Current Clinical Pharmacology - Volume 10, Issue 2, 2015

Introduction: Generalized anxiety disorder (GAD) is a prevalent and very disabling anxiety disorder. First-line medications are antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and noradrenalin reuptake inhibitors (SNRIs). However, a substantial number of patients do not reach remission while on antidepressants and they may develop troublesome side effects, which highlights the necessity of new therapeutic options for GAD. Methods: The purpose of this review is to discuss all non-antidepressant treatments studied in GAD. We searched MedLine for English articles published between 1980 and 2012, containing the following keywords: “generalized (or generalised) anxiety disorder” OR “anxiety disorder”, AND “drug therapy” OR “herbal medicine”. 76 articles were finally selected. Results: Pregabalin is the anticonvulsant with the most robust level of evidence in GAD. It rapidly reduces anxiety, has a safe side effect profile and presents a low potential for abuse. Among antipsychotics, quetiapine is the one of choice in GAD, with similar efficacy to SSRIs in low dosages, yet with lower overall tolerability. Benzodiazepines, buspirone and hydroxyzine are Food and Drugs administration (FDA) approved for GAD and have relatively good evidence of efficacy. Other drugs (betablockers, zolpidem, riluzole, etc.) and natural remedies (e.g. Piper methysticum) could be potential treatment options, yet additional research is warranted. Conclusion: Pregabalin and quetiapine are the two most promising non-antidepressant treatments for GAD.

Introduction: Obsessive-compulsive disorder (OCD) is associated with significant morbidity and dysfunction. First-line OCD treatments - serotonin reuptake inhibitors (SRIs), cognitive behavioral therapy (CBT) and their combination - though widely used, are not sufficient in treating resistant cases. This eventually raises the need for finding novel strategies, whether by adding-on drugs or switching to a different psychopharmacological class. The aim of this paper is to present a comprehensive review of non-antidepressant pharmacological treatment that has been evaluated for the management of OCD. Materials and methods: A research has been conducted using MedLine and the following Medical Subject Headings (MeSH) terms were used: Obsessive compulsive disorder AND drug therapy. Articles that conformed to specific inclusion criteria were stratified per drug and per quality of evidence. For each drug, articles having the best level of evidence were retained. Results: Sixty-eight articles were reviewed and presented by drug class as follows: antipsychotics, mood stabilizers, gamma-amino-butyric acid (GABA) analogues and GABA reuptake inhibitors, benzodiazepines, glutamatergic agents and other miscellaneous drugs. Discussion: There is substantial collective evidence supporting the use of antipsychotics as an augmentation treatment of resistant OCD patients. Although not always consistent, the following drugs showed some efficacy upon randomized controlled trials: risperidone, olanzapine, quetiapine, aripiprazole, haloperidol, topiramate, pindolol, morphine, ondansetron and celecoxib. The efficacy of glutamatergic agents is promising. Numerous other pharmacological agents have been studied yet the results are inconclusive due to several limitations mainly of methodological nature.

Introduction: Panic disorder (PD) is a common anxiety disorder. Despite neurophysiological advances, its pathogenesis is still not well elucidated. Although the recommended pharmacological agents have demonstrated efficacy and a rather acceptable tolerability, yet many patients do not respond fully and still suffer from residual symptoms. There is a need for new pharmacological classes with better tolerability and efficacy, and faster onset of action. The purpose of this review is to illustrate the existing non-antidepressant treatment of PD as well as the recent advances in the treatment of PD. Methods: 38 articles discussing pharmacological treatment of PD were selected for this review. They were mainly openlabel studies, case-reports and review articles. Results: We reviewed the studies on anticonvulsants, benzodiazepines, gamma amino butyric acid (GABAergic) products, atypical antipsychotics, clonidine, as well as emerging drugs in the treatment of PD such as metabotropic glutamate II agonists, and D-cycloserine. Conclusion: Although most of the drugs tested were proven effective and well tolerated, the studies on the nonconventional agents are restricted to open-label trials and case reports. Further studies are required to establish their efficacy and tolerability in the treatment of panic disorder.

