Central Nervous System Side Effects Research Articles

A Pharmacist-initiated Project to Reduce Meperidine Use in Surgical Patients

Background Meperidine continues to be widely used, especially as a postoperative analgesic agent, despite numerous pain management guidelines have recommended against its use due to its shorter duration of action and potential for serious central nervous system side effects. This study evaluated the effectiveness of a pharmacist intervention on reducing the analgesic use of meperidine. Methods The usage rate of meperidine in surgical patients before (from October 2008 to July 2009) and after (from October 2009 to July 2010) pharmacist interventions were compared. Pharmacists initiated meperidine clinical pathways to eliminate meperidine use in favor of morphine therapy. Pharmacists provided in-service education and also gave direct intervention on inappropriate prescriptions via telephone calls. Results The mean meperidine usage rate was decreased from 49.00% to 33.51% among surgical departments after the pharmacist intervention ( p p Conclusion Through a series of pharmacist interventions provided by pharmacists, a significant reduction in the use of meperidine in surgical patients was achieved. Sustained interventions are needed to achieve better and long-term effects in the eradication of meperidine use.

GABAB receptor-mediated selective peripheral analgesia by the non-proteinogenic amino acid, isovaline

Peripherally restricted analgesics are desirable to avoid central nervous system (CNS) side effects of opioids. Nonsteroidal anti-inflammatory drugs produce peripheral analgesia but have significant toxicity. GABAB receptors represent peripheral targets for analgesia but selective GABAB agonists like baclofen cross the blood–brain barrier. Recently, we found that the CNS-impermeant amino acid, isovaline, produces analgesia without apparent CNS effects. On observing that isovaline has GABAB activity in brain slices, we examined the hypothesis that isovaline produces peripheral analgesia mediated by GABAB receptors. We compared the peripheral analgesic and CNS effect profiles of isovaline, baclofen, and GABA (a CNS-impermeant, unselective GABAB agonist). All three amino acids attenuated allodynia induced by prostaglandin E2 injection into the mouse hindpaw and tested with von Frey filaments. The antiallodynic actions of isovaline, baclofen, and GABA were blocked by the GABAB antagonist, CGP52432, and potentiated by the GABAB modulator, CGP7930. We measured Behavioural Hyperactivity Scores and temperature change as indicators of GABAergic action in the CNS. ED95 doses of isovaline and GABA produced no CNS effects while baclofen produced substantial sedation and hypothermia. In a mouse model of osteoarthritis, isovaline restored performance during forced exercise to baseline values. Immunohistochemical staining of cutaneous layers of the analgesic test site demonstrated co-localization of GABAB1 and GABAB2 receptor subunits on fine nerve endings and keratinocytes. Isovaline represents a new class of peripherally restricted analgesics without CNS effects, mediated by cutaneous GABAB receptors.

Design of a Potent CB1 Receptor Antagonist Series: Potential Scaffold for Peripherally-Targeted Agents.

Antagonism of cannabinoid-1 (CB1) receptor signaling has been demonstrated to inhibit feeding behaviors in humans, but CB1-mediated central nervous system (CNS) side effects have halted the marketing and further development of the lead drugs against this target. However, peripherally restricted CB1 receptor antagonists may hold potential for providing the desired efficacy with reduced CNS side effect profiles. In this report we detail the discovery and structure-activity-relationship analysis of a novel bicyclic scaffold (3) that exhibits potent CB1 receptor antagonism and oral activity in preclinical feeding models. Optimization of physical properties has led to the identification of analogues which are predicted to have reduced CNS exposure and could serve as a starting point for the design of peripherally targeted CB1 receptor antagonists.

