Current Drug Targets (v.14, #8)

Treatment of Luteal Phase Defects in Assisted Reproduction by Elkin Munoz, Esther Taboas, Susana Portela, Jesus Aguilar, Iria Fernandez, Luis Munoz, Ernesto Bosch (832-842).
Abnormal luteal function is a common issue in assisted reproduction techniques associated with ovarian stimulationprobably due to low levels of LH in the middle and in the late luteal phase. This defect seems to be associated withsupraphysiological steroid levels at the end of follicular phase. The luteal phase insufficiency has not got a diagnostic testwhich has proven reliable in a clinical setting. Luteal phase after ovarian stimulation becomes shorter and insufficient, resultingin lower pregnancy rates. Luteal phase support with progesterone or hCG improves pregnancy outcomes and nodifferences are found among different routes of administration. However, hCG increases the risk of ovarian hyperstimulationsyndrome. In relation to the length of luteal support, the day of starting it remains controversial and it does not seemnecessary to continue once a pregnancy has been established. After GnRHa triggering ovulation, intensive luteal supportor hCG bolus can overcome the defect in luteal phase, but more studies are needed to show the LH utility as support.

GnRH-Agonist Triggering to Avoid Ovarian Hyperstimulation Syndrome: A Review of the Evidence by Maria Cerrillo Martinez, Francisco J. Ruiz, Juan A. Garc-a-Velasco (843-849).
Ovarian hyperstimulation syndrome (OHSS) is the most serious iatrogenic complication associated with ovarianstimulation. It is only in recent years that the understanding of OHSS has advanced sufficiently to develop treatmentoptions aimed at reducing the incidence and effects of OHSS. Currently, there is no good test or method for identifyingsusceptible patients. Nevertheless, progress has been made in the prevention of OHSS. Physicians have a wide range oftreatment options, including coasting, re-initiation of a GnRH antagonist, and application of agonists, like dopamine in theluteal phase or triggering oocyte maturation with a bolus of GnRH agonist. These treatments, together with other procedures,like oocyte/embryo vitrification, have allowed physicians to improve the prediction and prevention of OHSS.

The Impact of Genetics Profile (Gene Polymorphisms) in Obese Non- PCOS Women Entering an IVF/ICSI Program by Elli Anagnostou, Petros Drakakis, Spyridon Marinopoulos, Despina Mavrogianni, Dimitrios Loutradis (850-855).
Data concerning the effects of increased body mass index (BMI) on ovarian and pregnancy outcome are rich,but the results are rather controversial. Regarding pharmacogenetics, gene polymorphisms of hormonal receptor genes,such as Estrogen Receptor alpha (ESR1), Estrogen Receptor beta (ESR2) and FSH receptor (FSHR) genes, are associatedwith ovarian stimulation and pregnancy outcome and may constitute a useful tool for ART experts for the prediction ofthis outcome. The aim of this study is to track differences in the distribution of gene polymorphisms among obese non-PCOS and non-obese patients concerning three distinct genes which are involved in the ovarian stimulation mechanism:PvuII polymorphism of ESR1 gene, RsaI polymorphism of ESR2 gene and Ser680Asn variation of FSHR gene, using restrictionfragment length polymorphism analysis and real-time polymerase chain reaction. A total of 151 normally ovulatingfemale patients underwent IVF or ICSI. Interestingly, the pregnancy rate in the BMI≥30 kg/m2 group was higher in astatistically significant way (40.9% versus 17.8%, p=0.023). The obese patients of this study were in need of increased totalFSH dose in order to achieve a satisfactory oocyte number (p<0.001) and needed more days of stimulation (p=0.002),but also presented lower basal FSH levels (p=0.032), which may explain, to an extend, the better pregnancy outcome.Concerning the polymorphisms of ESR1, ESR2 and FSHR genes, we did not observe differences in the genotype distributionwhen we compared the obese non-PCOS population with the non-obese population. Thus, obesity does not constitutean additional indication to perform a genetic analysis before entering an IVF/ICSI program.

