Table of Contents

Abstract: The HDAC inhibitors are a new family of antineoplastic agents. Since the entry of these agents into our therapeutic armamentarium, there has been increasing interest in their use. Although this family comprises chemical compounds from unrelated chemical classes that have different HDAC isoform specificities, they surprisingly have very similar toxicity profiles. In contrast, the observed toxicity profile is somewhat different from that of traditional cytotoxic chemotherapeutic agents and from other epigenetic agents. While some of the side effects may be familiar to the oncologist, others are less commonly seen. As some patients remain on therapy for a prolonged period of time, the long-term sequelae need to be characterized. In addition, since preclinical models suggest promising activity when used in combination with other antineoplastic agents, combination trials are being pursued. It will thus be important to distinguish the relative toxicity attributed to these agents and be alert to the exacerbation of toxicities observed in single agent studies. Notably, few of the agents in this class have completed phase 2 testing. Consequently, more clinical experience is needed to determine the relative frequency of the observed side effects, and to identify and develop approaches to mitigate potential clinical sequelae.

Abstract: We are normally unaware of the complex signalling events which continuously occur within our internal organs. Most of us only become cognisant when sensations of hunger, fullness, urgency or gas arise. However, for patients with organic and functional bowel disorders pain is an unpleasant and often debilitating reminder. Furthermore, chronic pain still represents a large unmet need for clinical treatment. Consequently, chronic pain has a considerable economic impact on health care systems and the afflicted individuals. In order to address this need we must understand how symptoms are generated within the gut, the molecular pathways responsible for generating these signals and how this process changes in disease states.

Abstract: Cogent evidence shows that cannabis plays a variable role on behavioral regulation and the pathophysiology of most psychiatric conditions. Accordingly, cannabis has been alternatively shown to exacerbate or ameliorate mental symptoms, depending on its composition and route of consumption, as well as specific individual and contextual characteristics. The vulnerability to the psychological effects of cannabis is influenced by a complex constellation of genetic and environmental factors. In the present article, we will review the current evidence on the pharmacological, individual and situational factors that have been documented to affect the behavioral and psychiatric effects of cannabinoids.

Abstract: Melanoma remains one of the cancers for which a decline in morbidity has not been achieved with current scientific and medical advances. Mono-therapies targeting melanoma have been largely ineffective, increasing the need for identification of new drugable targets. Multiple tumor suppressors and oncogenes that impart genetic predisposition to melanoma have been identified and are being studied in an attempt to provide insight on the development of anti-melanoma therapies. Metabotropic Glutamate Receptor I (GRM1) has recently been implicated as a novel oncogene involved in melanomagenesis. GRM1 (mGlu₁, protein) belongs to the G protein coupled receptor (GPCR) super family and is normally functional in the central nervous system. Our group showed in a transgenic mouse model system that ectopic expression of Grm1 in melanocytes is sufficient to induce spontaneous melanoma development in vivo. GPCRs are some of the most important therapeutic drug targets discovered to date and they make up a significant proportion of existing therapies. This super family of transmembrane receptors has wide spread expression and interacts with a diverse array of ligands. Diverse physiological responses can be induced by stimulator(s) or suppressor(s) of GPCRs, which contributes to their attractiveness in existing and emerging therapies. GPCR targeting therapies are employed against a variety of human disorders including those of the central nervous system, cardiovascular, metabolic, urogenital and respiratory systems. In the current review, we will discuss how the identification of the oncogenic properties of GRM1 opens up new strategies for the design of potential novel therapies for the treatment of melanoma.

Abstract: An allosteric modulator is a ligand that binds to an allosteric site on the receptor and changes receptor conformation to produce increase (positive cooperativity) or decrease (negative cooperativity) in the binding or action of an orthosteric agonist (e.g., acetylcholine). Since the identification of gallamine as the first allosteric modulator of muscarinic receptors in 1976, this unique mode of receptor modulation has been intensively studied by many groups. This review summarizes over 30 years of research on the molecular mechanisms of allosteric interactions of drugs with the receptor and for new allosteric modulators of muscarinic receptors with potential therapeutic use. Identification of positive modulators of acetylcholine binding and function that enhance neurotransmission and the discovery of highly selective allosteric modulators are mile-stones on the way to novel therapeutic agents for the treatment of schizophrenia, Alzheimer’s disease and other disorders involving impaired cognitive function.