Primary Afferent Nociceptor as a Target for the Relief of Pain

Primary Afferent Nociceptor as a Target for the Relief of Pain

Muscle relaxants for pain management in rheumatoid arthritis

Pain management is a high priority for patients with rheumatoid arthritis (RA). Muscle relaxants include drugs that reduce muscle spasm (for example benzodiazepines such as diazepam (Valium), alprazolam (Xanax), lorazepam (Ativan) and non-benzodiazepines such as metaxalone (Skelaxin) or a combination of paracetamol and orphenadrine (Muscol)) and drugs that prevent increased muscle tone (baclofen and dantrolene). Despite a paucity of evidence supporting their use, antispasmodic and antispasticity muscle relaxants have gained widespread clinical acceptance as adjuvants in the management of patients with chronic musculoskeletal pain. The aim of this review was to determine the efficacy and safety of muscle relaxants in pain management in patients with RA. The muscle relaxants that were included in this review are the antispasmodic benzodiazepines (alprazolam, bromazepam, chlordiazepoxide,cinolazepam, clonazepam, cloxazolam, clorazepate, diazepam, estazolam, flunitrazepam, flurazepam, flutoprazepam, halazepam, ketazolam, loprazolam, lorazepam, lormetazepam, medazepam, midazolam, nimetazepam, nitrazepam, nordazepam, oxazepam, pinazepam, prazepam, quazepam, temazepam, tetrazepam, triazolam), antispasmodic non-benzodiazepines (cyclobenzaprine, carisoprodol, chlorzoxazone, meprobamate, methocarbamol, metaxalone, orphenadrine, tizanidine and zopiclone), and antispasticity drugs (baclofen and dantrolene sodium). We performed a search of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 4th quarter 2010), MEDLINE (1950 to week 1 November 2010), EMBASE (Week 44 2010), and PsycINFO (1806 to week 2 November 2010). We also searched the 2008 to 2009 American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) abstracts and performed a handsearch of reference lists of relevant articles. We included randomised controlled trials which compared a muscle relaxant to another therapy (active, including non-pharmacological therapies, or placebo) in adult patients with RA and that reported at least one clinically relevant outcome. Two blinded review authors independently extracted data and assessed the risk of bias in the trials. Meta-analyses were used to examine the efficacy of muscle relaxants on pain, depression, sleep and function, as well as their safety. Six trials (126 participants) were included in this review. All trials were rated at high risk of bias. Five cross-over trials evaluated a benzodiazepine, four assessed diazepam (n = 71) and one assessed triazolam (n = 15). The sixth trial assessed zopiclone (a non-benzodiazepine) (n = 40) and was a parallel group study. No trial duration was longer than two weeks while three single dose trials assessed outcomes at 24 hours only. Overall the included trials failed to find evidence of a beneficial effect of muscle relaxants over placebo, alone (at 24 hrs, 1 or 2 weeks) or in addition to non-steroidal anti-inflammatory drugs (NSAIDs) (at 24 hrs), on pain intensity, function, or quality of life. Data from two trials of longer than 24 hours duration (n = 74) (diazepam and zopiclone) found that participants who received a muscle relaxant had significantly more adverse events compared with those who received placebo (number needed to harm (NNTH) 3, 95% CI 2 to 7). These were predominantly central nervous system side effects, including dizziness and drowsiness (NNTH 3, 95% CI 2 to 11). Based upon the currently available evidence in patients with RA, benzodiazepines (diazepam and triazolam) do not appear to be beneficial in improving pain over 24 hours or one week. The non-benzodiazepine agent zopiclone also did not significantly reduce pain over two weeks. However, even short term muscle relaxant use (24 hours to 2 weeks) is associated with significant adverse events, predominantly drowsiness and dizziness.

The spectrum of anticonvulsant efficacy of retigabine (ezogabine) in animal models: Implications for clinical use

Retigabine [RTG (international nonproprietary name); ezogabine (EZG; U.S. adopted name)] is a first-in-class antiepileptic drug (AED) that reduces neuronal excitability by enhancing the activity of KCNQ (K(v)7) potassium (K(+)) channels. RTG/EZG has recently been approved by the European Medicines Agency and the U.S. Food and Drug Administration as adjunctive therapy in adults with partial-onset seizures. In this review we discuss the activity that RTG/EZG has demonstrated across a broad spectrum of in vitro/in vivo animal models of seizures, including generalized tonic-clonic, primary generalized (absence), and partial seizures, in addition to the compound's ability to resist and block the occurrence of seizures induced by a range of stimuli across different regions of the brain. The potency of RTG/EZG in models refractory to several conventional AEDs and the work done to assess antiepileptogenesis and neuroprotection are discussed. Studies that have evaluated the central nervous system side effects of RTG/EZG in animals are reviewed in order to compare these effects with adverse events observed in patients with epilepsy. Based on its demonstrated effect in a number of animal epilepsy models, the synergistic and additive activity of RTG/EZG with other AEDs supports its potential use in therapeutic combinations for different seizure types. The distinct mechanism of action of RTG/EZG from those of currently available AEDs, along with its broad preclinical activity, underscores the key role of KCNQ (K(v)7) K(+) channels in neuronal excitability, and further supports the potential efficacy of this unique molecule in the treatment of epilepsy.