Systemic chemotherapy frequently causes primary ovarian insufficiency. In prepubertal girls, currently the onlyoption to preserve ovarian function is ovarian tissue preservation. The use of gonadotropin-releasing hormone analoguesgiven in combination with chemotherapy has been studied in reproductive age women. The exact mechanism is unknown,but some of the proposed protective mechanisms could theoretically protect the prepubertal ovary as it has been theorizedin many of the studies on reproductive age women. None of the studies implies an adverse affect of GnRH analogue administrationin terms of worsening health or cancer status. As 83% of children diagnosed with cancer will survive intoadulthood, GnRH analogue administration to female childhood cancer patients in combination with chemotherapy mightrepresent a valuable attempt to preserve future ovarian function and fertility when ovarian tissue preservation is not an option.

Improving the Embryo Implantation Via Novel Molecular Targets by Jingjie Li, Xiaoyan Liang, Zijiang Chen (864-871).
With the development of modern assisted reproductive technology(ART), the treatment of infertility and thepregnant outcome by ART have been significantly improved. However, implantation failure, particularly the unexplainedrepeated implantation failure (RIF), is still the unsolved and principal problem to affect the outcome of ART. The completedembryo, the receptive uterus and a series of precisely controlled molecular events between the blastocyst and endometriumare all indispensable for the success of implantation. Thus, deep insight into the molecular mechanisms thatimpact the endometrial receptivity and embryo implantation is an effective way to improve the implantation rate. Here thenovel molecular targets and biomarkers have been reviewed that are reported and proved during more recent years in theaspects of ion channels, aquaporins, long noncoding RNAs and microRNAs, kruppel like factors, metabolism relatedmolecules and the endogenous retroviruses. Evaluation of implantation markers may help clinicians to predict pregnancyoutcome and detect occult implantation deficiency. Moreover, these novel molecular targets are expected to apply to theclinical practice from bench to bedside and improve the implantation efficiency in ART and natural conception.

Aromatherapy and the Central Nerve System (CNS): Therapeutic Mechanism and its Associated Genes by Xiao Nan Lv, Zhu Jun Liu, Huan Jing Zhang, Chi Meng Tzeng (872-879).
Molecular medical research on aromatherapy has been steadily increasing for use as an adjuvant therapy inmanaging psychiatric disorders and to examine its therapeutic mechanisms. Most studies, as well as clinically applied experience,have indicated that various essential oils, such as lavender, lemon and bergamot can help to relieve stress, anxiety,depression and other mood disorders. Most notably, inhalation of essential oils can communicate signals to the olfactorysystem and stimulate the brain to exert neurotransmitters (e.g. serotonin and dopamine) thereby further regulatingmood. However, little research has been done on the molecular mechanisms underlying these effects, thus their mechanismof action remains ambiguous. Several hypotheses have been proposed regarding the therapeutic mechanism of depression.These have mainly centered on possible deficiencies in monoamines, neurotrophins, the neuroendocrine system,c-AMP, cation channels as well as neuroimmune interactions and epigenetics, however the precise mechanism or mechanismsrelated to depression have yet to be elucidated. In the current study, the effectiveness of aromatherapy for alleviatingpsychiatric disorders was examined using data collected from previously published studies and our unpublished data.A possible signaling pathway from olfactory system to the central nerve system and the associated key molecular elementsof aromatherapy are also proposed.

Perioperative Handling of Antiplatelet Drugs. A Critical Appraisal by Matteo Nicola Dario Di Minno, Marco Milone, Pasquale Mastronardi, Pasquale Ambrosino, Alessandro Di Minno, Alessandro Parolari, Elena Tremoli, Domenico Prisco (880-888).
Because of more and more accurate cardiovascular prevention programs and the increasing mean age of thegeneral population, the use of antiplatelet treatments is progressively increasing in the last years. Moreover, the widespreaduse of bare-metal stents (BMS) and drug-eluting stents (DES) significantly increased the number of subjects withthe need of a combined antiplatelet treatment: Aspirin (ASA) and Clopidogrel (CLO).</P><P>Within the first year after coronary stenting, approximately 5% of patients needs to undergo non-cardiac surgery interventions.In such patients, current guidelines suggest to stop antiplatelet agents 7-10 days before surgery to avoid the risk ofincreasing blood loss. On the other hand, it has been shown that the risk of surgical bleeding, if antiplatelet drugs are continued,is lower than that of coronary thrombosis if they are withdrawn. Thus, an accurate stratification of the populationaccording to the thrombotic risk is needed and the bleeding and the thrombotic risk should be considered in parallel. Althougha growing amount of recommendations have been released by several Societies, the perioperative handling of antiplateletdrugs still represents a major concern in clinical practice. In this review we report the major literature data aboutthe perioperative handling of antiplatelet drugs. Moreover, in order to describe future treatment perspectives and to identifyvaluable alternatives to current antiplatelet agents in the perioperative period, pharmacokinetic and pharmacodynamiccharacteristics of newer antiplatelet drugs are reported and analyzed.