Abstract: The annual worldwide suicide rate currently averages approximately 13 per 100,000 individuals per year (0.013% per year), with higher average rates for men than for women in all but a few countries, very low rates in children, and relatively high rates in elderly men. Suicide rates vary markedly between countries, reflecting in part differences in case-identification and reporting procedures. Rates of attempted suicide in the general population average 20–30 times higher than rates of completed suicide, but are probably under-reported. Research on the relationship between pharmacotherapy and suicidal behavior was rare until a decade ago. Most ecological studies and large clinical studies have found that a general reduction in suicide rates is significantly correlated with higher rates of prescribing modern antidepressants. However, ecological, cohort and case-control studies and data from brief, randomized, controlled trials in patients with acute affective disorders have found increases, particularly in young patients and particularly for the risk of suicide attempts, as well as increases in suicidal ideation in young patients. whether antidepressants are associated with specific aspects of suicidality (e.g., higher rates of completed suicide, attempted suicide and suicidal ideation) in younger patients with major affective disorders remains a highly controversial question. In light of this gap this paper analyzes research on the relationship between suicidality and antidepressant treatment.

Abstract: Current marketed antiepileptic drugs (AEDs) consist of a variety of structural classes with different mechanisms of action. These agents typically have non-overlapping efficacy and side-effect profiles presenting multiple treatment options for the patient population. However, approximately 30% of seizure sufferers fail to respond to current therapies often because poorly tolerated side-effects limit adequate dosing. The scope of this review is to summarize selected advances in 2^nd and 3^rd generation AEDs as well as compounds in development with novel mechanisms of action.

Abstract: The essential oil of the aerial part (leaves, flowers and stem) of Chenopodium ambrosioides was obtained by hydrodistillation and its chemical composition analyzed by GC and GC/MS, which permitted the identification of 14 components, representing 98.8% of the total oil. Major components were α-terpinene (51.3%), p-cymene (23.4%) and p-mentha-1,8-diène (15.3%). The antifungal properties of this essential oil were investigated in vitro by the well diffusion and broth microdilution methods. The in vitro antifungal activity was concentration dependent and minimum inhibitory concentration values varied from 0.25 to 2 mg/mL. The in vivo antifungal activity was evaluated on an induced vaginal candidiasis rat model. The in vivo activity of the oil on mice vaginal candidiasis was not dose-dependent. Indeed, all the three tested doses; 0.1%, 1% and 10% led to the recovery of mice from the induced infection after 12 days of treatment. The effect of the essential oil on C. albicans ATCC 1663 fatty acid profile was studied. This oil has a relatively important dose-dependent effect on the fatty acids profile.

Abstract: There is an increasing recognition that the endocannabinoid system is the crucial cytokine-hormone system regulating early human pregnancy. The synchronous development of the fertilized embryo and the endometrium to ensure timely implantation has been shown to be one of the pivotal steps to successful implantation. This development is thought to be regulated by a finely balanced relationship between various components of the endocannabinoid system in the endometrium, the embryo and the Fallopian tube. In addition, this system has also been shown to be involved in the regulation of the development and maturation of the gametes prior to fertilization. In this review, we will examine the evidence from animal and human studies to support the role of the endocannabinoid system in gametogenesis, fertilization, implantation, early pregnancy maintenance, and in immunomodulation of pregnancy. We will discuss the role of the cannabinoid receptors and the enzymes involved in the synthesis and degradation of the key endocannabinoid ligands (e.g., anandamide and 2-arachinoylglycerol) in early reproduction.

Abstract: Chemotherapy-induced nausea and vomiting (CINV) is a complex pathophysiological condition and consists of two phases. The conventional CINV neurotransmitter hypothesis suggests that the immediate phase is mainly due to release of serotonin (5-HT) from the enterochromaffin cells in the gastrointestinal tract (GIT), while the delayed phase is a consequence of release of substance P (SP) in the brainstem. However, more recent findings argue against this simplistic neurotransmitter and anatomical view of CINV. Revision of the hypothesis advocates a more complex, differential and overlapping involvement of several emetic neurotransmitters/modulators (e.g. dopamine, serotonin, substance P, prostaglandins and related arachidonic acid derived metabolites) in both phases of emesis occurring concomitantly in the brainstem and in the GIT enteric nervous system (ENS) [1]. No single antiemetic is currently available to completely prevent both phases of CINV. The standard antiemetic regimens include a 5-HT₃ antagonist plus dexamethasone for the prevention of acute emetic phase, combined with an NK₁ receptor antagonist (e.g. aprepitant) for the delayed phase. Although NK₁ antagonists behave in animals as broad-spectrum antiemetics against different emetogens including cisplatin-induced acute and delayed vomiting, by themselves they are not very effective against CINV in cancer patients. Cannabinoids such as D⁹-THC also behave as broad-spectrum antiemetics against diverse emetic stimuli as well as being effective against both phases of CINV in animals and patients. Potential side effects may limit the clinical utility of direct-acting cannabinoid agonists which could be avoided by the use of corresponding indirect-acting agonists. Cannabinoids (both phyto-derived and synthetic) behave as agonist antiemetics via the activation of cannabinoid CB₁ receptors in both the brainstem and the ENS emetic loci. An endocannabinoid antiemetic tone may exist since inverse CB₁ agonists (but not the corresponding silent antagonists) cause nausea and vomiting.

