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Vitamin C and Bone Health: Evidence from Cell, Animal and Human Studies

Chin KY, Ima-Nirwana S

Curr Drug Targets, 2018;19(5):439-450.
PMID: 26343111 DOI: 10.2174/1389450116666150907100838

BACKGROUND: Vitamin C, traditionally associated with scurvy, is an important nutrient for maintaining bone health. It is essential in the production of collagen in bone matrix. It also scavenges free radicals detrimental to bone health.
OBJECTIVE: This review aims to assess the current evidence of the bone-sparing effects of vitamin C derived from cell, animal and human studies.
RESULTS: Cell studies showed that vitamin C was able to induce osteoblast and osteoclast formation. However, high-dose vitamin C might increase oxidative stress and subsequently lead to cell death. Vitamin C-deficient animals showed impaired bone health due to increased osteoclast formation and decreased bone formation. Vitamin C supplementation was able to prevent bone loss in several animal models of bone loss. Human studies generally showed a positive relationship between vitamin C and bone health, indicated by bone mineral density, fracture probability and bone turnover markers. Some studies suggested that the relationship between vitamin C and bone health could be U-shaped, more prominent in certain subgroups and different between dietary and supplemental form. However, most of the studies were observational, thus could not confirm causality. One clinical trial was performed, but it was not a randomized controlled trial, thus confounding factors could not be excluded.
CONCLUSION: vitamin C may exert beneficial effects on bone, but more rigorous studies and clinical trials should be performed to validate this claim.
Phytometabolites Targeting the Warburg Effect in Cancer Cells: A Mechanistic Review

Hasanpourghadi M, Looi CY, Pandurangan AK, Sethi G, Wong WF, Mustafa MR

Curr Drug Targets, 2017;18(9):1086-1094.
PMID: 27033190 DOI: 10.2174/1389450117666160401124842

Phytometabolites are functional elements derived from plants and most of them exhibit therapeutic characteristics such as anti-cancer, anti-inflammatory and anti-oxidant effects. Phytometabolites exert their anti-cancer effect by targeting multiple signaling pathways. One of the remarkable phenomena targeted by phytometabolites is the Warburg effect. The Warburg effect describes the observation that cancer cells exhibit an increased rate of glycolysis and aberrant redox activity compared to normal cells. This phenomenon promotes further cancer development and progression. Recent observations revealed that some phytometabolites could target metabolic-related enzymes (e.g. Hexokinase, Pyruvate kinase M2, HIF-1) in cancer cells, with little or no harm to normal cells. Since hyper-proliferation of cancer cells is fueled by higher cellular metabolism, phytometabolites targeting these metabolic pathways can create synergistic crosstalk with induced apoptotic pathways and sensitize cancer cells to chemotherapeutic agents. In this review, we discuss phytometabolites that target the Warburg effect and the underlying molecular mechanism that leads to tumor growth suppression.
The Molecular Concept of Atheromatous Plaques

Thent ZC, Chakraborty C, Mahakkanukrauh P, Nik Ritza Kosai Nik Mahmood N, Rajan R, Das S

Curr Drug Targets, 2017;18(11):1250-1258.
PMID: 27138760 DOI: 10.2174/1389450117666160502151600

BACKGROUND: Recently, there are scientific attempts to discover new drugs in the biotechnology industry in order to treat various diseases including atherosclerosis.
OBJECTIVE: The main objective of the present review was to highlight the cellular, molecular biology and inflammatory process related to the atheromatous plaques.
METHODS: A thorough literature search of Pubmed, Google and Scopus databases was done.
RESULTS: Atherosclerosis is considered to be a leading cause of death throughout the world. Atherosclerosis involves oxidative damage to the cells with production of reactive oxygen species (ROS). Development of atheromatous plaques in the arterial wall is a common feature. Specific inflammatory markers pertaining to the arterial wall in atherosclerosis may be useful for both diagnosis and treatment. These include Nitric oxide (NO), cytokines, macrophage inhibiting factor (MIF), leucocytes and Pselectin. Modern therapeutic paradigms involving endothelial progenitor cells therapy, angiotensin II type-2 (AT<sub>2</sub>R) and ATP-activated purinergic receptor therapy are notable to mention.
CONCLUSION: Future drugs may be designed aiming three signalling mechanisms of AT<sub>2</sub>R which are (a) activation of protein phosphatases resulting in protein dephosphorylation (b) activation of bradykinin/nitric oxide/cyclic guanosine 3',5'-monophosphate pathway by vasodilation and (c) stimulation of phospholipase A(2) and release of arachidonic acid. Drugs may also be designed to act on ATP-activated purinergic receptor channel type P2X7 molecules which acts on cardiovascular system.
The Smart Programmable CRISPR Technology: A Next Generation Genome Editing Tool for Investigators

