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Mexazolam: Clinical Efficacy and Tolerability in the Treatment of Anxiety

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Mexazolam: Clinical Efficacy and Tolerability in the Treatment of Anxiety Neurol Ther DOI 10.1007/s40120-014-0016-7 REVIEW Mexazolam: Clinical Efficacy and Tolerability in the Treatment of Anxiety He´lder Fernandes • Ricardo Moreira To view enhanced content go to www.neurologytherapy-open.com Received: March 13, 2014 Ó The Author(s) 2014. This article is published with open access at Springerlink.com ABSTRACT published manuscripts of interest known by the authors (not indexed on PubMed) have been Introduction: Mexazolam is indicated for the added for completeness. Relevant information management of anxiety with or without was selected for inclusion by the authors. psychoneurotic conditions. In adult patients, Results: A number of early studies the recommended daily dosage of mexazolam is demonstrated the ability of mexazolam to 1–3 mg, administered three times daily. The reduce anxiety symptoms with few side effects objective of this article is to review the available in patients with disorders associated with information on the benzodiazepine (BZD) anxiety. Following on from this preliminary mexazolam and its clinical utility in treating evidence, controlled studies directly comparing patients with anxiety. mexazolam with other BZDs showed that the Methods: The PubMed database was searched drug is more effective than bromazepam and using the keyword ‘‘mexazolam’’ with no date or oxazolam, and is at least as effective as language restrictions applied to the search. As alprazolam. A larger, multicenter, phase IV only 11 papers were retrieved, some previously study also showed that mexazolam 2 or 3 mg/ Electronic supplementary material The online day rapidly improved Hamilton Anxiety Rating version of this article (doi:10.1007/s40120-014-0016-7) Scale scores and substantially reduced the contains supplementary material, which is available to authorized users. frequency and severity of numerous somatic anxiety symptoms in patients with anxiety H. Fernandes (&) disorders. With regard to safety, the clinical Department of Research and Development, Bial- Portela & Ca, S.A, S. Mamede do Coronado, Portugal evidence indicates that mexazolam is generally e-mail: [email protected] well tolerated, with a low incidence of R. Moreira drowsiness and sedation. Furthermore, the Clinic of Psychiatry and Mental Health, Sa˜o Joa˜o lack of psychomotor or cognitive performance Hospital Centre, Porto, Portugal impairment following mexazolam R. Moreira administration may lead to better treatment Department of Clinical Neurosciences and Mental Health, Faculty of Medicine, University of Porto, compliance. Porto, Portugal Neurol Ther Conclusion: The available clinical evidence Following an accurate diagnosis, the suggests that mexazolam is an effective recommended treatment options for anxiety therapeutic option for the management of disorders include psychotherapies and anxiety. However, larger, well-controlled pharmacological therapies [6–8]. clinical trials are needed to directly compare Benzodiazepines (BZDs) are a class of drugs and contrast mexazolam’s efficacy and safety that bind to specific BZD-type receptors on the with other BZDs. gamma-aminobutyric acid (GABA) chloride ion complex and facilitate GABA inhibitory effects Keywords: Anxiety; Benzodiazepine; Efficacy; [9, 10]. Although BZDs are not generally Mexazolam; Psychiatry; Psychomotor and recommended for first-line, long-term cognitive performance; Tolerability management of anxiety disorders in clinical practice, their use as second-line treatment is INTRODUCTION widespread [11]. In 1956, Dr. Leo Sternbach discovered the Epidemiological research has indicated that first BZD, chlordiazepoxide (approved in 1960), anxiety disorders are among the most which was followed by the release of its common psychiatric disorders in the United congener, diazepam, in 1963 [11]. Since the States [1–3]. Furthermore, data from a World release of chlordiazepoxide and diazepam, more Health Organization World Mental Health than 1,000 BZDs have been synthesized. [11]. survey reported anxiety disorders to be the More recently, four non-BZD hypnotics most common mental disorder (estimated (zaleplon, zolpidem, zopiclone, and lifetime prevalence of 4.8–31.0%) in numerous eszopiclone), also known as the so-called countries across Africa, Asia, the Americas, z-drugs, were introduced. Although these Europe, and the Middle East [4]. compounds are effective for the initial The most commonly occurring anxiety treatment of insomnia, their clinical effects are disorders include generalized anxiety disorder, not sustained through the night [11]. panic attacks, panic disorder, specific phobia, Today, there are a wide range of BZDs social anxiety disorder, agoraphobia, trauma- available