Current Medicinal Chemistry - Volume 26, Issue 25, 2019

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is considered a severe side effect of therapeutic agents with limited treatment options. The incidence of CIPN in cancer patients is approximately 3–7% in cytostatic monotherapy and as high as 38% in cases of polychemotherapy. The prevalence of CIPN was found to be 68% within the first month of chemotherapy treatment. In some cases, CIPN can resolve, partially or completely, after completion of the treatment; in other cases, it can remain for a long time and affect the patient's quality of life. Objective: The aim of this study is to present up-to-date data regarding available treatment options for the management of CIPN. Materials and Methods: The up-to-date guidelines of ESMO (European Society for Medical Oncology), ASCO (American Society of Clinical Oncology), ONS (Oncology Nursing Society), NCI (National Cancer Institute), and NCCN (National Comprehensive Cancer Network) were reviewed and included in the manuscript. Results: The use of tricyclic antidepressant (TCA), selective serotonin norepinephrine reuptake inhibitor (SSNRI), pregabalin, and gabapentin are recommended as first-line treatment. Other treatment options were offered as second and third lines of treatment (lidocaine patches, capsaicin high-concentration patches, tramadol, and strong opioids, respectively); however, lower significance was demonstrated. Inconclusive results were found in the use of cannabinoids, drug combinations, antiepileptics, antidepressants, and topical drugs. Conclusion: TCA, other antidepressants, and opioids could be recommended as treatment. Yet, we could not recommend an ideal therapeutic agent for the prevention or treatment of CIPN. Therefore, CIPN continues to be a challenge to clinicians and our patients.

Cancer chemotherapies or antitumor agents mainly remain the backbone of current treatment based on killing the rapidly dividing cancer cell such as tylophora alkaloids and their analogues which have also demonstrated anticancer potential through diverse biological pathways including regulation of the immune system. The introduction of durable clinically effective monoclonal antibodies, however, unmasked a new era of cancer immunotherapies. Therefore, the understanding of cancer pathogenesis will provide new possible treatment options, including cancer immunotherapy and targeted agents. Combining cytotoxic agents and immunotherapies may offer several unique advantages that are complementary to and potentially synergistic with biologic modalities. Herein, we highlight the dynamic mechanism of action of immune modulation in cancer and the immunological aspects of the orally active antitumor agents tylophora alkaloids and their analogues. We also suggest that future cancer treatments will rely on the development of combining tumor-targeted agents and biologic immunotherapies.

Adipokines constitute a family of protein factors secreted by white adipose tissue (WAT), that regulate the functions of WAT and other sites. Leptin, adiponectin and resistin, are the main adipokines present in serum and saliva, targeting several tissues and organs, including vessels, muscles, liver and pancreas. Besides body mass regulation, adipokines affect glucose homeostasis, inflammation, angiogenesis, cell proliferation and apoptosis, and other crucial cell procedures. Their involvement in tumor formation and growth is well established and deregulation of adipokine and adipokine receptors’ expression is observed in several malignancies including those located in the head and neck region. Intracellular effects of adipokines are mediated by a plethora of receptors that activate several signaling cascades including Janus kinase/ Signal transducer and activator of transcription (JAK/ STAT pathway), Phospatidylinositol kinase (PI3/ Akt/ mTOR) and Peroxisome proliferator-activated receptor (PPAR). The present review summarizes the current knowledge on the role of adipokines family members in carcinogenesis of the head and neck region. The diagnostic and prognostic significance of adipokines and their potential role as serum and saliva biomarkers are also discussed.

