Current Drug Metabolism - Volume 19, Issue 8, 2018

Background: Antidepressants have been widely prescribed for depression, anxiety, sleep disorders, and in the management of behavioural symptoms of adult-old patients. Although generally safe, newer generation antidepressants are not devoid of the risk of inducing clinically relevant adverse events. Objectives: To investigate the association between newer generation antidepressants and the occurrence of cardiovascular adverse events and electrocardiogram (ECG) abnormalities. Method: Studies were included in the review according to the following criteria: a) clinical trials (placebo-controlled or not) or case reports; b) short- or long-term interventions with antidepressants; c) prescription of newer generation antidepressants as first-line treatment; d) samples of adult or adult-old patients. From a total of 301 articles addressing the association between antidepressants and cardiovascular adverse events as primary or secondary outcomes, we selected 30 controlled clinical trials and 10 case reports. Results: In most clinical studies, the effects of antidepressants on cardiac function are usually computed as secondary outcome variables, however with limited information. Conversely, case reports tend to present more comprehensive sets of clinical and laboratorial parameters, but the generalization of such data is limited by the small number of observations. The occurrence of QTc prolongation (with increased risk of torsade de pointes) has been reported. Aging, higher dosages of antidepressants, drug interaction, and pre-existing cardiovascular comorbidities were found as risk factors for the aforementioned cardiovascular and ECG abnormalities. Conclusion: Prescribing antidepressants requires caution given their potential impact on cardiac function, and the clinician should carefully monitor cardiovascular and ECG parameters particularly in cases with underlying heart disease.

Background: The incidence and mortality rates of cancer in patients with Bipolar Disorder (BD) is higher compared with the general population. The role of Lithium (Li) in cancer proliferation/inhibition is still a controversial issue in the literature. Objective: Based on a clinical case with lithium intake and development of a renal tumor, we aimed to explore the relationship between Li use and tumor proliferation, with regard to the mechanism of action of Li. Method: We present evidence of a female patient with bipolar disorder I, who had been on Li for several years, either as monotherapy or in combination with Valproate (VPA). While on Li monotherapy, the patient had undergone unilateral nephrectomy due to a chromophobe cell renal tumor. A literature search was performed using keywords bipolar disorder, medical comorbidity, cancer, renal tumor, lithium, mood stabilizers, valproate and mechanism of action. Results: The limited data on the relationship between Li and cancer proliferation in clinical populations support neither a positive relationship between long-term Li use and increased urinary tract cancers nor an overall cancer risk. Growing evidence identifies effects of Li on cancer proliferation through inhibition of glycogen synthase kinase-3β (GSK-3β), modulations of redox status, inflammatory changes, pro-/anti-apoptotic mechanisms, and mitochondrial function changes. Conclusion: Despite the presence of contradictory data, a substantial body of evidence mainly from molecular studies points to Li's anti-carcinogenic effects. However, the underlying mechanistic pathways remain unclear. Mitochondrial dysfunction and redox modulations are potential areas for research on the relationship between Li and cancer proliferation.

Background: Bipolar disorder (BD) is a debilitating mental ailment characterized by recurrent episodes of mania and depression. Primary mood-stabilizing drugs like lithium and valproate alleviate the hypomanic or mild to moderate manic episodes in patients with BD. One of the extensively studied underlying mechanisms for these pharmacological interventions is inhibition of intracellular signaling cascades associated with glycogen synthase kinase-3 beta (GSK-3β), a multi-functional serine-threonine kinase. Objective and Method: To summarize the different mechanistic aspects associated with GSK-3β signaling involved in the pathophysiology of BD and highlights drug discovery approaches pursued for the development of GSK-3β inhibition with detailed strength, weakness, opportunity, and threat (SWOT) analysis. In this review, we endeavor to establish the correlation between neuronal GSK-3β inhibition and anti-manic response of different therapeutics used for the treatment of patients with BD. Results: The gene depletion or pharmacological inhibition of GSK-3β reproduces some of the behavioral effects of lithium including reduction of depression- and manic-like behaviors in rodents, which attested the intracellular GSK- 3β inhibition as one of the critical steps in mediating behavioral effect of mood-stabilizers. Furthermore, converging evidence supported the participation of GSK-3β in the regulation of various neurobehavioral functions governed by neurotransmitters dopamine and serotonin. Apart from its crucial involvement in the mechanism of action of mood stabilizers, GSK-3β signaling pathways have also received attention for their role in the effects of psychoactive therapies like antidepressants, antipsychotics, and neurotrophic factors. Conclusion: We anticipate that the GSK-3β could be a druggable target for several incurable neuropsychiatric disorders including BD.