for use in clinical practice. Despite and stressor-related disorders, obsessive– sharing the same mechanism of action, they compulsive and related disorders, separation vary in their duration of action (short- vs. long- anxiety disorder, and illness anxiety disorder acting) and difference in pharmacokinetic [5]. These disorders are marked by excessive profiles translate, in clinical practice, into fear, anxiety, and associated avoidance differences in their main therapeutic effect behaviors, but are distinguished from each (anxiolytic vs. hypnotic) [11, 12]. BZDs with a other by the types of objects or situations that strong anxiolytic effect at therapeutic doses, induce the fear or avoidance. Anxiety disorders such as diazepam, are effective for the relief of are marked by persistence, rather than transient anxiety states, while BZDs with a predominant fear or anxiety, and tend to have their onset in hypnotic effect, such as flurazepam, are used for childhood or adolescence (Diagnostic and the short-term treatment of insomnia [11]. Statistical Manual of Mental Disorders BZDs such as clonazepam are also associated [DSM]-5) [5]. with anticonvulsant effects [13]. Neurol Ther In addition to their clinical effectiveness, the most relevant information (all preclinical one of the main advantages of BZDs in the and clinical data, determinant to the treatment of anxiety is their early onset of interpretation of the several characteristics of action [14], which may explain why these mexazolam discussed in the article, were agents continue to be widely prescribed. considered to be relevant information by the However, BZDs may be associated with a authors). No date or language restrictions were number of adverse effects, particularly at applied to the search. higher doses, which include sedation, physical The analysis in this article is based on and psychic dependence, and impaired previously conducted studies, and does not concentration, memory and psychomotor involve any new studies of human or animal performance [14]. Furthermore, withdrawal subjects performed by any of the authors. symptoms and rebound anxiety may be associated with the long-term use of these MEXAZOLAM agents [14]. The frequency and severity of these adverse events may also vary between Mexazolam (also known as CS-386) is currently BZDs. BZDs have also been linked to substance indicated for the management of anxiety with abuse/misuse and dependence when used long- or without psychoneurotic conditions when the term [15]. disorder is severe, disabling, or subjecting the With the current availability of a variety of individual to extreme distress [16]. The duration BZDs, clinicians are frequently faced with of treatment should be as short as possible and difficulties in choosing the most appropriate the dosage of mexazolam should be adjusted BZD for an individual patient. Therefore, it is based on an individual patient’s age and the important for clinicians to have a good severity of symptoms. In adults, the average understanding of the main characteristics and daily dose is 1–3 mg, which is preferably differences of these drugs. The BZD mexazolam, administered three times daily (TID); the daily although currently used in the treatment of dosage should not exceed 1.5 mg in elderly anxiety disorders, is not well known and clinical patients. Mexazolam is not indicated for use in publications are limited and so, in this context, pediatric patients [16]. the objective of this article is to review the available information on mexazolam and its Chemical Properties clinical utility in treating patients with anxiety. Mexazolam (10-chloro-11b-(2-chlorophenyl)-3- METHODS methyl-2,3,7,11b-tetrahydrobenzo[f] oxazolo[3,2- d] [1, 4] diazepin-6(5H)-one) is an anxiolytic The PubMed database was searched for articles oxazolo-BZD that is structurally similar to using the keyword ‘‘mexazolam’’. Only 11 oxazolam and cloxazolam [17]. results were retrieved. In order to ensure the review article was as comprehensive as possible, Pharmacokinetic Considerations some previously published manuscripts of interest known by the authors have been After the oral administration of mexazolam, its added. Subsequently, the authors have selected active metabolites chloronordiazepam (CND) Neurol Ther and chloroxazepam (COX), but not the and cloxazolam at improving performance in unaltered drug, are detected in the blood. conflict behavior or lever-pressing tests Mexazolam appears to be hydroxylated and (regarded as a measure of an antianxiety conjugated in the liver through two different effect) [21, 22]. Mexazolam was also shown to metabolic pathways (BZD-type [active inhibit megimide-induced convulsions in mice metabolites] and benzophenone-type [inactive [23]. In electrophysiological tests using cats, metabolites]) [16]. The time-to-peak plasma mexazolam showed a stronger action than
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