Background: Neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and cerebral ischemic stroke, impose enormous socio-economic burdens on both patients and health-care systems. However, drugs targeting these diseases remain unsatisfactory, and hence there is an urgent need for the development of novel and potent drug candidates. Methods: Animal toxins exhibit rich diversity in both proteins and peptides, which play vital roles in biomedical drug development. As a molecular tool, animal toxin peptides have not only helped clarify many critical physiological processes but also led to the discovery of novel drugs and clinical therapeutics. Results: Recently, toxin peptides identified from venomous animals, e.g. exenatide, ziconotide, Hi1a, and PcTx1 from spider venom, have been shown to block specific ion channels, alleviate inflammation, decrease protein aggregates, regulate glutamate and neurotransmitter levels, and increase neuroprotective factors. Conclusion: Thus, components of venom hold considerable capacity as drug candidates for the alleviation or reduction of neurodegeneration. This review highlights studies evaluating different animal toxins, especially peptides, as promising therapeutic tools for the treatment of different neurodegenerative diseases and disorders.

Objective: Aging is a natural biological phenomenon that occurs in human beings. With increasing of age, there is an appearance of deleterious changes related to progression onto pathological conditions, including hypertension, heart disease, diabetes, hearing and vision impairments, as well as sleep disorders. It is important to recognize that some sleep disturbances reported by aged subjects include insomnia, obstructive sleep apnea, restless legs syndrome, among others. Moreover, accumulating evidence indicates that coexistence of medical issues with sleep disorders constitutes clinical challenges for treatment of comorbidities in elderly. Here, we have attempted to review and summarize the available literature that assesses the sleep disturbances in aging. In addition, we highlight the management of sleep disorders associated with aging. Due to the particular health condition of aged adults, the development of effective pharmacological interventions for sleep disorders treatment in aging is warranted. Methods: Review of studies retrieved from the PubMed. Results: The sleep-wake cycle includes abnormalities classified as sleep disorders. Comorbidity between sleep disturbances and aging-related health issues will represent a public health challenge to be addressed in the near future. Moreover, this scenario will suggest an area that requires further drug investigation and design of new pharmacological and pharmaceutical strategies to treat sleep disorders in the elderly population. Conclusion: The review highlights the sleep disturbances in aging. We focus on current knowledge in medicinal chemistry and further design of new treatments tools for managing sleep disturbances in the aged population.

Background: Preeclapmsia (PE) is characterized by early onset symptoms such as elevated blood pressure, proteinuria and edema in the pregnant woman, and may result in seizures in the affected female. Currently, there are no therapeutic drugs available to treat this condition, but there are interventions to regulate the symptoms based on the gestational period of the fetus, although the largely favored option is delivery of the fetus and placenta. Objective: A search for biomolecules associated with PE was conducted so as to identify diagnostic markers and therapeutic leads. Results: The literature search resulted in the identification of biomolecules such as Corin and Placental Protein 13 (PP13), among others that are associated with PE. Thereby, giving an insight into the various mechanistic pathways involved in the causation of PE. However, it is also evident that PE cannot be solely attributed to any single mechanism but is due to an interplay of different factors that have led to the development of this disease condition. Conclusion: The identified biomarkers would ultimately help in understanding this complex disease and perhaps lead to the discovery of potential effective molecular targets for clinical trials, thereby providing a valuable therapeutic option for affected pregnant women.

P-glycoprotein, also known as ABCB1 in the ABC transporter family, confers the simultaneous resistance of metastatic cancer cells towards various anticancer drugs with different targets and diverse chemical structures. The exploration of safe and specific inhibitors of this pump has always been the pursuit of scientists for the past four decades. Naturally occurring flavonoids as benzopyrone derivatives were recognized as a class of nontoxic inhibitors of P-gp. The recent advent of synthetic flavonoid dimer FD18, as a potent P-gp modulator in reversing multidrug resistance both in vitro and in vivo, specifically targeted the pseudodimeric structure of the drug transporter and represented a new generation of inhibitors with high transporter binding affinity and low toxicity. This review concerned the recent updates on the structure-activity relationships of flavonoids as P-gp inhibitors, the molecular mechanisms of their action and their ability to overcome P-gp-mediated MDR in preclinical studies. It had crucial implications on the discovery of new drug candidates that modulated the efflux of ABC transporters and also provided some clues for the future development in this promising area.

