Current Pharmaceutical Design - Volume 22, Issue 7, 2016

Drug-induced photosensitivity of the skin is drawing increasing attention. In past few decades, photosensitivity has been reported with an array of drugs, and is now recognized as a noteworthy medical problem by clinicians, regulatory authorities and pharmaceutical industry. The photosensitivity is of two types i.e., phototoxicity and photoallergy. Phototoxic disorders have a high incidence, whereas photoallergic reactions are much less frequent in human population. Several hundred substances, chemicals, or drugs may invoke phototoxic and photoallergic reactions. In order to avoid photosensitive reactions, it is essential to understand the mechanism behind the photosensitizing properties of such substances before these drugs are introduced in clinical settings. Photosensitization is inter-related to photochemical reaction, through the knowledge of which the photosensitivity of a drug can be anticipated. This review highlights the current research status on photosensitizing drugs and its correlation to phototoxicity. Different mechanisms of photodegradation of photolabile drugs have also been discussed.

Obesity is rising to unprecedented numbers, affecting a growing number of children, adolescents and young adult men. These individuals face innumerous health problems, including subfertility or even infertility. Overweight and obese men present severe alterations in their body composition and hormonal profile, particularly in ghrelin, leptin and glucagon-like peptide-1 (GLP-1) levels. It is well known that male reproductive health is under the control of the individual’s nutritional status and also of a tight network of regulatory signals, particularly hormonal signaling. However, few studies have been focused on the effects of ghrelin, leptin and GLP-1 in male reproduction and how energy homeostasis and male reproductive function are linked. These hormones regulate body glucose homeostasis and several studies suggest that they can serve as targets for anti-obesity drugs. In recent years, our understanding of the mechanisms of action of these hormones has grown significantly. Curiously, their effect on male reproductive potential, that is highly dependent of the metabolic cooperation established between testicular cells, remains a matter of debate. Herein, we review general concepts of male fertility and obesity, with a special focus on the effects of ghrelin, leptin and GLP-1 on male reproductive health. We also discuss the possible pharmacological relevance of these hormones to counteract the fertility problems that overweight and obese men face.

Amphotericin B (AmB)-deoxycholate micellar formulation, Fungizone®, is the drug of choice for the treatment of unidentified mycotic infections. However, it usage has been marred by long therapeutic regimes and severe side effects. The less toxic lipid associated AmB formulations have been limited by their high expense, with some loss in activity. The quest for decreasing AmB cytotoxicity as well as production cost has resulted in the development of AmB super-aggregate as an alternative to its existing lipid formulations. AmB super-aggregate is spectroscopically distinct from the aggregate present in Fungizone, displaying enhanced thermodynamic stability. The poly-aggregated form of AmB exhibits reduced toxicity in mammalian cells in vitro and to mice in vivo, while maintaining its ‘gold standard’ antifungal activity. Poly-aggregated AmB interacts predominantly with serum albumin and also attenuates its ability to induce potentially harmful cytokines. Bio-distribution studies have demonstrated that the selfassociated AmB shows greater accumulation in reticulo-endothelial organs while sparing kidney, one of the principal organs where its toxic effects are seen. The super-aggregated AmB can thus be used to improve the therapeutic index of AmB against a plethora of fungal infections including candidiasis and cryptococcosis, thus providing a fitting solution to growing demand of an active, less toxic substitute of AmB.

Gastric cancer (GC) is the amongst the most common cancer types causing second largest number of cancer related deaths globally. GC is characterized as an aggressive malignancy which is very tough to be detected at an early stage. GC has been defined as a complex, multistep process involving multiple genetic and epigenetic alterations leading to aberrant expression of key regulating factors. GC according to WHO has been defined as malignant epithelial tumors of the gastric mucosa with glandular differentiation. About one half of the GCs are located in the lower stomach, and remaining is located in the corpus and fundus of the stomach (20%), lesser curvature (20%), cardia (10%) and greater curvature (3%). GC has been classified into intestinal and diffuse types based on epidemiological and clinico- and histopathological features. The etiology of GC is multifactorial and includes dietary as well as non-dietary factors. Despite a lot of research efforts, GC remains to be the cancer without clear symptoms at onset, poor prognosis, with metastasis and recurrence. Thus, there is an urgent need for identifying novel and diagnostic GC biomarkers and techniques with high sensitivity and specificity. In the present review, we provide a synopsis of proteomics based GC biomarkers discovered from various cancerous specimens such as blood, gastric fluid, tissues, cells and H. pylori infected cancer cell lines. The advent of proteomics based GC biomarkers will be a great asset for the early detection and treatment of GC.

