervention provided by a dietitian is highly successful at preventing olanzapine-induced weight gain.     

Parasympathetic response to acute stress is attenuated in young Zucker obese rats

We compared arterial blood pressure (BP) and heart rate (HR) control in 9- to 11-week old obese Zucker rats (n=10; weight=452+/-45 g, average+/-SD) to age-matched, lean Zucker animals (n=13; weight=280+/-46 g). BP was measured by indwelling catheter. Baseline pressure was 113.1+/-7.0 mm Hg in the lean vs. 111.7+/-5.6 in the obese rats (NS). Baseline HR was 413+/-43 in the lean vs. 422+/-22 bpm in the obese animals (NS). Rats were classically conditioned by following a 15-second tone (CS+) with a 0.5-second tail shock. There were no between-group differences in the BP response to CS+. Conversely, heart rate (HR) decreased significantly (p<0.05) more during the last 10 s of the tone in the lean group (-46.0+/-21.5 bpm) vs. the obese (-17.8+/-21.7 bpm). This bradycardia was blocked by atropine. Finally, the change in HR divided by the change in arterial BP (DeltaHR/DeltaBP) following an intravenous bolus of phenylephrine (PE; 5 microg/kg) and following sodium nitroprusside (NP; 5 microg/kg) was determined. The DeltaHR/DeltaBP following PE was smaller in the obese (n=6; -1.36+/-0.60) vs. lean (n=5; -2.80+/-0.92); there was no difference in the response following NP. These data indicate that the BP response to a behavioral challenge did not differ in the obese rat vs. the lean animal, but that the obese subjects had an attenuated parasympathetic response to the stress, probably secondary to alterations in baroreflex function.     

Body weight gain after administration of antipsychotic drugs: correlation with leptin, insulin and reproductive hormones

Excessive body weight gain, hyperprolactinemia and low gonadal steroid serum levels are often observed during chronic administration of antipsychotic drugs (AP). Clinical and experimental findings suggest that leptin, the peptidic hormone involved in long-term body weight regulation, and reproductive hormones are interrelated. Therefore, we assessed circulating leptin levels in healthy, lean women (n = 12) and men (n = 7) before and after short-term administration of the AP sulpiride (SUL, 200 mg/day). In addition, we studied psychotic obese (n = 9) and lean women (n = 13) under chronic treatment with diverse AP. No significant weight changes were observed after SUL administration in healthy women--initial weight: 54.9+/-2.6 Kg; final weight: 55.04+/-2.6, NS. Leptin levels did not change either: 11.9+/-1.5 ng/ml. vs. 10.6+/-1.3, NS. By contrast, a small, but significant weight gain was found in SUL-treated men--60.6+/-1.9 Kg. vs. 61.3+/-2.1, p = 0.004. Leptin and insulin levels were significantly higher after SUL administration--leptin: 2.77+/-0.22 ng/ml. vs. 13.9+/-2.5, p=0.035; insulin: 3.59+/-0.17 mIU/ml vs. 8.81+/-0.81, p = 0.0001. In these subjects, leptin levels positively correlated with body weight change (p = 0.006), and serum prolactin change (p = 0.001). Obese psychotic women (Body Mass Index, BMI, Kg/m2 = 31.5+/-1.03) displayed higher leptin levels than non-obese psychotic women (BMI = 25.5+/-0.52): 26.8+/-4.8, vs. 12.8+/-3.4 ng/ml, p = 0.006. In these women, a significant positive correlation was found between leptin levels and BMI (p = 0.0001), and between leptin and basal insulin levels (p = 0.001). These results show that the expected circulating leptin elevation which is observed when body weight raises, is preserved in people treated with AP drugs.     

