Amélie Paquette

A Systematic Review of Amnestic and Non-Amnestic Mild Cognitive Impairment Induced by Anticholinergic, Antihistamine, GABAergic and Opioid Drugs

BackgroundMild cognitive deficits are experienced by 18% of community-dwelling older adults, many of whom do not progress to dementia. The effect of commonly used medication on subtle impairments in cognitive function may be under-recognized.ObjectiveThe aim of the review was to examine the evidence attributing amnestic or non-amnestic cognitive impairment to the use of medication with anticholinergic, antihistamine, GABAergic or opioid effects.MethodsMEDLINE and EMBASE were searched for randomized, doubleblind, placebo-controlled trials of adults without underlying central nervous system disorders who underwent detailed neuropsychological testing prior to and after oral administration of drugs affecting cholinergic, histaminergic, GABAergic or opioid receptor pathways. Seventy-eight studies were identified, reporting 162 trials testing medication from the four targeted drug classes. Two investigators independently appraised study quality and extracted relevant data on the occurrence of amnestic, non-amnestic or combined cognitive deficits induced by each drug class. Only trials using validated neuropsychological tests were included. Quality of the evidence for each drug class was assessed based on consistency of results across trials and the presence of a dose-response gradient.ResultsIn studies of short-, intermediate- and long-acting benzodiazepine drugs (n = 68 trials), these drugs consistently induced both amnestic and non-amnestic cognitive impairments, with evidence of a dose-response relationship. H1-antihistamine agents (n = 12) and tricyclic antidepressants (n = 15) induced non-amnestic deficits in attention and information processing. Non-benzodiazepine derivatives (n = 29) also produced combined deficits, but less consistently than benzodiazepine drugs. The evidence was inconclusive for the type of cognitive impairment induced by different bladder relaxant antimuscarinics (n = 9) as well as for narcotic agents (n = 5) and antipsychotics (n = 5). Among healthy volunteers >60 years of age, low doses of commonly used medications such as lorazepam 0.5 mg, oxybutynin immediate release 5 mg and oxycodone 10 mg produced combined deficits.ConclusionNon-amnestic mild cognitive deficits are consistently induced by first-generation antihistamines and tricyclic antidepressants, while benzodiazepines provoke combined amnestic and non-amnestic impairments. Risk-benefit considerations should be discussed with patients in order to enable an informed choice about drug discontinuation or substitution to potentially reverse cognitive adverse effects.

Effects of ovariectomy on PPAR alpha, SREBP-1c, and SCD-1 gene expression in the rat liver.

Objective:To investigate whether estrogen deficiency modifies the expression of important genes involved in hepatic lipid regulation, PPAR&agr;, SREBP-1c, and SCD-1, in association with fat accumulation in the liver of ovariectomized rats. Design:Thirty female Sprague-Dawley rats were divided into three groups: sham-operated (n = 12), ovariectomized (n = 12), and ovariectomized with 17&bgr;-estradiol replacement (n = 6). All animals were killed 8 weeks after surgery. In addition to liver triacylglycerol determination, transcripts levels and protein content of peroxisome proliferator-activated receptor &agr;, liver sterol regulatory element-binding protein 1c, and stearoyl coenzyme Adesaturase 1 were quantified by quantitative real-time polymerase chain reaction and Western blot, respectively. Results:As expected, liver triacylglycerol levels were higher (51%; 21.9 ± 2.6 vs 14.5 ± 1.2 mg/g; P < 0.01) in ovariectomized compared with sham-operated rats. Peroxisome proliferator-activated receptor &agr; mRNA levels were 66% lower (P < 0.01), whereas sterol regulatory element-binding protein 1 and stearoyl coenzyme A desaturase 1 transcript levels were 80% and 41% higher (P < 0.05), respectively, after estrogen removal. Our data on gene expression obtained with quantitative real-time polymerase chain reaction for peroxisome proliferator-activated receptor &agr; and sterol regulatory element-binding protein 1c were confirmed by Western blots. All the effects of ovariectomy were prevented by 17&bgr;-estradiol replacement, indicating a role for estrogens in the prevention of hepatic fat accumulation. Conclusions:Our results suggest that a reduction in lipid oxidation and an increase in lipogenesis are defective mechanisms leading to lipid accumulation in the liver of ovariectomized rats. We conclude that estrogen deficiency induced by ovariectomy changes the expression of genes that favor the development of a steatotic phenotype.