The use of the carbohydrate glucose as an energetic source is essential for an adequate function of the human body. The complex regulation of this molecule involves the coordinated action of various organs such as pancreas, liver and brain. Any disruption of this physiological balance may result in a dangerous compromise of general metabolic activities increasing the possibility of developing T1DM, T2DM and possibly AD. Astrocytes convert glucose into lactate and transfer it to neurons. This lactate is essential for neuronal metabolism and for various processes including the formation of synapses, dendrites and the expression of genes involved in memory. The brain is highly susceptible to variations in glucose blood levels, and both hypoglycemia and hyperglycemia can be dangerous. Pathological hyperglycemia induces changes in plasmatic osmotic pressure, mitochondrial production of free radicals, oxidative stress and activation of neuronal apoptosis, among others. Both AD and diabetes are chronic diseases having age as an important risk factor. As the brain ages, it seems to become much more susceptible to cellular damage induced by excess of circulating glucose and this could explain the appearance of cognitive changes observed in some patients with diabetes. Excessive circulation of pro-inflammatory agents has been observed in insulin resistance and is likely that some of these mediators may cross the bloodbrain barrier and induce abnormal neuroinflammation. GSK-3 is overexpressed in diabetes and also has been reported to regulate tau phosphorylation and production of Aβ peptides in the brain. Currently, diabetes (hyperglycemia) is considered as a risk factor for the development of AD. A novel therapeutic approach, using intranasal insulin and anti-diabetic medications in patients suffering from AD is being explored and is discussed in this review.

The neuroimmune system represents a dense network of biochemical signals associated with neurotransmitters, neuropeptides, neurohormones, cytokines, chemokines, and growth factors synthesized in neurons, glial cells and immune cells, to maintain systemic homeostasis. Endogenous and/or exogenous, noxious stimuli in any tissue are captured by sensor cells to inform the brain; likewise, signals originating at the central nervous system (CNS) level are transmitted to peripheral immune effectors which react to central stimuli. This multidirectional information system makes it possible for the CNS to respond to peripheral damage and for alterations in brain function to be reflected in peripheral immune changes. Different CNS disorders, such as anxiety, depression, psychosis, stroke, Alzheimer’s disease, Parkinson’s disease, attention-deficit hyperactivity disorder, migraine, epilepsy, vascular dementia, mental retardation, cerebrovascular encephalopathy, multiple sclerosis, brain tumors, cranial nerve neuropathies, mental retardation and post-traumatic brain injury exhibit changes in CD3, CD4, CD7, HLA-DR, CD25, CD28, and CD56 immune markers. Histamine is an important pleiotropic factor in neuroimmune regulation. This biogenic amine shows age-and sex-dependent changes in the CNS, and is significantly altered, together with interleukin- 1β and TNF-α, in Alzheimer’s disease and other neurodegenerative disorders in which neuroinflammation appears to be an aggravating phenotype. Therapeutic intervention to halt progression of deleterious neuroinflammatory reactions in CNS disorders is a major challenge for molecular pharmacology in the future.

Vaccination has become one of the most promising immunotherapeutic approaches in the prevention and treatment of Alzheimer’s disease (AD) and related neuropathological hallmarks. Numerous immunotherapeutic interventions have attempted to achieve adaptive immunity against Aβ with a range of different antigenic designs and immunomodulatory strategies, most of them with great success in AD mouse model studies. Most of these studies have shown that both active and passive immunization can drastically reduce amyloid deposition and prevent the decline in cognitive performance. New approved clinical trials are under investigation to test the effectiveness of those different vaccination approaches, although previous data showed modest clinical success with some adverse inflammatory events in immunized elderly patients. The search for new approaches to overcome these severe side effects has led to novel technical methods such as live vector or DNA vaccines, although the use of innovative adjuvants combined with selected amyloid peptides is among the most auspicious. In this review, we compare and discuss the past and contemporary vaccines and the future strategies that may lead to a viable improvement in AD prevention and treatment.