Factors associated with duration of survival in Alzheimer's disease

With a computerized data base, a data retrieval system, and a computer program using the actuarial method of life-table analysis, we compared survival rates in different subgroups of patients with dementia of the Alzheimer type (DAT; n = 199). Men (n = 71) had a shorter duration of survival than women (n = 128), with 500-day survival (mean +/- SEM) 84 +/- 5% vs. 99 +/- 3%, p less than 0.01; 1000-day survival 49 +/- 10% vs. 96 +/- 8%, p less than 0.001; 50% survival 1000 days vs. 1550 days. Patients younger than 65 years at onset had a decreased relative duration of survival compared with patients over 65 at onset, suggesting a more malignant course. Patients with a longer duration of illness tended to die sooner, but this effect was not statistically significant. The Kahn-Goldfarb mental-status quotient was not a predictor of survival. Patients with high Haycox behavioral score (greater than 20; n = 50), indicating more severe behavioral impairment, had lower survival rates at 500 days than patients with low scores (less than 12; n = 65) (80 +/- 6% vs. 95 +/- 3%, p less than 0.05). Hachinski ischemic score, measuring signs and symptoms of vascular disease, had no correlation with survival. Factors associated with decreased duration of survival in DAT include male sex, presenile onset, and increased severity of behavioral impairment.     

Metabolic changes in elderly patients with major depression: evidence for increased accumulation of visceral fat at follow-up

The accumulation of visceral fat is promoted by a specific endocrine syndrome, which is similarly found in major depression. The aim of this study was to investigate whether visceral fat depots increase in depressed patients during a follow-up period explaining the increased risk for cardiovascular disorders. Intraabdominal fat was measured in 29 depressed patients and 17 controls by computer tomography at the level of lumbar vertebra 4. In patients fat measurements were done initially during a major depressive episode and again after a follow-up period of 14 months; in controls the mean time interval between measurements was 28 months. In both groups, saliva was taken at 800 h over a period of seven days prior to each CT for the estimation of free cortisol. In patients only, an oral glucose tolerance test was also carried out. Compared to controls hyper- and normocortisolemic depressed patients showed a larger accumulation of visceral fat mass over time (hypercort.:132.0 +/- 45 vs. 144.7 +/- 47 cm(2), p = 0.07; normocort.: 115.5 +/- 53 vs. 135.0 +/- 51 cm(2), p = 0.002; controls: 130.1 +/- 66 vs. 137.3 +/- 76 cm(2), p = 0.4), despite similar weight gain (hypercort.: 2.1 +/- 5 kg, normocort.: 1.7 +/- 5 kg and controls: 2.3 +/- 4 kg). Further, normocortisolemic patients showed a trend for an higher percentile increase in visceral fat accumulation than controls (23.9 +/- 27 vs. 5.8 +/- 28%, p = 0.07). At follow-up, free cortisol concentrations were still above normal in patients who had been hypercortisolemic at first assessment (35.0 +/- 8 vs. 28.8 +/- 18 nmol/l, p = 0.1). Fasting and 2 h glucose concentrations were higher in hypercortisolemic compared to normocortisolemic patients at the index examination (6.2 +/- 1.1 vs. 5.0 +/- 0.05 mmol/l, p = 0.02; 11.5 +/- 2.7 vs. 7.8 +/- 1.9 mmol/l, p = 0.01). The larger proportion of visceral fat accumulation in patients may constitute a link for explaining the increased cardiovascular mortality in patients suffering from major depression.     

Topiramate for the treatment of binge eating disorder associated with obesity: a placebo-controlled study.

BACKGROUND: In a single-center, placebo-controlled study, topiramate reduced binge eating and weight in patients with binge eating disorder (BED) and obesity. The current investigation evaluated the safety and efficacy of topiramate in a multicenter, placebo-controlled trial. METHODS: Eligible patients between 18 and 65 years with >or= 3 binge eating days/week and a body mass index (BMI) between 30 and 50 kg/m2 were randomized. RESULTS: A total of 407 patients enrolled; 13 failed to meet inclusion criteria, resulting in 195 topiramate and 199 placebo patients. Topiramate reduced binge eating days/week (-3.5 +/- 1.9 vs. -2.5 +/- 2.1), binge episodes/week (-5.0 +/- 4.3 vs. -3.4 +/- 3.8), weight (-4.5 +/- 5.1 kg vs. .2 +/- 3.2 kg), and BMI (-1.6 +/- 1.8 kg/m2 vs. .1 +/- 1.2 kg/m2) compared with placebo (p < .001). Topiramate induced binge eating remission in 58% of patients (placebo, 29%; p < .001). Discontinuation rates were 30% in each group; adverse events (AEs) were the most common reason for topiramate discontinuation (16%; placebo, 8%). Paresthesia, upper respiratory tract infection, somnolence, and nausea were the most common AEs with topiramate. CONCLUSIONS: This multicenter study in patients with BED associated with obesity demonstrated that topiramate was well tolerated and efficacious in improving the features of BED and in reducing obesity.     