Chakraborty C, Teoh SL, Das S

Curr Drug Targets, 2017;18(14):1653-1663.
PMID: 27231109 DOI: 10.2174/1389450117666160527142321

BACKGROUND: The present era is fast experiencing rapid innovation in the genome-editing technology. CRISPR Cas9-mediated targeted genetic manipulation is an easy, cost-effective and scalable method. As a result, it can be used for a broad range of targeted genome engineering.
OBJECTIVE: The main objective of the present review is to highlight the structural signature, classification, its mechanism and application from basic science to medicine and future challenges for this genome editing tool kit.
RESULTS: The present review provides a brief description of the recent development of CRISPR-Cas9 genome editing technology. We discuss the paradigms shift for this next generation genome editing technology, CRISPR. The CRISPR structural significance, classification and its different applications are also being discussed. We portray the future challenges for this extraordinary genome in vivo editing tool. We also highlight the role of CRISPR genome editing in curing many diseases.
CONCLUSION: Scientists and researchers are constantly looking one genome editing tool that is competent, simple and low-cost assembly of nucleases. It can target any particular site without any off-target mutations in the genome. The CRISPR-Cas9 has all of the above characteristics. The genome engineering technology may be a strong and inspiring technology meant for the next generation of drug development.
Editorial

Sulaiman AH, Musa R

Curr Drug Targets, 2019;20(2):145.
PMID: 30648501 DOI: 10.2174/138945012002181203145147
Toll-like Receptor as a Molecular Link between Metabolic Syndrome and Inflammation: A Review

Wong SK, Chin KY, Ima-Nirwana S

Curr Drug Targets, 2019;20(12):1264-1280.
PMID: 30961493 DOI: 10.2174/1389450120666190405172524

Metabolic Syndrome (MetS) involves a cluster of five conditions, i.e. obesity, hyperglycaemia, hypertension, hypertriglyceridemia and low High-Density Lipoprotein (HDL) cholesterol. All components of MetS share an underlying chronic inflammatory aetiology, manifested by increased levels of pro-inflammatory cytokines. The pathogenic role of inflammation in the development of MetS suggested that toll-like receptor (TLR) activation may trigger MetS. This review summarises the supporting evidence on the interactions between MetS and TLR activation, bridged by the elevation of TLR ligands during MetS. The regulatory circuits mediated by TLR activation, which modulates signal propagation, leading to the state of chronic inflammation, are also discussed. Taken together, TLR activation could be the molecular basis in the development of MetS-induced inflammation.
The Emerging Role of the Hippo Pathway in Lung Cancers: Clinical Implications

Teoh SL, Das S

Curr Drug Targets, 2017 Nov 30;18(16):1880-1892.
PMID: 27628948 DOI: 10.2174/1389450117666160907153338

BACKGROUND: The incidence of lung cancers has increased globally. Increased exposure to tobacco, passive smoking, less consumption of vegetables and fruits and occupational exposure to asbestos, arsenic and chromium are the main risk factors. The pathophysiology of lung cancer is complex and not well understood. Various microRNAs, genes and pathways are associated with lung cancers. The genes involved in lung cancers produce proteins involved in cell growth, differentiation, different cell cycles, apoptosis, immune modulation, tumor spread and progression. The Hippo pathway (also known as the Salvador-Warts-Hippo pathway) is the latest emerging concept in cancers. The Hippo pathway plays an important role in controlling the size of the tissue and organ by virtue of its action on cell proliferation and apoptosis.
OBJECTIVE: In the present review, we highlight the mammalian Hippo pathway, role of its core members, its upstream regulators, downstream effectors and the resistance cases in lung cancers.
RESULTS: Specific interaction of Mer with cell surface hyaluronan receptor CD44 is vital in cell contact inhibition, thereby activating Hippo pathway. Both transcription co-activators YAP and TAZ (also known as WWTR1, being homologs of Drosophila Yki) are important regulators of proliferation and apoptosis, and serve as major downstream effectors of the Hippo pathway. Mutation of NF2, the upstream regulator of Hippo pathway is linked to the cancers.
CONCLUSION: Targeting YAP and TAZ may be important for future drug delivery and treatment.
Plant Polyphenols as Neuroprotective Agents in Parkinson's Disease Targeting Oxidative Stress