Background: Cardiovascular disease (CVD) and depression are extremely prevalent and debilitating conditions. Evidence suggest that there is a two-way relationship between depression and CVD. Inflammation is implicated in the pathophysiology of both conditions, thus representing a central candidate mediating the link between these disorders. Depression is consistently associated with increased inflammation and increased blood levels of inflammatory molecules. In recent years, studies have shown that depression significantly increases the risk of developing inflammatory-related diseases such as CVD, precipitated by the same inflammatory pathways involved in the pathophysiology of CVD. Objective and Method: The aim of this work is to discuss the role of inflammation in depression and CVD and review the evidence of the benefits and side effects of anti-inflammatory drugs in both the diseases. Results: Drugs with anti-inflammatory properties have shown benefit in alleviating signs and symptoms in CVD and in depression. This was shown to be particularly true for the following classes of drugs: non-steroidal antiinflammatory drugs (NSAIDS), polyunsaturated fatty acids (PUFAs) statins and cytokine inhibitors. Finally, antidepressant drugs initially used exclusively to treat depression also lead to improvement in CVD indicators, while lowering inflammation markers in patients at the same time. This evidence further strengthens the suggestion of the biological link between depression and CVD through inflammation. Conclusion: Strategies that can mitigate this risk profile are highly needed in the clinical setting, and these particular groups of drugs have the possibility of becoming increasingly important in treatment strategies aiming to improve both the conditions.

Background: The etiopathogenesis of psychiatric disorders is still not completely understood. Growing evidence supports the hypothesis that mental illness and related disturbances do not necessarily originate in the brain. Inflammation has been suggested to play a central role in psychiatric disorders and altered levels of peripheral cytokines have been reported in several studies. Recently, it has emerged that bacteria populating the human gut could modulate low-grade inflammation, as well as high-order brain functions, including mood and behavior. These bacteria constitute the microbiota, a large population comprising 40,000 bacterial species and 1,800 phila involved in key processes important to maintain body homeostasis. Method: In this review, we present and discuss studies exploring the role of dysbiosis and products of the gutmicrobiota in the pathogenesis of psychiatric disorders, as well as their potential involvement in mediating the effect of antidepressants, mood stabilizers, and antipsychotics. Results: Although this field is still at its early stage of development, a growing number of studies suggest that an altered composition of the gut microbiota, together with translocation of bacterial products into the systemic circulation, might play a role in the pathogenesis of psychiatric disorders as well as in response to psychotropic medications. Conclusion: An altered composition and functioning of gut microbiota have been reported in psychiatric disorders, and recent findings suggest that gut bacteria could be involved in modulating the efficacy of psychotropic medications.

Background: Streptococcus pyogenes, a major human pathogen, causes a wide variety of invasive systemic infections such as acute pharyngitis, skin and soft-tissue infections, especially necrotizing fasciitis. Objective: This review focuses on the properties of pathogenicity of S. pyogenes and outlines ways to combat infection caused by these bacteria through alternative plant-based medicine. Conclusion: This Gram positive bacterium has an ability to form mature biofilm and this sessile life style plays an important role in S. pyogenes pathogenicity. The virulence of these bacteria is further strengthened by its ability to communicate within the micro-colonies through quorum sensing. Most treatments are now aimed at either elimination of this bacterium or suppression of its virulence. The emergence of antibiotic resistance among S. pyogenes and treatment failure has become an added concern globally. One of its virulence properties, biofilm formation, has made it more resistant to antibiotic therapy. This has vitalized the necessity for searching alternative therapies for its treatment. The growing research in herbal medicines has led to the discovery of various phytochemicals to limit the virulence of S. pyogenes.

Background: Alzheimer's disease (AD) is recognized as progressive multifaceted and multi-factorial neurodegenerative disorder which causes dementia among elderly people. Although, researchers in this field have put considerable efforts for the investigation of novel and appropriate therapeutic measures towards the cure of AD, unfortunately, no effective prevention therapy for this disease is available till date. In fact, various aspects involved in the onset and progression of AD are still disputed or uncovered. However, to achieve definite and direct cure of AD, researcher's attention has been drawn towards exploration of new therapeutics targets. In this review, we have discussed the current progress of various aspects of pathophysiological mechanisms behind AD, together with recent investigational therapeutic approaches and present tools with an emphasis on Multi Target Directed Drugs approach. Method: We have scrutinized numerous peer-reviewed research articles to assemble and discuss significant research findings and success achieved in the last decade pertinent to the application of Multi-Target Directed Drugs in the treatment of AD. Results: The main emphasis of the review was to understand the various aspects of pathophysiological mechanisms involved in AD, along with the recent developments on potential AD targets and application of Multi-Target Directed Drugs approach against AD. In addition, a brief overview of major drawbacks of conventional anti-AD drugs has also been included. We found that several strategies including in silico approach could be used for multi-target drug designing against AD. However, various synthetic/natural compounds and nano-formulations have the ability to be developed as multi-target drugs for AD. Conclusion: The present review comprises imperative information regarding AD pathology and disease process along with recent researches going on to develop treatment strategies against AD. Thus, this review might be helpful for physician, neurologist and scientist in understanding the diverse roots of AD for designing primary cure skills and scaffold of pharmacological treatment to manage AD.

Background: Peptide toxins are naturally occurring rich sources of highly specific bioactive compounds from venomous animals acting on various types of ion channels. Objective: This study mainly highlights targeting of one of the largest families of ion channels i.e. potassium channels via venom toxins. Method: Data for reported venom toxins from diverse species is gathered and analyzed at sequence and structural extent. Results: The similarities and differences among toxins have been demonstrated along with structure activity relationship of potassium channels with these toxins. Conclusion: This review highlights the importance of functionally important residues and structural scaffolds of venoms interacting with potassium channels.