Metformin as an adjunctive treatment to control body weight and metabolic dysfunction during olanzapine administration: a multicentric, double-blind, placebo-controlled trial

BACKGROUND: Excessive body weight gain (BWG) is a clinically relevant side effect of olanzapine administration. The primary objective of this study was to assess whether metformin prevents or reverses BWG in patients with schizophrenia or bipolar disorder under olanzapine administration. Secondarily we evaluated diverse metabolic variables. METHODS: Eighty patients taking olanzapine (5-20 mg daily for more than 4 consecutive months) were randomly allocated to metformin (n=40; 850 to 2550 mg daily) or placebo (n=40) group in a 12-week double-blind protocol. Waist circumference (WC) body weight (BW), body mass index (BMI) fasting glucose, glycated hemoglobin (Hb1c), insulin, an insulin resistance index (HOMA-IR) lipids, leptin, c-reactive protein, fibrinogen, cortisol and the growth hormone (GH) were evaluated at baseline and at week 12 of treatment. RESULTS: The metformin group lost 1.4+/-3.2 kg (p=0.01) and tended to decrease its leptin levels, whereas the placebo group maintained a stable weight: -0.18+/-2.8 kg (p=0.7). The HOMA-IR significantly increased after placebo (p=0.006) and did not change after metformin (p=0.8). No ostensible differences were observed in the other variables, even though metformin did not improve the lipid profile and the Hb1c levels. CONCLUSIONS: Metformin may safely assist olanzapine-treated patients in body weight and carbohydrate metabolism control.     

The effectiveness and tolerability of aripiprazole for pediatric bipolar disorders: a retrospective chart review

OBJECTIVE: The aim of this retrospective chart review was to evaluate the effectiveness and tolerability of aripiprazole for the treatment of children and adolescents with bipolar disorders. METHODS: The medical charts of all children and adolescents with a DSM-IV diagnosis of bipolar disorder, type I, type II, not otherwise specified (NOS), or schizoaffective disorder, bipolar type, and who were treated with aripiprazole were reviewed by two child and adolescent psychiatrists who independently confirmed their DSM-IV diagnoses, severity, and the improvement of illness using the Clinical Global Impression (CGI) Severity and Improvement scores for bipolar disorder (CGI-BP) and the Clinical Global Assessment Scale (CGAS). RESULTS: Thirty patients who were treated with aripiprazole were identified (mean starting dose=9 +/- 4 mg/day, mean final dose=10 +/- 3 mg/day). The overall response rate, defined by a CGI-Improvement score of < or = 2 at endpoint, was 67%. There was a statistically significant improvement in CGAS scores (48 +/- 11 to 65 +/- 11, signed rank = 191, p <0.0001) and CGI-S scores (4.2 +/- 0.8 to 2.8 +/- 1.0, signed rank=-172, p <0.0001, effect size=1.90) from baseline to endpoint. No serious adverse events were identified. Common side effects were sedation (n=10, 33%), akathisia (n=7, 23%), and gastrointestinal disturbances (n=2, 7%). Baseline and endpoint weights were available for 14 (47%) of the patients. Change in weight ranged from +5 to -21 kg and 12 (86%) of 14 patients lost weight (mean weight loss was 3 +/- 6 kg). CONCLUSIONS: This retrospective chart review suggests that aripiprazole may be effective and well tolerated for children and adolescents with bipolar disorders. Controlled studies of aripiprazole for the treatment of pediatric bipolar disorder are necessary.     