Hor SL, Teoh SL, Lim WL

Curr Drug Targets, 2020;21(5):458-476.
PMID: 31625473 DOI: 10.2174/1389450120666191017120505

Parkinson's disease (PD) is the second most prevalent progressive neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the human midbrain. Various ongoing research studies are competing to understand the pathology of PD and elucidate the mechanisms underlying neurodegeneration. Current pharmacological treatments primarily focused on improving dopamine metabolism in PD patients, despite the side effects of long-term usage. In recent years, it is recognized that oxidative stress-mediated pathways lead to neurodegeneration in the brain, which is associated with the pathophysiology of PD. The importance of oxidative stress is often less emphasized when developing potential therapeutic approaches. Natural plant antioxidants have been shown to mediate the oxidative stress-induced effects in PD, which has gained considerable attention in both in vitro and in vivo studies. Yet, clinical trials on natural polyphenol compounds are limited, restricting the potential use of these compounds as an alternative treatment for PD. Therefore, this review provides an understanding of the oxidative stress-induced effects in PD by elucidating the underlying events contributing to oxidative stress and explore the potential use of polyphenols in improving the oxidative status in PD. Preclinical findings have supported the potential of polyphenols in providing neuroprotection against oxidative stress-induced toxicity in PD. However, limiting factors, such as safety and bioavailability of polyphenols, warrant further investigations so as to make them the potential target for clinical applications in the treatment and management of PD.
Curcumin Sensitizes Cancers Towards TRAIL-induced Apoptosis via Extrinsic and Intrinsic Apoptotic Pathways

Ngai SC

Curr Drug Targets, 2020;21(9):849-854.
PMID: 32116190 DOI: 10.2174/1389450121666200302124426

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a natural protein expressed in a wide range of tissues in our body. It is a promising anti-cancer agent due to its selective killing of cancer cells, rendering normal cells unharmed. However, resistance occurs either intrinsically or develops over the course of TRAIL treatment. In view of its specificity to cancer cells, there is a pushing need to overcome TRAIL resistance. Curcumin (Cur), a natural active constituent of turmeric, has been evidenced to have anti-cancer properties. However, it is limited by its sparing solubility and low bioavailability. Combinational therapy is one of the most frequently used strategies to overcome these limitations, which has been proved to be more effective than monotherapy by achieving synergistic effects and reducing toxicity. This review aims to discuss TRAIL and its underlying apoptotic mechanisms, the combinational treatment of Cur and TRAIL in view of their respective limitations, and the underlying apoptotic mechanisms activated by the sensitization of cancers by Cur towards TRAIL-induced apoptosis. Finally, this review discusses the research gap and the author's insight into this research area in bridging the research gap from bench to bedside.
Kratom Dependence and Treatment Options: A Comprehensive Review of the Literature

Bin Abdullah MFIL

Curr Drug Targets, 2020;21(15):1566-1579.
PMID: 32682371 DOI: 10.2174/1389450121666200719011653

Kratom, or Mitragyna speciosa Korth., is a tropical plant prevalent in Southeast Asia, and it is utilized as a traditional remedy for symptomatic relief of various illnesses. It has been labeled as an atypical opioid with significant narcotic-like properties, capable of inducing kratom dependence among those who misuse or abuse it. The prevalence of kratom use has drastically increased worldwide, raising concerns among healthcare providers, particularly regarding the availability of efficacious treatment options for kratom dependence. This manuscript provides a comprehensive narrative review of literature focusing on the psychoactive alkaloids of kratom, the possible neurobiological and pathophysiological models underlying the occurrence of kratom dependence, and the clinical presentations and effective treatment options available for kratom dependence. The psychoactive alkaloids of kratom, such as mitragynine (MG) and 7-hydroxymitragynine (7-HMG), act as partial mu opioid agonists and induce kratom dependence. As a result, regular kratom use leads to withdrawal symptoms on abstinence, along with craving, tolerance, and cross-tolerance to morphine. The psychological withdrawal symptoms reported include depressed mood, anxiety, restlessness, irritability, and feeling tense, while the physical withdrawal symptoms are myalgia and body ache, joint pain, lacrimation, running nose, yawning, insomnia, diarrhea, feverish sensation, loss of appetite, tremors, itching over the body, loss of concentration, and chills. Neonatal withdrawal symptoms, such as oral intolerance, restlessness, irritability, and vomiting, are also reported in newborns of women who are on regular kratom use. Sublingual buprenorphine-naloxone (Suboxone) is reported as a promising treatment for detoxification and maintenance replacement therapy for kratom-dependent users. Alternative treatments for in-patient detoxification include intravenous clonidine and a combination of oral dihydrocodeine and lofexidine. We conclude by adding a note on the research gap concerning kratom dependence, which future studies should focus on.
A Glance on the Role of Bacterial Siderophore from the Perspectives of Medical and Biotechnological Approaches