Abstract: Conversion between anti-epilectic drugs (AEDs) is frequently necessary in epilepsy care, exposing patients to a risk of incurring adverse effects and reduced quality of life. Little practical guidance is available to practitioners to guide conversions between AED monotherapies, or in adding a new adjunctive AED into a polytherapy regimen. This article reviews the impact of adverse effects of AEDs on quality of life in epilepsy patients, then reviews several important patient-related factors such as age, gender, medical and psychiatric co-morbidities, and co-medications that must be considered when selecting AEDs and ensuring tolerable and safe AED conversions. Practical strategies for transitional polytherapy AED conversion are then considered in different commonly encountered clinical scenarios in newly diagnosed and refractory epilepsy care, including inadequate seizure control, intolerable adverse effects, or idiosyncratic safety hazards. Successful conversion between AEDs requires regular monitoring for patient-reported adverse effects and appropriately reactive adjustment of AED therapy to maximize patient quality of life.

Abstract: This review discusses the role of the cannabinoid system in cartilage tissue and endeavors to establish if targeting the cannabinoid system has potential in mesenchymal stem cell based tissue-engineered cartilage repair strategies. The review discusses the potential of cannabinoids to protect against the degradation of cartilage in inflamed arthritic joints and the influence of cannabinoids on the chondrocyte precursors, mesenchymal stem cells (MSCs). We provide experimental evidence to show that activation of the cannabinoid system enhances the survival, migration and chondrogenic differentiation of MSCs, which are three major tenets behind the success of a cell-based tissue-engineered cartilage repair strategy. These findings highlight the potential for cannabinoids to provide a dual function by acting as anti-inflammatory agents as well as regulators of MSC biology in order to enhance tissue engineering strategies aimed at cartilage repair.

Abstract: Aggressive symptomatology presents across multiple psychiatric, developmental, neurological and behavioral disorders, complicating the diagnosis and treatment of the underlying pathology. Anti-Epileptic Drugs (AEDs) have become an appealing alternative in the treatment of aggression, mood lability and impulsivity in adult and pediatric populations, although few controlled trials have explored their efficacy in treating pediatric populations. This review of the literature synthesizes the available data on ten AEDs – valproate, carbamazepine, oxcarbazepine, phenytoin, lamotrigine, topiramate, levetiracetam, zonisamide, gabapentin and tiagabine – in an attempt to assess evidence for the efficacy of AEDs in the treatment of aggression in pediatric populations. Our review revealed modest evidence that some of the AEDs produced improvement in pediatric aggression, but controlled trials in pediatric bipolar disorder have not been promising. Valproate is the best supported AED for aggression and should be considered as a first line of treatment. When monotherapy is insufficient, combining an AED with either lithium or an atypical anti-psychotic can result in better efficacy. Additionally, our review indicates that medications with predominately GABA-ergic mechanisms of action are not effective in treating aggression, and medications which decrease glutaminergic transmission tended to have more cognitive adverse effects. Agents with multiple mechanisms of action may be more effective.

Abstract: Type 2 diabetes is a syndrome characterized by relative insulin deficiency, insulin resistance and increased hepatic glucose output. Medications used to treat the disease are designed to correct one or more of these metabolic abnormalities. Current recommendations of the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) include diet and exercise as first-line therapy plus hypoglycemic drugs. Actually there are seven distinct classes of anti-hyperglicemic agents, each of them displaying unique pharmacologic properties. The aim of this review is to describe the pathophysiological basis of their mechanism of action, a necessary step to individualize treatment of diabetic people, taking into proper consideration potential benefits and secondary effects of drugs.