Idazoxan does not prevent but worsens focal hypoxic-ischemic brain damage in neonatal Wistar rats

We examined the neuroprotective efficacy of a post-treatment with idazoxan (Idaz): an alpha2-adrenoceptor antagonist with activity at the I1- and I2-subtypes of the imidazoline receptor (I-receptor), in an experimental model of perinatal hypoxic-ischemic (HI) brain damage. Seventy-two, 7-day-old Wistar rats were subjected to permanent unilateral ligation of the common carotid artery and transient (2 hr) hypoxia (8% O(2)). The surviving animals were sub-divided into 3 groups: one "control" group received intraperitoneal (i.p.) injection of saline (Sigma; n = 21) and two "treated" groups received, 10 min post-HI, i.p. treatments with Idaz (I3: 3 mg/kg; n = 19) or (I8: 8 mg/kg; n = 20). Idaz effects were assessed by TTC-staining 72 hr post-HI for Sigma (n = 13), I3 (n = 11), and I8 (n = 12) groups and by MRI-examination 5 weeks post-HI for Sigma (n = 8), I3 (n = 8), and I8 (n = 6) groups. Total ratio of brain infarct areas were significantly (P < 0.01) different between Sigma and Idaz-treated rats: 20.9 +/- 4.0%, 35.6 +/- 5.9 % and 36.8 +/- 5.8% for Sigma, I3 and I8, respectively, when determined with TTC-staining and; 23.3 +/- 3.7%, 39.8 +/- 4.2%, and 43.2 +/- 10.1%, for Sigma, I3, and I8, respectively, when assessed by MRI. Our results suggest that Idaz, given as a post-HI treatment, does not exert neuroprotective effects but enhances the brain injury induced by focal neonatal cerebral HI. The deleterious mechanism may result from an overactivity of sympathetic tone and/or the immaturity of central I-receptors in newborn rats.     

Management of patients with Alzheimer's disease plus cerebrovascular disease: 12-month treatment with galantamine

We evaluated the long-term cognitive effects and safety of galantamine 24 mg/day in patients with Alzheimer's disease plus cerebrovascular disease (AD + CVD or mixed dementia). Subgroup analysis was performed of patients with AD + CVD who participated in a 6-month, multicenter, randomized, double-blind, parallel-group study and a 6-month, open-label, active-treatment extension. METHOD: Two hundred and eighty-five patients with AD + CVD were randomized to receive either placebo (n = 97) or galantamine 24 mg/day (n = 188) for 6 months. Two hundred and thirty-eight (84%) patients continued with the open-label phase of the study (86 from the placebo group, 152 from the galantamine group) and were treated with galantamine 24 mg/day. The primary efficacy measure was cognitive performance as assessed using the eleven-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog/11). Standard safety evaluations and adverse-event monitoring were performed throughout the 12-month study period. Patients with AD + CVD treated with galantamine experienced statistically and clinically significant improvement in cognition at month 6 (mean change in ADAS-cog/11 score -1.1; p < or = 0.05 vs. baseline) and maintained their cognitive function for the entire 12-month study (mean change in ADAS-cog/11 score +0.1). In contrast, the cognitive function deteriorated among those in the placebo group (mean change in ADAS-cog/11 at month 6 +2.0; p < or = 0.001 vs. baseline). Patients with AD + CVD who were switched from placebo to galantamine for the open-label phase of the trial did show improvement in cognitive function; however, they never attained the same cognitive level as patients who had been treated with galantamine for the entire 12 months [mean (+/- SE) ADAS-cog/11 scores in the placebo/galantamine group 25.7 +/- 1.32 and 24.2 +/- 1.57 at months 6 and 12, respectively, and in the galantamine/galantamine group 21.5 +/- 0.87 and 22.2 +/- 1.06 at months 6 and 12, respectively]. The results of this subgroup analysis indicate that galantamine is effective for long-term maintenance of the cognitive function in patients with AD + CVD and is safe and well tolerated in this patient population.     

Opposite to alpha2-adrenergic agonists, an imidazoline I1 selective compound does not influence reflex bradycardia in rabbits