AlMatar M, Albarri O, Makky EA, Var I, Köksal F

Curr Drug Targets, 2020;21(13):1326-1343.
PMID: 32564749 DOI: 10.2174/1389450121666200621193018

Iron, which is described as the most basic component found in nature, is hard to be assimilated by microorganisms. It has become increasingly complicated to obtain iron from nature as iron (II) in the presence of oxygen oxidized to press (III) oxide and hydroxide, becoming unsolvable at neutral pH. Microorganisms appeared to produce organic molecules known as siderophores in order to overcome this condition. Siderophore's essential function is to connect with iron (II) and make it dissolvable and enable cell absorption. These siderophores, apart from iron particles, have the ability to chelate various other metal particles that have collocated away to focus the use of siderophores on wound care items. There is a severe clash between the host and the bacterial pathogens during infection. By producing siderophores, small ferric iron-binding molecules, microorganisms obtain iron. In response, host immune cells produce lipocalin 2 to prevent bacterial reuptake of siderophores loaded with iron. Some bacteria are thought to produce lipocalin 2-resistant siderophores to counter this risk. The aim of this article is to discuss the recently described roles and applications of bacterial siderophore.
The Neurobiology and Psychiatric Perspective of Vaginismus: Linking the Pharmacological and Psycho-Social Interventions

Kadir ZS, Sidi H, Kumar J, Das S, Midin M, Baharuddin N

Curr Drug Targets, 2018;19(8):916-926.
PMID: 28228081 DOI: 10.2174/1389450118666170222153908

Vaginismus is an involuntary muscle contraction of the outer third of vaginal barrel causing sexual penetration almost impossible. It is generally classified under sexual pain disorder (SPD). In Diagnostic and Statistical Manual, 5th edition (DSM-5), it is classified under the new rubric of Genito-Pelvic Pain/Sexual Penetration Disorder. This fear-avoidance condition poses an ongoing significant challenge to the medical and health professionals due to the very demanding needs in health care despite its unpredictable prognosis. The etiology of vaginismus is complex: through multiple biopsycho- social processes, involving bidirectional connections between pelvic-genital (local) and higher mental function (central regulation). It has robust neural and psychological-cognitive loop feedback involvement. The internal neural circuit involves an inter-play of at least two-pathway systems, i.e. both "quick threat assessment" of occipital-limbic-occipital-prefrontal-pelvic-genital; and the chronic pain pathways through the genito-spinothalamic-parietal-pre-frontal system, respectively. In this review, a neurobiology root of vaginismus is deliberated with the central role of an emotional-regulating amygdala, and other neural loop, i.e. hippocampus and neo-cortex in the core psychopathology of fear, disgust, and sexual avoidance. Many therapists view vaginismus as a neglected art-and-science which demands a better and deeper understanding on the clinico-pathological correlation to enhance an effective model for the bio-psycho-social treatment. As vaginismus has a strong presentation in psychopathology, i.e. fear of penetration, phobic avoidance, disgust, and anticipatory anxiety, we highlighted a practical psychiatric approach to the clinical management of vaginismus, based on the current core knowledge in the perspective of neuroscience.
Natural Polyphenols in the Treatment of Alzheimer's Disease

Syarifah-Noratiqah SB, Naina-Mohamed I, Zulfarina MS, Qodriyah HMS

Curr Drug Targets, 2018;19(8):927-937.
PMID: 28356027 DOI: 10.2174/1389450118666170328122527