Metabolic syndrome (MS) is a constellation of risk factors that raise the risk for heart disease and other health problems, such as obesity. The clustering of metabolic abnormality is closely related to oxidative stress and inflammation, as well as the progression of atherosclerosis. Antioxidants are reducing agents which inhibit the oxidation of other molecules and can be used not only to prevent but also to treat health complications of MS and atherosclerosis. They can be ingested in the normal diet, since they are found in many food sources, or in supplement formulations. Herein, we aim to review the literature concerning the effect of antioxidants on MS. We focus on antioxidants with some evidence of action on this condition, like flavonoids, arginine, vitamin C, vitamin E, carotenoids, resveratrol and selenium. Experimental and clinical studies show that most of the above-mentioned antioxidants exhibit a wide range of effects in protecting the human body, especially in MS patients. However, the underlying mechanisms are not fully elucidated for most of these compounds. Also, some of them should be used with caution because their excess can be toxic to the body. In general, antioxidants (especially those present in foods) can be used by MS individuals because of their direct effect on oxidative stress. Additionally, they should be encouraged as part of a nutritional lifestyle change, since this is part of the therapy for all diseases involved in metabolic disorders.

Therapeutic antibodies are implicated into the very promising and fast growing area of pharmaceutics. Human hybridoma technology, allowing generation of natural human antibodies in a native form, seems to be the most direct way that require no additional modifications for production of therapeutic antibodies. However, technical difficulties in human hybridoma creation discovered in the 80s of the last century have switched the mainstream therapeutic antibody development into new directions like display and transgenic mice techniques. These approaches have provided remarkable achievements in antibody engineering within last 15 years, but also revealed other limitations. Thus, it is time to turn back to forgotten human hybridoma technology. In this review, we describe new advances in all components of human hybridoma technology and discuss challenges in generating novel therapeutic mABs based on hybridoma technologies.

Kinases are known to regulate the majority of human cellular processes such as communication, division, metabolism, survival and apoptosis therefore they can be promising targets in cancer diseases, viral infection and in other disorders. Small molecules acting as selective human protein kinase inhibitors are very attractive pharmacological targets. This review presents a number of examples of biologically active natural and synthetic benzo[b]furans and their derivatives, such as benzo[b]furan-2- and 3-ones, benzo[b]furan-2- and 3-carboxylic acids, as well as benzo[c]furans as potential inhibitors of various human protein kinases. The pathways of function and implication of the inhibitors in cancer and other diseases are discussed.

Obesity and metabolic syndrome (MS) are risk factors for diabetes, cancer, some cardiovascular and musculoskeletal diseases. Pharmacotherapy should be used when the body mass index (BMI) exceeds 30 kg/m² or 27 kg/m² with comorbidity. Efficacy and safety of pharmacotherapy depend on the mechanism of action of drugs. In this context, drugs affecting the central and peripheral mediator systems such as cannabinoid receptor antagonists (Rimonabant), neuronal reuptake inhibitor of NE and 5 HT (Sibutramine), neuronal reuptake inhibitor of NE 5-HT DA (Tesofensine), agonist of 5 HT 2C receptors (Lorcaserin) have a high risk of side effects on the central nervous and cardiovascular systems when used for a long period. Apparently, the drugs design targeting obesity should screen safer drugs that affect fat absorption (Orlistat), activate energy metabolism (Adipokines), inhibit MetAP2 (Beloranib) and other peripheral metabolic processes. The use of synergies of anti-obesity drugs with different mechanisms of action is an effective approach for developing new combined pharmaceutical compositions (Contrave®, EmpaticTM, Qsymia et al). The purpose of this article is to review the currently available anti-obesity drugs and some new promising trends in development of anti-obesity therapy.

Gastrointestinal (GI) disorders, especially microbial dysbiosis play role in several GI ailments such as irritable bowel syndrome, colorectal cancer, inflammatory bowel diseases, and antibiotic-associated diarrhoea. Role of inflammatory bowel disease (IBD) is multifactorial as it involves loss of maintaining intestinal epithelial barrier integrity, increased release of pro-inflammatory molecules, and microbial dysbiosis in gut microflora. Some specific pathogens also play a key role in the IBD development. The origin and causation are still in unfathomable condition and the exact root cause is unknown. Recently probiotic studies have been gaining importance because of their positive responses in their IBD experimental results. According to joint Food and Agricultural Organisation/World Health Organisation working group, probiotics are defined as live microorganisms which when administered in adequate amount confer health benefit on the host. These live beneficial microorganisms are considered helpful in improving gut colonization and perseverance thereby improves prophylactic effect. In the direction of IBD research, a number of studies are needed to standardize its methodology and its applicability on human usage. The particular review presents an overview of gut microflora and its impact on host health, types of IBD and existing therapies to treat this disorder, mechanism of several probiotic actions, role of probiotics in IBD prevention with their supporting evidences.

