Like gabapentin, pregabalin binds to the a-2-delta subunit of the voltage-gated calcium channel in the CNS, leading to decreased release of various neurotransmitters [21]. However, disappointing results were reported with Rec-0545, a potent and selective antagonist of the 5-HT1A receptor evaluated by Recordati in a proof-of-concept trial for the treatment of OAB patients [ 42 ].
VaNIllOIDS aND TRaNSIeNT ReCePTOR POTeNTIal VaNIllOIDS-aNTagONISTS
OPIOIDS
NOP ReCePTOR agONISTS
CaNNabINOIDS
DO in rats and also promoted more efficient bladder emptying; isolated detrusor from degarelix-treated rats responded with larger carbachol contractions than controls [113]. Based on these results and since GnRH-R is expressed in the rat bladder [113], local intravesical administration of this class of drugs can be considered.
PHOSPHODIeSTeRaSe INHIbITORS
NITRIC OxIDe-DONOR DRUgS
NONSTeROIDal aNTI-INFlammaTORy DRUgS
PROSTaglaNDIN ReCePTOR aNTagONISTS
DRUgS aCTINg ON RHO-KINaSe PaTHway
NeRVe gROwTH FaCTOR blOCKaDe
DRUgS aCTINg ON ION CHaNNelS
Unfortunately, clinical trials with some of these drugs (e.g., ELB245 and ZD0947) were disappointing due to failure to demonstrate superiority over placebo for the treatment of OAB[189], or due to side effects leading to early termination[190]. Nevertheless, there is an ongoing effort to develop new classes of more potent and selective KCOs that may lead to bladder selective agent development in the future. Via selective inhibition of capsaicin-responsive nociceptive neurons expressing tetrodotoxin-resistant sodium channels, ralfinamide is thought to induce anti-nociceptive effects in animal models of inflammatory and neuropathic pain, as well as beneficial effects in DO[193].
An increase in intrabladder pressure or upregulation of these channels can induce afferent signaling during bladder filling [196]. Consequently, ENaC/ASIC ion channels may become novel targets for the pharmacological treatment of inflammatory and overactive bladder diseases [194].
CONClUSION
Promising preclinical data from both in vitro and in vivo studies have been published supporting the possibility of restoring normal detrusor function with BK channel openers [168,178] and A-type KV channel openers [179,180]. Although their role is still debated, there are also interesting preclinical observations on KATP channel openers [181–184], SK channel [185,186], combined SK/IK channel [187] and the putative TREK-1 K2P channel [188]. Tetrodotoxin-resistant sodium channels (subtype NaV1.8) are expressed in capsaicin-responsive primary afferent neurons innervating the bladder and their blockade with antisense oligodeoxy-nucleotide reduced urinary frequency induced by acetic acid-induced bladder irritation acid [191].
Effect of the anticonvulsant drugs pregabalin and lamotrigine on urodynamic parameters in an animal model of neurogenic detrusor overactivity. The role of the transient receptor potential (TRP) superfamily of cation-selective channels in the management of the overactive bladder. Effects of TRPV4 cation channel activation on rat primary bladder afferent activities.
A dose-finding study of the luteinizing hormone receptor antagonist cetrorelix pamoate in the treatment of patients with symptomatic benign prostatic hyperplasia. Effects of the gonadotropin-releasing hormone antagonist ganirelix on normal voiding and prostaglandin E(2)-induced detrusor overactivity in conscious female rats. Nerve growth factor in the adult bladder regulates the shape and function of neurons.
Effects of intravenous administration of the K+ channel opener, ZD6169, in conscious rats with and without bladder outlet obstruction.
BRIEF ARTICLE
Effect of the maternal-fetal interface immunoregulation on the occurrence of intrahepatic cholestasis of pregnancy
Abstract
INTRODUCTION
MINIREVIEWS
Exposure to high levels of bile acids in the blood during pregnancy can cause damage to the fetus's heart, liver, lungs and other organs[1]. In addition, bile acids can increase the expression of oxytocin receptors in the uterine muscle fibers, which increases the sensitivity to oxytocin[2]. It may be related to the mutation of genes such as MDR3, BSEP, ATP8B1[5-7], imbalance of estrogen and progesterone[8], or thyroid hormones[9].
During the last decade, the association of placental immunological changes has been found to be increasingly associated with the development of ICP[10]. The embryo, as an alloantigen with paternal components, is essentially an allogeneic uterine allograft.