Patient with Central Nervous System Side Effects due to Lafutidine

Patient with Central Nervous System Side Effects due to Lafutidine

Pain management with morphine: variation in analgesic response secondary to genetic polymorphisms

Correspondence: Shailendra Kapoor 2300 E Cary St Richmond, VA 23223, USA Tel +1 804 2342345 Fax +1 804 3454561 Email shailendrakapoor@yahoo.com To the editor The recent article by Villesen et al in a recent issue of your journal was most interesting. Recent studies show that the potency of morphine in efficacious pain control may be influenced greatly by polymorphisms of certain genes. For instance, Klepstad et al have recently shown that cancer patients on opioid maintenance therapy who are homozygous for the variant G allele of the 118 A . G polymorphism of the mu opioid receptor (OPRM1) gene require higher doses of morphine for efficacious pain control in comparison with patients who are heterozygous. In fact, the morphine requirement is almost 93% less in AA genotypes in contrast with morphine requirements in cancer patients who carry the GG genotype of the OPRM1 gene. Similar pain modulation variation is seen with polymorphisms of the OPRM1 gene and perioperative fentanyl administration. Furthermore, more profound CNS depressant side effects after morphine administration are noticed in cancer patients with certain polymorphisms of the multidrug resistance-1 gene. Similarly, the potency of morphine in pain management in cancer patients is influenced and varies greatly with polymorphisms of the catechol-O-methyl transferase gene. For instance, individuals with the Met/Met genotype of the catechol-O-methyl transferase gene require 63% less morphine in comparison with those who have the Val/Val genotype of the catechol-O-methyl transferase gene. More profound central nervous system side effects are seen following morphine administration in cancer patients with single nucleotide polymorphisms in intron 1 of the catechol-O-methyl transferase gene. The above examples clearly illustrate the variation in adequate pain control with morphine secondary to genetic mutations. Further research is needed to identify other similar gene polymorphisms that may affect opioid requirements in patients being managed with other nonmorphine narcotics.

Developmental changes of brain distribution and localization of oseltamivir and its active metabolite Ro 64-0802 in rats

Oseltamivir, a prodrug of the neuraminidase inhibitor [3R, 4R, 5S]-4-Acetamide-5-amino-3-(1-ethylpropyl)-1-cyclohexene-1-carboxylate phosphate (Ro 64-0802), is widely used for treatment of influenza infections in Japan, but may be associated with mental instability and suicidal tendencies as a rare side effect, especially in infants and young patients. We examined developmental changes in the brain distribution of oseltamivir and Ro 64-0802, and in the expression of P-glycoprotein (P-gp) at the blood-brain barrier (BBB) in rats by 8 weeks. Brain concentration and Kp(,app,brain) (brain-to-plasma concentration ratio) of oseltamivir were highest in 2-week-old rats (1.45 µg/g brain and 0.14, respectively), and were negatively correlated with both age and P-gp expression at the BBB. In contrast, brain concentration and Kp(,app,brain) of Ro 64-0802 after oral gavage of oseltamivir were lowest in 2-week-old rats (0.02 µg/g brain and 0.02), and increased with age. Mass imaging analysis revealed that both compounds were distributed homogenously in brain cross-sections, including the hippocampus. From these results, it was estimated that oseltamivir concentration throughout the brain cross-sections was 70-fold and 0.9-fold higher than that of Ro 64-0802 in 2-week-old and 8-week-old rats, respectively. Such developmental changes of prodrug/drug concentration ratio, if they also occur in humans, may provide a rational basis for the putative central nervous system (CNS) side effects in young patients.

Low-dose gabapentin for intractable hiccups in a heart transplant recipient

Intractable hiccups can be a serious complication in transplant recipients. Unfortunately, many of the pharmacotherapies used to stop hiccups are associated with severe side effects as well as drug-drug interactions with immunosuppressants. We report a case of a heart transplant recipient who had had intractable hiccups for 2 months, resulting in severe insomnia, diminished appetite, and weight loss. To treat the hiccups, treatment with oral baclofen (5-10 mg 3 times daily) was started. After 6 weeks of therapy, the baclofen was titrated down and discontinued because it had not stopped the hiccups and was causing severe central nervous system side effects. Gabapentin (100 mg twice daily) was then prescribed and within 24 hours of the start of that treatment, the hiccups had resolved completely. After 3 weeks of therapy, the patient had no side effects and the gabapentin was subsequently discontinued. One year after stopping the gabapentin, the patient remains free of hiccups. Gabapentin appears to be a promising medication for the treatment of intractable hiccups in thoracic transplant recipients because of its lack of serious side effects at low doses, rapid onset of action, and lack of drug-drug interactions with transplant medications.