Neurodegenerative disease is an incurable disease which involves the degeneration or death of the nerve cells. Alzheimer's Disease (AD) is a neurodegenerative disease discovered in 1906 by Alois Alzheimer, a German clinical psychiatrist and neuroanatomist. The main pathological hallmarks of this disease are the formation of extracellular amyloid β (Aβ) plaques and intracellular neurofibrillary tangle (NFT). The accumulation of the amyloid protein aggregates in the brain of AD patients leads to oxidative stress and inflammation. Other postulated reasons for the development of this disease are cholinergic depletion and excessive glutamatergic neurotransmission. The current drugs approved and marketed for the treatment of AD are cholinesterase inhibitors (ChEIs) and N-methyl-Daspartate (NMDA) receptor antagonists. The function of ChEIs is to avoid cholinergic depletion; whereas the function of NMDA receptor antagonist is to block excessive glutamatergic neurotransmission. Unfortunately, the current drugs prescribed for AD show only modest improvement in terms of symptomatic relief and delay the progression of the disease. This review will discuss about several polyphenolic compounds as potential natural treatment options for AD. Three compounds are highlighted in this review - Curcumin (Cur), Resveratrol (Rsv) and Epigallocatechin-3- gallate (EGCG). These compounds have huge potential for AD treatment, especially due to their low frequency of adverse events. However, the current conventional pharmaceutical drugs remain as the mainstay of treatment for AD.
The Role of Atypical Antipsychotics in Sexuality: Road to Recovery in Schizophrenia

Adam RL, Sidi H, Midin M, Zakaria H, Das S, Mat KC

Curr Drug Targets, 2018;19(12):1402-1411.
PMID: 28464773 DOI: 10.2174/1389450118666170502130126

Sexuality is an important dimension in human beings as a form of expression of individuality. For many decades, sexual functioning has been a neglected area among patients suffering from schizophrenia. It was a presumption that patients with schizophrenia could be asexual and this could be secondary to overwhelming situations of delusion, hallucination, hostility and negative symptoms among others. The deficient in sexual functioning are due to innate factors, i.e. negative symptoms (apathy, avolition and amotivation) and also as a result of prefrontal dysfunction, i.e. inability to plan and execute meaningful relationship. Adverse effects of the psychopharmacological agents, especially the typical antipsychotics, e.g. dystonia, excessive sedation and hyperprolactinemia may interfere with patients' sexual activity. In this review, we highlight the neurobiology of schizophrenia in the context of understanding sexual functioning and to integrate the knowledge of dopamine-serotonin neurotransmitter's interaction and the receptors' target. Interventional approaches consist of psychopharmacological and psychosocial interventions. In the perspective of sexuality, we recommend atypical antipsychotic should be placed as the first line treatment for both drug naïve patients and also to patients who are already receiving psychopharmacological agents in consideration for a drug-switch from typical to atypical antipsychotics. Aripiprazole, clozapine, olanzapine and quetiapine exert benefits in terms of sexual functioning recovery due to their atypical mechanism of action. However, the potential adverse effect like metabolic syndrome should be adequately managed to prevent negative consequences. Psychosocial interventions, i.e. psychoeducation, destigmatization, supportive psychotherapy and psychiatric rehabilitation also play a crucial role in the management. In conclusion, restoration of sexual function is an achievable recovery target in patients with schizophrenia through these biopsycho- social interventions.
Pharmacological Effects of Turmeric on Learning, Memory and Expression of Muscarinic Receptor Genes (M1, M3 and M5) in Stress-induced Mouse Model

Khalid A, Shakeel R, Justin S, Iqbal G, Shah SAA, Zahid S, et al.

Curr Drug Targets, 2017;18(13):1545-1557.
PMID: 28302036 DOI: 10.2174/1389450118666170315120627