This work aimed to study the respective effects of central alpha2-adrenergic receptors (alpha2-ARS) and I1 imidazoline receptors (I1Rs) in the facilitatory effects of imidazoline-like drugs on the reflex bradycardia (RB). Experiments were performed in anaesthetized rabbits. The reflex bradycardic response was induced by phenylephrine injected i.v. LNP 509, rilmenidine and dexmedetomidine were administered intracisternally (i.c.). LNP509 (1 mg/kg, i.c.), a ligand highly selective for I1Rs, induced hypotension (54+/-3 vs. 93+/-2 mm Hg) and bradycardia (260+/-13 vs. 322+/-13 beats/min) (p<0.05, n=5) but did not affect RB. Rilmenidine (1 microg/kg, i.c.), a hybrid ligand which binds to both I1 and alpha2-ARS, also decreased arterial pressure (61+/-2 vs. 101+/-2 mm Hg) and heart rate (260+/-4 vs. 308+/-8) (p<0.01, n=5); it potentiated the RB (maximum R-R interval: 284+/-17 vs. 196+/-6 ms) (p<0.05, n=5). Dexmedetomidine (1 microg/kg, i.c.), a ligand selective for alpha2-ARs, reduced blood pressure (53+/-3 vs. 104+/-2 mm Hg) and heart rate (246+/-4 vs. 312+/-8 beats/min) (p<0.05, n=5) and potentiated the RB (maximum R-R interval: 518+/-38 vs. 194+/-4 ms) (p<0.05, n=5). The potentiation of RB was much greater than that observed with rilmenidine and was significantly prevented by L-NNA injected centrally. This study shows that: (i) an exclusive action on I1Rs which decreases arterial pressure, does not potentiate the RB ii) activation of alpha2-ARs potentiates the RB (iii) the R-R prolongation caused by alpha2-ARs stimulation is prevented by central NOS inhibition.     

Weight gain induced by haloperidol, risperidone and olanzapine after 1 year: findings of a randomized clinical trial in a drug-naïve population

BACKGROUND: There is little information about weight gain induced by antipsychotics at long-term. OBJECTIVE: To quantify the weight gain induced by first (haloperidol) and second generation antipsychotics (olanzapine and risperidone) in a cohort of drug-na?ve subjects after 1 year of treatment. METHODS: This is a prospective, randomized clinical trial, including a representative sample of first episode psychotic incident cases from a population area of 555.000 people. The main outcome measures were changes in body weight and body mass index at 3 months and at 12 months. Both a per protocol analysis and an intention to treat analysis were conducted. RESULTS: A total of 164 drug-na?ve patients were included. At 12 months 144 patients were evaluated. Of them, 66% completed the protocol and 34% needed treatment switch. We found statistically significant differences in weight gain at 3 months: 3.8 kg (+/-4.1) for haloperidol, 5.9 kg (+/-5.1) for risperidone and 8.4 kg (+/-5.0) for olanzapine (F=7.045; p=0.002). After 1 year the difference in weight gain had disappeared: 9.7 kg (+/-5.7) for haloperidol, 8.9 kg (+/-8.8) for risperidone and 10.9 kg (+/-7.2) for olanzapine (F=0.817; p=0.445). CONCLUSIONS: Drug-na?ve patients experience an extraordinary weight gain after 1 year of treatment with haloperidol, olanzapine or risperidone. The main difference among these treatments is the pattern of weight gain but not the final amount of weight gain.     

Effect of olanzapine on cognition during treatment of behavioral and psychiatric symptoms in patients with dementia: a post-hoc analysis

OBJECTIVE: This study was conducted to determine the effect of olanzapine treatment on cognition in elderly patients with behavioral and psychiatric symptoms (BPSD) associated with dementia. METHODS: This was a post-hoc analysis of three randomized double-blind, clinical trials of olanzapine (n = 682) vs placebo (n = 257) in dementia patients with BPSD in long-term or continuing-care settings. One study was 6 weeks long; the other two were 10 weeks duration, and their data were combined. Patients were subgrouped according to baseline Mini Mental State Examination (MMSE) scores: Group I = 23-26; Group II = 19-22; Group III = 14-18; Group IV = 7-13; Group V = 1-6. BPSD was assessed by the Neuropsychiatric Inventory (NPI). RESULTS: Within-treatment group cognitive decline in patients was significant in the combined studies, but not in the 6-week study. Between-treatment cognitive changes were non-significant in the 6-week study, but showed a statistical trend in the combined studies (olanzapine, -0.78 +/- 0.19 vs placebo, -0.32 +/- 0.25; p = 0.06). In the subgroup analysis, there was a significant between-treatment difference in cognitive changes in MMSE subgroup IV in the combined studies (olanzapine, -0.63 +/- 0.26 vs placebo, 0.27 +/- 0.41, p = 0.04). Improvement in BPSD was correlated with better cognitive outcome (r = -0.2; p < 0.01). CONCLUSIONS: Although the overall differences in cognitive changes in patients treated with olanzapine vs placebo were small and non-significant, negative effects on cognition in some patients cannot be excluded, especially in patients with more pronounced cognitive decline or whose behavioral and psychiatric symptoms are not responding to treatment.     