Low-dose Gabapentin for Intractable Hiccups in a Heart Transplant Recipient

Intractable hiccups can be a serious complication in transplant recipients. Unfortunately, many of the pharmacotherapies used to stop hiccups are associated with severe side effects as well as drug-drug interactions with immunosuppressants. We report a case of a heart transplant recipient who had had intractable hiccups for 2 months, resulting in severe insomnia, diminished appetite, and weight loss. To treat the hiccups, treatment with oral baclofen (5-10 mg 3 times daily) was started. After 6 weeks of therapy, the baclofen was titrated down and discontinued because it had not stopped the hiccups and was causing severe central nervous system side effects. Gabapentin (100 mg twice daily) was then prescribed and within 24 hours of the start of that treatment, the hiccups had resolved completely. After 3 weeks of therapy, the patient had no side effects and the gabapentin was subsequently discontinued. One year after stopping the gabapentin, the patient remains free of hiccups. Gabapentin appears to be a promising medication for the treatment of intractable hiccups in thoracic transplant recipients because of its lack of serious side effects at low doses, rapid onset of action, and lack of drug-drug interactions with transplant medications.

Does adding ketamine to morphine patient-controlled analgesia safely improve post-thoracotomy pain?

A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was 'is the addition of ketamine to morphine patient-controlled analgesia (PCA) following thoracic surgery superior to morphine alone'. Altogether 201 papers were found using the reported search, of which nine represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. This consisted of one systematic review of PCA morphine with ketamine (PCA-MK) trials, one meta-analysis of PCA-MK trials, four randomized controlled trials of PCA-MK, one meta-analysis of trials using a variety of peri-operative ketamine regimes and two cohort studies of PCA-MK. Main outcomes measured included pain score rated on visual analogue scale, morphine consumption and incidence of psychotomimetic side effects/hallucination. Two papers reported the measurements of respiratory function. This evidence shows that adding ketamine to morphine PCA is safe, with a reported incidence of hallucination requiring intervention of 2.9%, and a meta-analysis finding an incidence of all central nervous system side effects of 18% compared with 15% with morphine alone, P = 0.31, RR 1.27 with 95% CI (0.8-2.01). All randomized controlled trials of its use following thoracic surgery found no hallucination or psychological side effect. All five studies in thoracic surgery (n = 243) found reduced morphine requirements with PCA-MK. Pain scores were significantly lower in PCA-MK patients in thoracic surgery papers, with one paper additionally reporting increased patient satisfaction. However, no significant improvement was found in a meta-analysis of five papers studying PCA-MK in a variety of surgical settings. Both papers reporting respiratory outcomes found improved oxygen saturations and PaCO(2) levels in PCA-MK patients following thoracic surgery. We conclude that adding low-dose ketamine to morphine PCA is safe and post-thoracotomy may provide better pain control than PCA with morphine alone (PCA-MO), with reduced morphine consumption and possible improvement in respiratory function. These studies thus support the routine use of PCA-MK instead of PCA-MO to improve post-thoracotomy pain control.

Absence Seizures Associated With Efavirenz Initiation

Efavirenz, used in treating pediatric human immunodeficiency virus infection, has central nervous system side effects. We report on a 5-year-old girl with perinatally acquired human immunodeficiency virus infection, presenting with new onset absence seizures after starting treatment with efavirenz. Plasma efavirenz values were above therapeutic range. The child was homozygous for the CYP2B6-516T/T genotype, which is associated with poor efavirenz clearance. Seizures abated after efavirenz discontinuation.