BACKGROUND: Stress is involved in memory impairment through multiple mechanisms, including activation of hypothalamic-pituitary axis, which in turn activates release of corticosterone in blood. Cholinergic system blockade by the muscarinic antagonist, scopolamine, also impairs memory.
OBJECTIVE: This study aimed to investigate the effect of turmeric (20mg/kg) on learning and memory and cholinergic system in a mouse model of stress along with cholinergic blockade.
METHODS: Restrained stress was induced and cholinergic receptors were blocked using scopolamine in mice. Animals were treated with turmeric (turmeric rhizome powder which was also subjected to NMR analyses) and learning and social behavior was examined. Effect of turmeric on cholinergic muscarinic receptors (mAChR; M1, M3 and M5) gene expression was assessed by RT-PCR in both pre-frontal cortex and hippocampus.
RESULTS: Ar-turmerone, curcuminoids and α-linolenic acid were the lead compounds present in turmeric extract. Increased serum corticosterone levels were observed in stressed mice when compared to the control group, while turmeric treatment significantly reduced serum corticosterone level. Turmeric treatment caused an improved learning and memory in Morris water maze test in stressed animals. Social novelty preference was also restored in turmeric treated animals. Following turmeric treatment, M5 expression was improved in the cortex and M3 expression was improved in the hippocampus of stress + scopolamine + turmeric treated group.
CONCLUSIONS: These findings highlight the therapeutic role of turmeric by increasing the expression of M3, M5 and improving learning and memory. Turmeric can be an effective candidate for the treatment of amnesia caused by the stress.
Co-Morbid Erectile Dysfunction (ED) and Antidepressant Treatment in a Patient - A Management Challenge?

Zainol M, Sidi H, Kumar J, Das S, Ismail SB, Hatta MH, et al.

Curr Drug Targets, 2019;20(2):182-191.
PMID: 28302034 DOI: 10.2174/1389450118666170315110902

Throughout the world, antidepressants (AD) and phosphodiesterase-5 inhibitors (PDE-5i) are the commonly prescribed psychopharmacological agents for treating patients with co-morbid mental health problem and sexual dysfunction (SD). The serotonergic and noradrenergic ADs, although effective, are not without any SD adverse-effects, especially erectile dysfunction (ED). ED is a failure to obtain a satisfactory erection for rewarding sexual coitus during the phases of male's sexual arousal. It is recognized as an important reason why non-adherence to treatment was observed in patients who were on AD. AD intervention caused remission to some of the pre- treatment psychopathology of ED. However, in many patients, AD potentially magnified the unwanted sexual sideeffects. This made the situation challenging for the mental health professional. These challenges are based on the complexity of ED, its etiology and the associated risk factors, which further add to its AD side-effect. The neuro-psychopharmacological basis for AD treatment selection was deliberated. Bio-psycho-social interventions are recommended at two pivotal stages. Firstly, a step should be taken for proper assessment (e.g. detailed history, psychosocial and laboratory investigations); and identify few modifiable risk factors for ED and associated mental health issues. Secondly, with guidance of an algorithm pathway, a practical intervention should include strategies such as dose reduction, augmentation or changing to an AD with lesser or no sexual adverse-effects. It is recommended that bupropion and mirtazepine to be prescribed when patients develop adverse sexual effects with serotonin selective reuptake inhibitor (SSRI), serotonin norepinephrine reuptake inhibitor (SNRI) and tricyclic antidepressant (TCA). Few suggestions which may be borne in mind are revising sexual scripts and improving sexual techniques, life-style modifications, psychotherapy and other nonpharmacological approaches which may be beneficial to both patients and their partners.
Kratom and Future Treatment for the Opioid Addiction and Chronic Pain: Periculo Beneficium?

Ismail I, Wahab S, Sidi H, Das S, Lin LJ, Razali R

Curr Drug Targets, 2019;20(2):166-172.
PMID: 28443503 DOI: 10.2174/1389450118666170425154120

Kratom (Mitragyna speciosa), a naturally existing plant found in South-East Asia, is traditionally used as a herb to help elevate a person's energy and also to treat numerous medical ailments. Other than the analgesic property, kratom has been used as an agent to overcome opioid withdrawal as it contains natural alkaloids, i.e. mitragynine, 7-hydroxymitragynine, and MGM-9, which has agonist affinity on the opioid receptors, including mu (µ) and kappa (κ). The role of neural reward pathways linked to µ-opioid receptors and both dopaminergic and gamma-Aminobutyric acid (GABA)-ergic interneurons that express µ-opioid receptors were deliberated. However, kratom has been reported to be abused together with other illicit substances with high risk of potential addiction. There are also anecdotes of adverse effects and toxicity of kratom, i.e. tremor, fatigue, seizure, and death. Different countries have distinctive regulation and policy on the plantation and use of this plant when most of the countries banned the use of it because of its addiction problems and side effects. The aim of this review is to highlight on the potential use of kratom, unique 'herbs" as a substitution therapy for chronic pain and opioid addiction, based on the neurobiological perspective of pain and the underlying mechanism of actions of drug addiction.
Understanding the Pathophysiology of Premature Ejaculation: Bridging the Link between Pharmacological and Psychological Interventions