Genetic polymorphisms within the interferon λ (IFN-λ) chromosomal region, mainly rs12979860 of IFN-λ4 gene (IFNL4), are known as associated with spontaneous hepatitis C virus (HCV) resolution and sustained viral response to therapy with pegylated interferon- α and ribavirin. Strong linkage disequilibrium of IFNL4 rs12979860 with IFNL4 rs368234815, which is casually associated with HCV spontaneous and therapeutical eradication, at least partially explains favorable HCV outcomes attributed to major homozygosity in rs12979860. Effects of IFN-based antiviral treatment are associated with pretreatment expression of the IFN-λ1 receptor, expression of hepatic IFN-stimulated genes, production of IFN- λ4, and preactivation of the JAK-STAT signaling. Nowadays direct-acting antivirals (DAAs) became a potent tool in the treatment of hepatitis C, but IFN-λs are still under investigation as potential antivirals and might be an option in HCV infection (DAA resistance, recurrent viremia, adverse effects). Patients with altered immunocompetence are especially prone to infections. In uremic subjects, polymorphisms within the IFN-λ chromosomal region associate with spontaneous HCV clearance, similarly like in the non-uremic population. Circulating IFN-λ3 shows a positive correlation with plasma titers of antibodies to surface antigen of hepatitis B virus (anti-HBs), which are crucial for protection against hepatitis B virus. More efficient anti-HBs production in the presence of higher IFN-λ3 levels might occur due to IFN-λ3-induced regulation of indoleamine 2,3-dioxygenase (IDO) expression. IFN-stimulated response element is a part of IDO gene promoter. It is worth further investigation whether IDO gene, circulating IDO, genetic polymorphisms within the IFN-λ region, and circulating IFN-λ3 act in concordance in immunological response to hepatotropic viruses.

Background: Plant tannins are polyphenolic substances with various molecular weights and a variable complexity. Due to the beneficial effects for controlling chronic disorders particularly diabetes mellitus, this class of secondary metabolites has gained more interest in the recent years. Objective: We aimed through this review to collect, analyze and discuss all available information related to the antidiabetic effect of isolated tannins (including both condensed and hydrolysable varieties) and tannin-rich plants as well as the possible mechanisms of action involved in this antidiabetic activity. Methods and Results: Our bibliographic research was conducted to gather more than 41 medicinal plants containing tannins and 19 isolated tannins and tannin-rich crud extracts which were revealed to possess glucose lowering effect according to pharmacological studies. Conclusion: Hence, according to findings of the present review, tannins could be useful for prevention and management of diabetes mellitus and its associated complications and these natural products could be promising compounds for the discovery of new hypoglycemic agents.

Schizophrenia is a chronic psychiatric disorder that affects about 1 in 100 people around the world and results in persistent emotional and cognitive impairments. Untreated schizophrenia leads to deterioration in quality of life and premature death. Although the clinical efficacy of dopamine D2 receptor antagonists against positive symptoms of schizophrenia supports the dopamine hypothesis of the disease, the resistance of negative and cognitive symptoms to these drugs implicates other systems in its pathophysiology. Many studies suggest that abnormalities in glutamate homeostasis may contribute to all three groups of schizophrenia symptoms. Scientific considerations also include disorders of gamma-aminobutyric acid-ergic and serotonergic neurotransmissions as well as the role of the immune system. The purpose of this review is to update the most recent reports on the discovery and development of non-dopaminergic agents that may reduce positive, negative, and cognitive symptoms of schizophrenia, and may be alternative to currently used antipsychotics. This review collects the chemical structures of representative compounds targeting metabotropic glutamate receptor, gamma-aminobutyric acid type A receptor, alpha 7 nicotinic acetylcholine receptor, glycine transporter type 1 and glycogen synthase kinase 3 as well as results of in vitro and in vivo studies indicating their efficacy in schizophrenia. Results of clinical trials assessing the safety and efficacy of the tested compounds have also been presented. Finally, attention has been paid to multifunctional ligands with serotonin receptor affinity or phosphodiesterase inhibitory activity as novel strategies in the search for dedicated medicines for patients with schizophrenia.