Platelet activation and high tissue factor level predict acute stent thrombosis in pig coronary arteries: prothrombogenic response of drug-eluting or bare stent implantation within the first 24 hours

Increased thrombogenicity of drug-eluting stents (DESs) has recently been reported. The aim of the present study was to investigate the prothrombogenic effect of DESs and Bare stents, and determine factors predictive of acute stent thrombosis (AST) in preclinical experiments using new stent design or coating. Circulating pre- and post-stenting parameters of platelet activation (mean platelet volume, MPV; platelet distribution width, platelet large cell ratio), thrombin activation (thrombin-antithrombin complex, TAT and prothrombin fragments, F1+2), tissue factor antigen (TF-ag) and -activity (TF-act) and plasminogen activator inhibitor-1 (PAI-1) were measured in 141 consecutive pigs. Stent implantations were performed after pretreatment with aspirin and clopidogrel with unfractionated heparin anticoagulation. Nineteen pigs (groups AST-DES, n = 12; and AST-Bare, n = 7) died mean 6.3 +/- 2.9 h after stent implantation from AST. The remaining 122 control (C) pigs (groups C-DES, n = 76, and C-Bare, n = 46) survived the 1-month follow-up. Non-significantly elevated levels of post-stent F1+2 and TAT were measured in AST groups. Post-stenting MPV was increased significantly in the groups ASTDES and AST-Bare as compared with the groups C-DES and C-Bare (11.73 +/- 1.12 and 11.6 +/- 0.68 vs. 8.85 +/- 0.78 and 9.04 +/- 0.81 fL; p < 0.001), similarly to TF-ag (189.1 +/- 87.5 and 127 +/- 34.9 vs. 42.5 +/- 24.6 and 35.3 +/- 37.6 pg/ml; p < 0.001, respectively), Tfact (3.23 +/- 0.95 and 2.73 +/- 1.68 vs. 1.43 +/- 1.12 and 1.61 +/- 1.31 pM; p < 0.01, respectively) and PAI-1 (99.1 +/- 15.8 and 99 +/- 14.7 vs.53.4 +/- 40.2 and 46.9 +/- 42.4 ng/ml;p < 0.01, respectively). Multivariate analysis revealed elevated post-stenting plasma levels of TF-ag (p = 0.016) and MPV (p = 0.001) as independent risk factors for developing AST within the first 24 h in a porcine coronary stent model.     

Oxypurinol administration fails to prevent hypoxic-ischemic brain injury in neonatal rats

The purpose of the present study was to determine whether oxypurinol, a xanthine oxidase inhibitor, reduces free radicals and brain injury in the rat pup hypoxic-ischemia (HI) model. Seven-day-old rat pups had right carotid arteries ligated followed by 2.5h of hypoxia (8% oxygen). Oxypurinol or vehicle was administered by i.p. injection at 5 min after reoxygenation and once daily for 3 days. Brain damage was evaluated by weight deficit of the right hemisphere at 22 days following hypoxia. Oxypurinol treatments did not reduce weight loss in the right hemisphere. Brain weight loss in the right hemisphere were -26.2+/-3.6, -15.2+/-6.9, -21.7+/-4.4, -15.8+/-5.1, and -16.7+/-3.4% in vehicle (n=33), 10 (n=17), 20 (n=16), 40 (n=15), and 135 mg/kg (n=13) oxypurinol-treated groups (p>0.05), respectively. Brain thiobarbituric acid-reacting substances (TBARS) were assessed 3 and 6h after reoxygenation. Concentrations of TBARS rose 1.5-fold due to HI. Oxypurinol did not significantly reduce an HI-induced increase in brain TBARS. Thus, xanthine oxidase may not be the primary source of oxy-radicals in pup brain and as such oxypurinol does not prevent free radical-mediated lipid peroxidation or protect against brain injury in the neonatal rat HI model.     