Systematic Review and Meta-Analysis:: Do Clinical Trials Testing Antimuscarinic Agents for Overactive Bladder Adequately Measure Central Nervous System Adverse Events?

Experimental studies in healthy volunteers suggest that some antimuscarinic agents confer a risk of cognitive impairment, yet clinical trials of people with overactive bladder report only rare central nervous system (CNS) side effects. A lack of systematic measurement and reporting of CNS outcomes in clinical trials may partially explain this discrepancy. The purpose of this review and meta‐analysis was to ascertain the reporting bias associated with adverse CNS events in clinical drug trials of younger and older adults with overactive bladder. Articles were identified from MEDLINE and EMBASE databases until 2010 using the search terms “clinical trial” AND (one of) “oxybutynin, tolterodine, fesoterodine, propiverine, solifenacin, darifenacin, and trospium.” Eligibility criteria included original randomized trials involving adults with overactive bladder; standard doses of medication; reports of confusion, somnolence, sedation, dizziness, drowsiness, asthenia, insomnia, and vertigo; no evidence of dementia at baseline; and trials in English. Seventy‐seven percent (242/314) of eligible trials identified in the search neither measured nor reported CNS outcomes. Of the remaining 23%, it was difficult to distinguish whether CNS adverse events were systematically measured or spontaneously reported. Only one of 72 trials that were retained objectively measured changes in cognitive performance (Mini‐Mental State Examination). Dizziness was the most frequently reported side effect, in 3% of oxybutynin, 3.2% of propiverine, and 1.8% of tolterodine users, compared with 1.6% with placebo. Confusion was reported in fewer than 1% of cases. Age‐stratified analyses of CNS outcomes from trials in adults aged 65 and older with overactive bladder were found in only eight publications. Meta‐analyses were conducted with 33 randomized, double‐blind, placebo‐controlled trials to determine the effect of each drug and dose on different CNS outcomes. Study heterogeneity, dosing inconsistency, and reporting bias limited interpretation of the findings from the meta‐analyses. More‐detailed standardized measurement of age‐stratified CNS outcomes in clinical trials is required to better inform patients and clinicians about CNS risks associated with antimuscarinic agents.

Methodological Challenges in Determining Longitudinal Associations Between Anticholinergic Drug Use and Incident Cognitive Decline

To compare the effect of using different anticholinergic drug scales and different models of cognitive decline in longitudinal studies.

Substituting food restriction by resistance training prevents liver and body fat regain in ovariectomized rats.

Objective Fat mass gain and regain following weight loss are major concerns and may be even more critical after menopause. The present study was undertaken to evaluate the effect of a resistance training protocol on body weight and fat mass in ovariectomized Sprague–Dawley rats following diet-induced weight loss. Design Rats were randomly divided into ovariectomized (Ovx) and sham-operated (Sham) groups. Five weeks after ovariectomy, Ovx rats were subjected to a 26% food restriction (OvxFR) for 8 weeks. Following this period, OvxFR rats went back to a normal ad libitum feeding and were divided into two groups: either sedentary or undergoing a resistance training program for an additional 5 weeks, which consisted of climbing a 6-m vertical grill, 20–40 times, with progressively increasing load four times/week. Results The food restriction program decreased (p < 0.01) body mass, fat pad weight (intra-abdominal and subcutaneous), and liver triacylglycerol (TAG) levels as compared to normally fed Ovx rats. Stopping the food restriction program over a 5-week period resulted in a partial regain in body weight and intra-abdominal fat pad weight (p < 0.05), and in an almost complete regain in liver TAG compared to normally fed Ovx rats. On the other hand, no significant increases in these variables were noted when the food restriction was replaced by resistance training over the same 5-week period. Conclusion These results indicate that a resistance training program could be useful in preventing body weight as well as adipose tissue and liver fat regain in Ovx rats, following diet-induced weight loss. It is suggested that changing from a food restriction regimen to a resistance training program can be an interesting strategy to promote successful long-term weight reduction in postmenopausal women.