Commentary [The Mood in the Field of Antidepressant Drug Discovery

As with most areas of pharmacotherapeutics, a significant percentage of patients are not fully served by existing medicines in the area of major depressive disorder (MDD) [1, 2]. Only about one third of patients respond to current antidepressants and less than one third display symptom remission. Another third of the patients do not respond to multiple therapeutic interventions (treatment resistant depression or TRD) leaving a huge unmet medical need in a disease area that affects millions of people each year [2]. A report by Berman and colleagues [3] and its subsequent replication by Zarate et al. [4] have inspired new ideas about antidepressant drug action. In patients that did not respond to at least two adequate antidepressant regimens, the dissociative anesthetic, ketamine, produced immediate and relatively long-lasting relief of mood symptoms after a single intravenous dose. The work has been systematically replicated in different cohorts of TRD patients including those suffering with bipolar depression [5, 6]. The idea that blockade of N-methyl-D-asparte (NMDA) receptors by ketamine would be antidepressant was deduced from connections of NMDA receptors, long-term potentiation, and electroconvulsive therapy by Trullas and Skolnick in 1990 [7]. Additional clinical validation came with the finding that an NMDA receptor antagonist selective for NR2B receptors was also effective in TRD patients [8]. Given the efficacy of ketamine and the difficulties of using ketamine as a prescription drug (it is abused and produces marked central nervous system side effects as do other NMDA receptor antagonists [9]), finding novel agents that can mimic the antidepressant effects without the safety issues becomes a goal of those seeking improved therapeutic options for TRD patients. A large clue already in hand in the new discovery effort is that ketamine is known to block NMDA receptors. In this vein, other NMDA receptor blockers might be viable treatment agents without the side effects. Zn2+ also blocks NMDA receptors and is antidepressant; work in TRD patients has shown it to be effective as an adjunct with imipramine [10]. Other ways of producing functional dampening of NMDA receptor function are already being explored. GLYX-13, a putative glycine-site functional partial agonist, has preclinical antidepressant-like activity and is being funded now for Phase II clinical investigation [11]. The vigorous activity in the area of TRD therapeutics is a testament to the mood that shines over many laboratory benches as answers to important questions seem within reach. What are the key biological actions of ketamine that enable relief from TRD? One of the first clues came from the preclinical laboratory. Ketamine and other NMDA receptor antagonists produced effects in the mouse-forced swim test that were comparable to those of other antidepressant drugs; these behavioral effects of ketamine were prevented by an alpha-amino-3-hydroxy-5- methylisoxazole-4-propionic acid (AMPA) receptor antagonist [12]. Thus, ketamine, by virtue of its glutamate releasing effects, produces activation of AMPA receptors that is responsible for the antidepressant-like signatures observed. Convergent biochemical, neurobiological, and behavioral data implicate AMPA receptor amplification as a core feature of antidepressant drug action [13]. It is not unreasonable to speculate that other methods of increasing AMPA receptor function would also produce fast-acting antidepressant response in TRD patients. What drugs exist that most directly facilitate AMPA receptor function? Positive allosteric modulators of AMPA receptors are one such possibility and display robust antidepressant effects in rodent models [13, 14] but have yet to be put to clinical proof of concept in TRD [14]. Zn2+, with augmenting effects in TRD patients [10], is also AMPA antagonist sensitive [15]. Antagonists of metabotropic mGlu2/3 receptors also engender antidepressant-like neurochemical and behavioral effects in a host of preclinical models and a number of these effects are prevented by AMPA receptor antagonists [1, 14]....

Effect of ciprofloxacin and levofloxacin on some oxidative stress parameters in brain regions of male albino rats

The present study aimed to investigate the possibility of involved oxidative stress due to the oral administration of either ciprofloxacin or levofloxacin (under therapeutic level) in the three brain regions, cerebral cortex, hippocampus and striatum of male albino rats weighing (100 ± 20 g). The ciprofloxacin and levofloxacin administered groups exhibited significant elevation in lipid peroxidation (LPO), nitric oxide (NO) contents and superoxide dismutase (SOD) enzyme activity in cortex, hippocampus and striatum. The redox status (reduced glutathione/oxidized glutathione) and glutathione peroxidase (GPx) and Na + , K + , -adenosine triphosphatase (Na + , K + , -ATPase) enzymes activity were significantly reduced in a dose dependant manner in the three brain regions. Generally, the data suggest the contribution between these antibiotics and oxidative stress in brain regions which through light on the need of studies for design and development of new quinol on e derivatives with broader antibacterial activity and better pharmaco-kinetics avoiding central nervous system (CNS) side effects.

Central Anticholinergic Syndrome Following Dobutamine–Atropine Stress Echocardiography

We present a case of central anticholinergic syndrome following dobutamine-atropine stress echocardiography in an elderly female. Although atropine toxicity is a recognized complication of stress echocardiography, no case reports are currently available. The central nervous system side effects of atropine are varied in severity (mild cognitive impairment to severe coma) and spectrum (agitation or somnolence), and thus are often overlooked. Management includes prompt recognition, stopping the offending agent, providing supportive care, and consideration of physiostigmine. Atropine is used in up to 60% of dobutamine stress echocardiograms, and has the potential to cause morbidity.