Weight gain during treatment of bipolar I patients with olanzapine

BACKGROUND: Body weight increase during long-term treatment with olanzapine in schizophrenia patients is well documented, but weight gain and its association with other medical measures are less well evaluated in bipolar disorder patients. METHOD: We analyzed data from a 3-week, randomized, placebo-controlled trial of olanzapine for acute mania in DSM-IV bipolar I patients, followed by open continuation treatment with olanzapine up to a year. We examined factors associated with increased body mass index (BMI), including ratings of clinical change and selected physiologic measures. RESULTS: Among 113 subjects treated with olanzapine for a mean +/- SD of 28.6 +/- 19.9 weeks, BMI increased from a baseline mean of 28.8 +/- 6.2 kg/m(2), by 7.9 +/- 10.8% (p < .001), into the obese range (31.0 +/- 6.1 kg/m(2)). Initial BMI change (first 3 weeks of drug exposure) predicted final BMI increases (Spearman rank correlation r(s) = 0.32, p < .001). History of longer illness (p = .006) and lifetime substance abuse (p = .02) were associated with below-median BMI increases. BMI increased much more among 40 subjects achieving symptomatic recovery than in the 73 who did not (by 11.9 +/- 13.2% vs. 5.3 +/- 7.7%; p = .004), with correspondingly longer olanzapine exposure (44.7 +/- 11.8 vs. 19.7 +/- 17.7 weeks; p < .001) at similar doses. On average, serum cholesterol increased 4.8 times more (17.5% vs. 3.6%) and endpoint cholesterol levels were newly 240 mg/dL or greater 3.6 (95% CI = 1.5 to 8.0) times more frequently in subjects with above-median BMI gain, who also experienced significantly larger increases in systolic and diastolic blood pressure, pulse rates, and nonfasting serum glucose than low-BMI-gain subjects. CONCLUSIONS: Weight gain associated with long-term olanzapine treatment for mania was common, substantial, time-dependent, predicted by initial increases, and temporally associated with significant changes in cardiovascular and metabolic measures in bipolar I patients with prolonged illness and already-high basal BMI. An association of weight gain with favorable clinical response probably reflects longer olanzapine treatment.     

Decreased baroreflex sensitivity in isoproterenol-treated mice with cardiac hypertrophy

The baroreflex has been shown to be impaired in rat models of cardiac hypertrophy. In the present study, we investigated the effects of beta-adrenoceptor-induced cardiac hypertrophy on the baroreflex in mice. Male Swiss Webster mice weighing 20-25 g were treated with the beta-adrenoceptor agonist isoproterenol (IPM; 15 microg/g/day, s.c.) for 7 days or with vehicle (control, CM). After treatment, IPM (n=9) and CM (n=9) were anesthetized with ketamine + xylazine (91.0: 9.1 mg/kg, i.p.) and had their carotid artery and jugular vein cannulated to test the arterial baroreflex. The baroreflex was evaluated by measuring changes in heart rate (HR) in response to acute increases and decreases in mean arterial pressure (MAP) induced by bolus injections of phenylephrine and sodium nitroprusside (1.5-24.0 microg/kg, i.v.) in conscious animals. IPM showed an increased cardiac weight/body weight (1.18 +/- 0.03 mg/g) ratio compared to CM (0.95 +/- 0.03 mg/g, p<0.05), but similar values of resting MAP (108 +/- 4 vs. 111 +/- 2 mm Hg) and HR (606 +/- 25 vs. 629 +/- 26 bpm). Sigmoidal barocurve analysis showed that isoproterenol treatment significantly reduced the following parameters: baroreflex sensitivity (IPM: -4.26 +/- 0.19 vs. CM: -5.92 +/- 0.54 bpm/mm Hg, p<0.05), reflex bradycardia plateau (IPM: 387 +/- 26 vs. CM: 318 +/- 19 bpm, p<0.05) and HR range (IPM: 369 +/- 30 vs. CM: 442 +/- 20 bpm, p<0.05). Linear regression analysis of baroreflex function also showed a diminished reflex bradycardia (CM: -8.92 +/- 0.87 bpm/mm Hg vs. IPM: -4.94 +/- 0.52 bpm/mm Hg, p<0.05), but similar reflex tachycardia (CM: -3.88 +/- 0.45 bpm/mm Hg vs. IPM: -3.52 +/- 0.43 bpm/mm Hg). In conclusion, beta-adrenoceptor-induced cardiac hypertrophy in mice led to impaired sensitivity of the cardiac baroreflex, which could be due to a diminished vagal activity to the heart.     