Overexpression of the human epidermal growth factor receptor 2 (HER2) is identified in approximately 25-30% of breast cancers and indicates a poor prognosis. Trastuzumab, the anti-HER2 monoclonal antibody (mAb), hasshown significant clinical effects selectively in HER2-overexpressing metastatic breast cancer (MBC) with improvedoverall survival and reduced recurrent risk. However, there is an urgent need to develop new strategies to overcome innateand acquired trastuzumab resistance, which has increasingly occurred. Recently, an increased understanding of mechanismsof trastuzumab resistance significantly promotes the development of novel targeted therapies for trastuzumabrefractorydisease. It is believed that aberrant activations of several signaling pathways involving the human epidermalgrowth factor receptor (EGFR/HER) family, phosphoinositide 3 kinase/Akt (PI3K/Akt) pathway, and vascular endothelialgrowth factor (VEGF) family, contribute to the development of trastuzumab resistance. Novel agents that target theserelevant signal pathways provide some potential solutions, such as tyrosine kinase inhibitors (TKIs) and mAbs. HER2 isalso recognized as an immunotherapeutic target. The failure to induce immune-mediated antitumor response is anotherimportant reason for trastuzumab resistance. Strategies to boost T cell-mediated immune responses specific to HER2 includingHER2 vaccines and bispecific antibodies (bsAbs) could be developed as a promising way to prevent relapse orcombat trastuzumab resistance. In this review, the emerging data from preclinical and clinical studies related to thesenovel therapies will be discussed.

Currently, schizophrenia, as a serious psychiatric disorder, continues affecting the quality of life in the psychotics.This disease is often debilitating and chronic, showing broad symptoms at one end by hallucinations, delusions,thought disorder and the other end by affective flattening, catatonia, social isolation. In order to combat this disease, manyantipsychotic drugs have been developed and introduced into clinical practice in the past half century. However, only asmall minority of them can treat effectively schizophrenia without side effects. In view of this situation, high attention hasbeen given to the exploration of desired antipsychotic agents influential especially through the modulation of dopamineand serotonin receptors with substantial strides made in recent years, leading to the discovery of many novel chemical entitieswith intriguing profiles. In this review, we summarize novel structural antipsychotics in development and discuss thefuture direction of ideal antipsychotic drug candiates. In particular, the promising atypical antipsychotic profiles of newmolecules and the inspirations for their design are highlighted.

Hypoxia-Inducible Factor-1 (HIF-1): A Potential Target for Intervention in Ocular Neovascular Diseases by Ramya Krishna Vadlapatla, Aswani Dutt Vadlapudi, Ashim K. Mitra (919-935).
Constant oxygen supply is essential for proper tissue development, homeostasis and function of all eukaryoticorganisms. Cellular response to reduced oxygen levels is mediated by the transcriptional regulator hypoxia-inducible factor-1 (HIF-1). It is a heterodimeric complex protein consisting of an oxygen dependent subunit (HIF-1α) and a constitutivelyexpressed nuclear subunit (HIF-1β). In normoxic conditions, de novo synthesized cytoplasmic HIF-1α is degradedby 26S proteasome. Under hypoxic conditions, HIF-1α is stabilized, binds with HIF-1β and activates transcription ofvarious target genes. These genes play a key role in regulating angiogenesis, cell survival, proliferation, chemotherapy,radiation resistance, invasion, metastasis, genetic instability, immortalization, immune evasion, metabolism and stem cellmaintenance. This review highlights the importance of hypoxia signaling in development and progression of various visionthreatening pathologies such as diabetic retinopathy, retinopathy of prematurity, age-related macular degenerationand glaucoma. Further, various inhibitors of HIF-1 pathway that may have a viable potential in the treatment of oxygendependentocular diseases are also discussed.