Resistance training prevents liver fat accumulation in ovariectomized rats

BACKGROUND Menopause is associated with increased lipid deposition in the liver and fat accumulation in the abdomen. OBJECTIVE The purpose of the present study was to determine the effects of adding a resistance training program (RT) to a restrictive diet (RD) on liver lipid accumulation and abdominal fat depots in ovariectomized (Ovx) rats. METHODS One group of sham-operated and three groups of Ovx rats were compared. Five weeks after surgery, Ovx rats were either submitted to an approximately 25% RD with or without RT for 3 or 8 weeks, while a third group of Ovx rats were fed ad libitum and remained sedentary. The RT program consisted of climbing a 6m vertical metal grill five times a week with an increasing load up to 75% of body weight attached to the tail. The number of repetitions increased from two to four sets of 10 repetitions. RESULTS Ovariectomy resulted in significantly higher (P<0.01) body weight, energy intake, intra-abdominal fat depots, plasma leptin levels (P<0.05), and liver triacylglycerol concentrations. All of these responses were (P<0.01) reduced in Ovx rats following the RD with the exception of liver lipid infiltration. The addition of RT to the RD treatment synergistically reduced abdominal fat deposition and plasma-free fatty acid levels. Moreover, liver lipid infiltration was completely prevented by the addition of the RT program. Muscle mass relative to body weight was significantly increased in Ovx-RD-RT compared to all other groups. CONCLUSION It is concluded that RT is an asset to minimize the deleterious effects of ovarian hormone withdrawal on liver lipid accumulation and abdominal fat accumulation in Ovx rats.

Resistance training attenuates fat mass regain after weight loss in ovariectomized rats

OBJECTIVE The aim of the present study was to investigate the effects of maintaining only one of the two components of a food restriction (FR)+resistance training (RT) regimen on the regain of body weight and fat mass (liver and adipocytes) in ovariectomized (Ovx) rats. METHODS Five week Ovx rats were submitted to a weight loss program consisting of a 26% FR combined with RT (OvxFR+RT) for 8 weeks. RT consisted of climbing a 1.5m vertical grid with a load attached to the tail, 20-40 times with progressively increasing loads 4 times/week. Following this weight loss intervention, OvxFR+RT rats were sub-divided into 3 groups for an additional 5 weeks: 2 groups went back to a normal ad libitum feeding with or without RT and the other group kept only FR. RESULTS Combined FR+RT program in Ovx rats led to lower body mass gain, liver triacylglycerol (TAG) levels, and fat mass gain compared to sedentary normally fed Ovx rats (P<0.01). Stopping both FR and RT over a 5 week period resulted in the regain of body weight, intra-abdominal fat pad weight and liver TAG (P<0.01). When only FR was maintained, the regain of body and fat pad weight as well as liver and plasma TAG concentrations was completely prevented. However, when only RT was maintained, regain in the aforementioned parameters was attenuated but not prevented (P<0.05). CONCLUSION It is concluded that following a FR+RT weight loss program, continuation of only RT constitutes an asset to attenuate body weight and fat mass regain in Ovx rats; although the impact is less than the maintaining FR alone. These results suggest that, in post-menopausal women, RT is a positive strategy to reduce body weight and fat mass relapse.

Effects of alternations (10 days) of high-fat with normal diet on liver lipid infiltration, fat gain, and plasma metabolic profile in rats.

The purpose of the present study was to test the hypothesis that short-term alternations of high-fat with normal chow feeding result in higher fat accumulation in liver than continuous intake of the same high-fat diet. Male Sprague-Dawley rats (7 weeks of age) were divided into 3 groups according to diet composition: standard chow (SD; 12,5% kcal as fat), high-fat (HF; 42% kcal as fat), and food cycles (FC) consisting of 10-day alternations between HF and SD diets beginning with the high-fat diet. Rats in each of these 3 groups were sacrificed after 10, 30, and 50 days (n = 10 rats/sub-groups). Energy intake, body weight, liver and muscle relative weights were not significantly (P > 0.05) different between FC- and HF-fed rats. Using the total energy intake for the 50-day period, it was calculated that approximately 30% less calories as fat was ingested in the FC- compared to the HF-fed rats. In spite of this, liver lipid infiltration as well as fat accretion in abdominal adipose tissues were increased (P < 0.01) similarly in FC- and HF-fed rats. Plasma FFA and insulin levels depicted strong tendencies (P < 0.07) to be higher in FC- than in continuous HF-fed rats at the end of the 50-day period. These results indicate that, despite a 30% reduction in ingested lipids, alternations of HF with normal chow diet compared to the continuous hyperlipidic diet caused the same level of infiltration of lipids in the liver and in the abdominal adipose tissues and, to a certain extent, may even result in a larger deterioration of the metabolic profile.