2-deoxy-D-glucose-induced hyperglycemia: role for direct sympathetic nervous system activation of liver glucose output

The hypothalamus plays an important integrative role in the control of peripheral metabolism, achieved by modulation of autonomic outflow to the endocrine pancreas, the liver and the adrenal medulla. This study examines the role of direct sympathetic nervous system control of hepatic glucose output during neuroglycopenia induced by the non-metabolizable glucose analogue 2-deoxy-D-glucose (2-DG). Steady-state tracer methodology was used to directly measure hepatic glucose output (Ra) in pentobarbitone-anesthetised male Wistar rats (220-320 g). Administration of 500 mg/kg 2-DG i.p. produced an increase in Ra from a control value of 7.3 +/- 0.3 mg/kg.min (n = 4) to 15.2 +/- 2.2 mg/kg.min-1 (n = 8), corresponding to an increase in plasma glucose (PG) from 6.4 +/- 0.1 mmol/l to 10.1 +/- 0.4 mmol/l. This rise was countered by the sympathetic noradrenergic blocker guanethidine (100 mg/kg i.p.), reducing Ra to 10.4 +/- 0.9 mg/kg.min-1 and PG to 6.1 +/- 0.3 mmol/l (n = 8), despite markedly lower plasma insulin (PI) levels (2-DG: PI = 94.7 +/- 18.6 mU/l (n = 7), 2-DG + guanethidine: PI = 41.4 +/- 3.3 mU/l (n = 8). Hyperglycemia and elevated liver glucose output were maintained in ADX animals treated with 2-DG, indicating an absence of adrenal-medullary influence (2-DG: Ra = 15.2 +/- 2.2 mg/kg.min-1, 2-DG + ADX = 15.6 +/- 1.0 mg/kg.min-1). Elevated Ra in the 2-DG + ADX was maintained despite markedly elevated insulin levels 349.3 +/- 72.6 mU/l (n = 7)).(ABSTRACT TRUNCATED AT 250 WORDS)     

Recombinant single-chain urokinase-type plasminogen activator (rscu-PA) induces thrombolysis and systemic fibrinolysis in a canine model of coronary artery thrombosis

The thrombolytic efficacy of recombinant single-chain urokinase-type plasminogen activator (rscu-PA) was studied in an open-chest canine model of coronary artery thrombosis. Dogs (n = 16) were anesthetized, a left thoracotomy performed, and a two cm segment of the left circumflex coronary artery was isolated and instrumented with an electromagnetic flow probe, an intracoronary stimulation electrode, and an adjustable mechanical occluder. Anodal direct current (100 microA) was applied to the stimulation electrode until thrombosis occurred (n = 14). After 30 min of thrombotic occlusion, rscu-PA was administered intravenously. Dogs were sacrificed either 6 h after thrombolysis or 6.5 h after initiation of rscu-PA when thrombolysis did not occur. In group A (30-50 micrograms/kg bolus rscu-PA + 20-40 micrograms/kg/min infusion rscu-PA for 30 min, n = 5) thrombolysis occurred in one case (20%) and this artery reoccluded. In group B (250 micrograms/kg bolus rscu-PA + 25 micrograms/kg/min infusion rscu-PA for 30 min, n = 6) all reperfused and only one reoccluded (16.6%). In group C (200 micrograms/kg bolus rscu-PA + 100 micrograms/kg/min rscu-PA infusion for 30 min, n = 2) both reperfused and neither reoccluded. Infarct size, determined as a percentage of left ventricle, was smaller when thrombolysis was followed by persistent reperfusion (n = 7), than when reperfusion did not occur (n = 4): 16.9 +/- 3.7% vs 31.3 +/- 2.2%, respectively (mean +/- SEM, p less than 0.02). If thrombolysis was followed by reocclusion, infarct size was 27.0 +/- 10.0%. In this study thrombolysis occurred when changes in prothrombin time, partial thromboplastin time, fibrinogen and fibrin split products were suggestive of systemic finbrinogenolysis. In conclusion, effective thrombolysis with rscu-PA appears to limit infarct size and to be accompanied by evidence of systemic fibrinolysis.