Yusof F, Sidi H, Das S, Midin M, Kumar J, Hatta MH

Curr Drug Targets, 2018;19(8):856-864.
PMID: 27993112 DOI: 10.2174/1389450117666161215161108

Premature ejaculation (PE) is one of the commonest male sexual dysfunctions. It is characterized by ejaculation which occurs before or soon after vaginal penetration, which causes significant psychological distress to the individual, and his partner. The exact cause of PE is still unknown but several mechanisms are proposed, and these involve complex interactions of neurophysiological, psychosocial, and cognitive factors. We discuss the role of serotonin, nitric oxide, phosphodiesterase enzymes and other neurotransmitters. Treatment of PE tends to co-occur with other sexual difficulties, especially erectile dysfunction (ED). Treatment with selective serotonin reuptake inhibitors (SSRIs) and Dapoxitene are also discussed in detail. The treatment strategy requires a comprehensive holistic approach incorporating both combination of psychopharmacological agent and cognitive-behavioral therapy (CBT). The present review highlights the integration of the hypothalamic-neural and reverberating emotional circuit and discusses the etiology and treatment for patients with PE.
New Insight in Improving Therapeutic Efficacy of Antipsychotic Agents: An Overview of Improved In Vitro and In Vivo Performance, Efficacy Upgradation and Future Prospects

Ei Thu H, Hussain Z, Shuid AN

Curr Drug Targets, 2018;19(8):865-876.
PMID: 27894237 DOI: 10.2174/1389450117666161125174625

Psychotic disorders are recognized as severe mental disorders that rigorously affect patient's personality, critical thinking, and perceptional ability. High prevalence, global dissemination and limitations of conventional pharmacological approaches compel a significant burden to the patient, medical professionals and the healthcare system. To date, numerous orally administered therapies are available for the management of depressive disorders, schizophrenia, anxiety, bipolar disorders and autism spectrum problems. However, poor water solubility, erratic oral absorption, extensive first-pass metabolism, low oral bioavailability and short half-lives are the major factors which limit the pharmaceutical significance and therapeutic feasibility of these agents. In recent decades, nanotechnology-based delivery systems have gained remarkable attention of the researchers to mitigate the pharmaceutical issues related to the antipsychotic therapies and to optimize their oral drug delivery, therapeutic outcomes, and patient compliance. Therefore, the present review was aimed to summarize the available in vitro and in vivo evidences signifying the pharmaceutical importance of the advanced delivery systems in improving the aqueous solubility, transmembrane permeability, oral bioavailability and therapeutic outcome of the antipsychotic agents.
Serotonin Selective Reuptake Inhibitors (SSRIs) and Female Sexual Dysfunction (FSD): Hypothesis on its Association and Options of Treatment

Rappek NAM, Sidi H, Kumar J, Kamarazaman S, Das S, Masiran R, et al.

Curr Drug Targets, 2018;19(12):1352-1358.
PMID: 28025939 DOI: 10.2174/1389450117666161227142947

Sexual dysfunctions are commonly seen in women on selective serotonin reuptake inhibitors (SSRIs). The complexities of female sexual functioning are reflected through modulation of inter- playing factors like the neuropsychophysiological factors, inter-personal and relationship issue, psychiatric co-morbidities and physical disorder. The incidence of SSRIs-induced FSD is difficult to estimate because of the potential confounding effects of SSRIs, presence of polypharmacy, marital effect, socio-cultural factors and due to the design and assessment problems in majority of the studies. The exact mechanism of FSD-induced SSRIs is unknown. It has been postulated that although SSRIs may modulate other neurotransmitter system such as nitric oxide (NO), noradrenergic and dopamine in inducing FSD. In the present review, we highlight current evidence regarding potential mechanism of SSRIs in causing FSD, which include low sexual desire (low libido), arousal difficulties (lack of lubrication), and anorgasmia. The specific association of FSD to SSRI use, has not been ellucidated. The relationship is dose-dependent, and may vary among the groups with respect to mechanism of serotonin and dopamine reuptake, induction of release of prolactin from the pituitary gland, anticholinergic side-effects, inhibition of NO synthesis and emotional-memory circuit encryption for sexual experiences. Various interventional strategies exist regarding the treatment of SSRI-induced FSD and this includes tolerance, titration dosage, substitution to another antidepressant drug and psychotherapy. There is a need of better understanding of SSRIs-induced FSD for better treatment outcome.

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