Introduction: Post-traumatic stress disorder (PTSD) is a frequent and disabling condition that occurs after exposure to a traumatic event, and Selective Serotonin Reuptake Inhibitors (SSRIs) are considered the first-line treatment approach for this disorder. However, a large proportion of patients remain symptomatic and other pharmacological agents have been investigated, based on the understanding of the underlying biological dysfunctions of PTSD. Methods: We conducted a review of the literature on the pharmacological options for PTSD other than the antidepressants, using MedLine and Web of Science databases, with search terms including the pharmacologic class of each agent plus PTSD, or pharmacotherapy, or fear conditioning. The literature review covered articles published until august 2012, including reviews and original articles. Results: Agents like antipsychotics, anticonvulsants, benzodiazepines, anti-adrenergic agents, have been studied in randomized clinical trials (RCTs), with general positive results for antipsychotics, especially as adjunct therapy, and for prazosin for sleep-related disturbances. However, one important target for novel medications is the modulation of the fear conditioning process, through the alteration of retrieval/reconsolidation or enhancement of fear extinction. This is traditionally targeted in prolonged exposure therapy, but pre-clinical findings from studies investigating agents like propanolol, clonidine, N-Methyl-D-aspartic Acid Receptor (NMDAR) compounds, 3,4-methylenedioxy-N-methylamphetamine (MDMA) and cannabinoids, indicate promising results in affecting the fear conditioning process and thus improving PTSD core symptoms. Discussion: Antipsychotics can be considered a reasonable alternative option to PTSD, with the largest body of evidence for risperidone, even though larger RCTs are warranted. Prazosin is also a promising agent, especially for sleep-related disturbances, while anticonvulsants and benzodiazepines lack empirical support. However, the most promising area for pharmacotherapy in PTSD is the modulation of the fear conditioning process, through agents used in adjunct to exposure therapy.

Social anxiety disorder is a debilitating mental illness with eventually serious comorbidities such as major depression and alcohol or substance abuse and dependence. Those comorbidities are much more common when social phobia is left neglected and untreated. It is characterized by excessive fears to one or most social situations (circumscribed versus generalized type). Social phobia has its onset typically in childhood or early adolescence and it is associated with significant functional impairment. Although cognitive behavioral therapy and the selective serotonin reuptake inhibitors are considered the mainstay treatment of this disorder, other psychotropic agents can be of value in the management of this condition. This review discusses the efficacy of beta-bockers, benzodiazepines, anticonvulsants, D-cycloserine, buspirone and atypical antipsychotics in the treatment of social anxiety disorder.

Specific phobias are among the most frequently diagnosed disorders in community with a twelve-month prevalence of 8.7% and a lifetime prevalence of 12.5%. Exposure-based therapies constitute the most effective treatment for this type of anxiety disorders. However, pharmacotherapies can still be considered for patients suffering from specific phobias in case they were non-adherent or resistant to exposure-based therapies or in case this kind of therapies was not accessible for them. Few data support the use of antidepressant in the treatment of specific phobias. A literature search via MedLine has been done in order to review all available studies in the domain of nonantidepressant pharmacotherapy of specific phobias. The importance of benzodiazepines such as diazepam, alprazolam and midazolam resides in the short-term reduction of subjective selfreported fear during the exposure to the feared object or situation. General anesthesia for the treatment of dental phobia does not seem to be efficient unless conducted with the inhalation anesthetic nitrous oxide which seems to be efficient on the short and on the long-term. Beta-adrenergic antagonists have been essayed with conflicting results. Cognitive enhancers such as D-cycloserine, glucocorticoids and yohimbine hydrochloride, seem to be more effective than placebo after a short term period of follow-up in treating specific phobia sympotms. In conclusion, promising efficient pharmacotherapies for specific phobias consists of drugs that enhance the efficacy of exposure-based therapies sessions by reducing anticipating phobia-related fear and/or by enhancing cognition during these sessions.

Tuberculosis (TB), a 19th century disease, is still present in the beginning of the Third Millennium. It has been considered pandemic, since around two billion people are infected with M. tuberculosis. Multi-drug resistant TB has been the biggest challenge for chemotherapy. In order to face this severe health problem, many institutions, private and public ones, have been investing in the search for new and better drug candidates. The pipeline of potential anti-TB drugs presents new molecules and formulations that have been submitted to pre-clinical and clinical assays. Medicinal Chemistry has an important role towards the objective of finding new leads through classic and modern processes. This paper reviews some aspects of this search, emphasizing the features of the main compounds under investigation and those that are in preliminary and final clinical trials and includes the contribution of our laboratory (LAPEN) in the area of designing new anti-TB drug candidates.

The effects of tofisopam, a GABA-receptor agonist, following oral administration (300mg) with and without allopurinol pretreatment on the plasma concentration and renal transport of uric acid and oxypurinol were investigated in 5 healthy subjects. Fractional and urinary excretions of uric acid were both significantly increased at 2-3 hours after tofisopam administration (559% and 459%, respectively), while plasma uric acid concentration was significantly decreased (36%) at 2.5 hours, suggesting that tofisopam affects uric acid metabolism via the tubular transport system. The hypouricemic effect of tofisopam was comparable to or greater than that of losartan and/or fenofibrate, which also have uric acid-lowering activity. In addition, with prior administration of allopurinol, the fractional and urinary excretions of oxypurinol were increased at 2-3 hours after tofisopam administration (51% and 33%, respectively), while the plasma oxypurinol concentration was significantly decreased at 1.5 and 2.5 hours (15% and 21%, respectively). Accordingly, tofisopam may be an attractive compound for treatment of hyperuricemia and/or gout, especially in patients complicated with autonomic dysfunction symptoms, though it is possible that the uric acid-lowering effect of oxypurinol is attenuated by tofisopam.