Intra- and Postoperative Very Low Dose Intravenous Ketamine Infusion Does Not Increase Pain Relief after Major Spine Surgery in Patients with Preoperative Narcotic Analgesic Intake

This study aims to demonstrate the analgesic efficacy and opioid-sparing effect of low dose ketamine in patients with preoperative narcotic intake undergoing major spine surgery. The study used a prospective, randomized, double-blinded, and placebo-controlled clinical trial. We evaluated the analgesic efficacy and safety of low dose IV ketamine infusion after major spine surgery in patients with preoperative narcotic analgesic intake. Ketamine group received IV ketamine infusion (2 µg/kg/min) and saline group received saline intraoperatively and the first 24 hours postoperatively. In addition, all patients received IV patient-controlled hydromorphone and epidural bupivacaine. Pain scores, narcotic requirement, and side effects were compared between the groups for 48 hours postoperatively. Thirty patients completed the study (N = 15 in each group). No difference in pain scores at rest and movement was noted between the groups (P > 0.05). Patients in ketamine group received 40.42 ± 32.86 mg IV hydromorphone at 48 hours compared with 38.24 ± 26.19 mg in saline group (P = 0.84). Central nervous system side effects were observed in five (33%) ketamine group patients compared with nine (60%) in saline group (P = 0.29). The addition of IV very low dose ketamine infusion regimen did not improve postoperative analgesia. Side effects were not increased with low dose ketamine.

Neuroprotective effect of carvedilol against aluminium induced toxicity: possible behavioral and biochemical alterations in rats

Aluminium, is a trace element available in the Earth's crust naturally and has a toxic potential for humans. It has been suggested as a contributing factor in the pathogenesis of Alzheimer's disease. β-Adrenoceptor blocking agents (β-blockers) have been established as therapeutics for the treatment of patients with hypertension, ischemic heart diseases, chronic heart failure, arrhythmias and glaucoma. Over the years, however, β-blockers have been associated with an incidence, albeit low, of central nervous system (CNS) side effects. In addition, noradrenergic receptors play a modulatory role in many nerve functions, including vigilance, attention, reward, learning and memory. Therefore, the present study has been designed to explore the possible role of carvedilol, an adrenergic antagonist against aluminium chloride-induced neurotoxicity in rats. Aluminium chloride (100mg/kg) was administered daily for six weeks that significantly increased cognitive dysfunction in the Morris water maze and oxidative damage as indicated by a rise in lipid peroxidation and nitrite concentration and depleted reduced glutathione, superoxide dismutase, catalase and glutathione S-transferase activity compared to sham treatment. Chronic aluminium chloride treatment also significantly increased acetylcholinesterase activity and the aluminium concentration in brain compared to sham. Chronic administration of carvedilol (2.5 and 5mg/kg, po) daily to rats for a period of 6 weeks significantly improved the memory performance tasks of rats in the Morris water maze test, attenuated oxidative stress (reduced lipid peroxidation, nitrite concentration and restored reduced glutathione, superoxide dismutase, catalase and glutathione S-transferase activity), decreased acetylcholinesterase activity and aluminium concentration in aluminium-treated rats compared to control rats (p<0.05). Results of this study demonstrated the neuroprotective potential of carve-dilol in aluminium chloride-induced cognitive dysfunction and oxidative damage.

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.

Antimuscarinic Drugs: Review of the Cognitive Impact When Used to Treat Overactive Bladder in Elderly Patients

The blockade of muscarinic receptors in the management of overactive bladder (OAB) symptoms provides beneficial as well as adverse effects. The cognitive changes observed are caused by the drugs' ability to cross the blood-brain barrier and bind to muscarinic receptors within the central nervous system (CNS). To date, while not specifically testing for CNS side effects, most of the controlled efficacy trials of multiple OAB medications have not shown significant adverse effects on cognitive function. However, elderly individuals, in whom OAB is more prevalent, often are excluded from these studies. The few trials that have performed cognitive testing in healthy elderly people taking antimuscarinics have clearly shown that oxybutynin can adversely affect cognition. Darifenacin, trospium, solifenacin, and tolterodine appear to have little to no risk of causing CNS side effects in this population. However, caution needs to be used in elderly patients with preexisting dementia.