Adult rheumatoid arthritis (RA) is an autoimmune disorder affecting joints and frequently characterised by initial local and later systemic inflammation. Researchers have, for many years, traced its cause to diverse genetic, environmental and especially immunological responses that work against the body’s own cells and tissues. Investigation into several of these biomarkers reveals interconnections that exist between multiple factors, which ultimately lead to specific pathologies. The goal of this paper is to highlight connections present between the major biological players long identified by researchers including more recently uncovered biomarkers in the RA repertoire and some of the pathophysiologies typically affiliated with the disease. Biomarkers reviewed, and becoming more clearly defined for RA include genetic, cytokines like tumor-necrosis factor-α (TNF-α), lymphocytes, nuclear antigens, antibodies to citrullinated peptides (anti-CPs), acute-phase proteins (APPs), microRNA, S100 proteins, platelets and erythrocytes. Some of the disease manifestations that have been connected are bone erosion, diabetes, metabolic syndrome, anemia, synovitis, felty’s syndrome, extra-articular manifestations (EAMs) such as atherosclerosis, rheumatoid nodules and cardiovascular (CV) events. Several RA markers associated with malignancy have been identified in literature although there is insufficient evidence of cancer in patients. Due to the complex nature of the disease, the appearance of symptoms and markers vary amongst individuals and the connections may manifest only in part. This manuscript addresses defining factors relevant to rapid identification of pathological influences these biomolecules could exert and to the management of the disease. Each of these biological players may have its place in connecting to symptomatic pathologies and help to highlight potential targets for therapy.

Design of selective anticancer drugs that are targeting RGD-binding integrin receptors which are known to be one of the perspective directions in the field of oncology. Significant progress in the development and application of these types compounds is already demonstrated. The accumulating body of basic and clinical evidence demonstrates potential significant effects on both in vitro and in vivo experimental models. However, the specific mechanism of action of these compounds is generally not a fully elucidated or the exact target responsible for the achievement of stated effects hasn't yet been defined sufficiently. To date eight types of integrin receptors, which are capable to recognize RGD-motif in natural ligands, has in fact been identified as (namely αIIbβ3, αvβ1, αvβ3, αvβ5, αvβ6, αvβ8, α5β1, α8β1). Even so, the estimation of the affinity of one particular RGD-bearing anticancer agent is often based on the determination of the binding efficacy to only one or rarely two integrin receptors. Traditionally the range of targets is restricted by the integrins, which are known to be highly expressed in a particular model system. While potential interactions of such an agent with other RGD-recognizing receptors usually remain beyond the research. Nonetheless, such interactions may also affect the viability and behavior of cancer cells. In this review we attempt to critically analyze the principles of selectivity achievement in the case of RGD-bearing natural ligands and the applicability of these principles in the context of the anticancer drug design.

Following the first small non-coding RNA identification in 1993, accumulated knowledge on the biogenesis, homeostasis and functional roles of microRNAs in different physiological and pathophysiological conditions has been discovered. MicroRNAs act through epigenetic regulation of gene expression. MiR-34a is a member of the MiR-34 family that is involved in p53 pathways, and is implicated in cell death/survival signaling. MiR-34a is associated with G1 cell cycle arrest, senescence and apoptosis, thereby possessing a tumor suppressor activity. Deregulation of MiR-34a has been reported in several types of cancers. MiR-34a downregulation has been correlated with cancer multidrug resistance (MDR), which is a major challenge for successful cancer chemotherapy. MiR-34a mimetic agents have been shown to attenuate drug resistance in different cancer cell lines. This review focuses on the in vitro, experimental and clinical findings dealing with the role of miR-34a downregulation in MDR, and potential therapeutic opportunities arising from this role of miR-34a.

Cardio vascular disease (CVD) is the end result of the accumulation of atheromatous plaques within the walls of the coronary arteries and remains the leading cause of death worldwide. Vascular inflammation and associated ongoing inflammatory responses have been considered as the critical culprits in the pathogenesis of CVD. Moreover, the activation of inflammatory pathways is not confined to coronary lesions only but involves the activation of neutrophils, monocytes and lymphocytes in peripheral blood. In view of high mortality rate associated with this devastated disease, it is essential that CVD and related complications should be taken care off at its earliest. To achieve that goal, some inflammatory mediators could be potentially targeted. In the current article, we will highlight targeting some inflammatory mediators viz. IL-1, IL-6, TNF-α etc for CVD management. As far as our knowledge goes, we are for the first time reporting the targeting inflammatory mediators especially IL-1, IL-6 and TNF-α together in a single article. Based on our review, we believe that scientific community will come up with certain anti-inflammatory agents against atherosclerosis in near future and hopefully that will be used for the successful management of CVD patients.