RESEARCH ADVANCES ON IMMUNE TOLERANCE BETWEEN THE MATERNAL-
These factors can lead to vasospasm and hypoxia at the surface of the placenta and increased vascular permeability[3]. When this happens in the liver, the Na+-K+-ATP activity and the bile salt transport function can decrease, causing intrahepatic cholestasis. Humoral immune tolerance at the maternal-fetal interface is achieved by blocking antibodies (BA) IgG and its subclasses.
BAs are produced idiotypically as anti-HLA antibodies that are reactive with the fetal half of the HLS self-antigens [23]. It can bind the trophoblast epitope surface antigen to evade recognition by maternal killer T cells, thereby allowing the fetus to evade the maternal immune response [24].
IMMUNE TOLERANCE DISORDER AND THE PATHOGENESIS OF ICP
IMMUNE ETIOLOGY STUDIES ON ICP
The strength of the maternal immune system response to paternal antigens of the fetus correlates with susceptibility to the development of ICP [40]. He believes that these results demonstrate that NK cell immune activity not only has potential immunoprotective effects, but is also the key cellular immune recognition mediated by the maternal-fetal interface [31,42]. Research findings have undoubtedly clarified our understanding of the changes in immune cell activation and other immune factors in ICP.
But the factors that disrupt the balance of immune tolerance at the maternal-fetal interface are not clear. Although IL-6 and IL-10 levels are associated with ICP [45], further studies are needed to clarify whether prenatal stress may be part of the pathogenesis of ICP.
TO INVESTIGATE THE IMMUNE
Nowak pointed out that women with activating killer cell immunoglobulin-like receptor (KIR) gene and the KIR inhibitory receptor gene ratio between 0.33-0.83 tend to have spontaneous abortion while women with a ratio between 0, 86-1,25 tend to have a NK cell protective effect, which suggests that the KIR genotypes most likely associate with pathological pregnancies, such as spontaneous abortion [30,41]. Guimond found that women with missing T cells can have a normal pregnancy, but the missing NK cells show pathological changes of pregnancy. This prompted an elucidation of immunogenetic factors in the pathogenesis of ICP, including the ligand NK cell surface antigen, receptor and their interaction in trophoblast cells.
Unfortunately, the genetic mechanism for the pathogenesis of ICP in immune genes is not yet clear. In addition, maternal factors such as neuroendocrine interactions also influence the decidual immune microenvironment.
IMBALANCE AS A MECHANISM OF ICP
TNF can also activate neutrophils, promote their aggregation in the liver and induce degranulation, releasing proteases and oxygen free radicals, causing liver cell damage [27,47]. Then, the cellular immune system activates and secretes Th1 cytokines into the mother's circulation, causing damage to the liver cells, resulting in ICP (Figure 1). These pathological changes thus contribute to increased fetal morbidity due to maternal changes, mediated (at least in part) by disruption of the maternal-fetal immune balance.
Due to the etiological factor and pathogenesis of ICP, there is currently no effective clinical standard to prevent and cure ICP. Any approach that modulates the immune tolerance of the maternal-fetal interface to the natural state may provide insights into the understanding of ICP, which may lead to a targeted treatment.
Role of CD4+ CD25 highly regulatory T cells in the pathogenesis of intrahepatic cholestasis of pregnancy]. Placental gene expression profiles of intrahepatic cholestasis during pregnancy reveal involvement of multiple molecular pathways in angiogenesis and inflammation. Expression of corticotrophin-releasing hormone and its receptor in patients with intrahepatic cholestasis of pregnancy.
Expression of human leukocyte antigen G on the human placenta and its gene polymorphism in relation to intrahepatic cholestasis during pregnancy. Lithocholic acid-induced placental tumor necrosis factor-α upregulation and syncytiotrophoblast cell apoptosis in intrahepatic cholestasis of pregnancy.
Mental health of perinatal women
Pregnancy and childbirth are expected to be auspicious times in women's lives, when physiological and psychological changes prepare women for motherhood duties. However, pregnancy and childbirth are seen as major stressors for some women as they struggle with self-esteem and undermining of self-esteem, followed by the feeling of being unable to care for the newborn. These negative feelings are followed by a deterioration in mental health status and can cause mental illness during the perinatal period[1].
PREVALENCE AND RISK FACTORS OF PERINATAL MENTAL ILLNESSES
PERINATAL MENTAL ILLNESS AND CHILD’S WELL-BEING
The association between antenatal depression and fetal and neonatal outcomes has been investigated in two meta-analyses[16,17]. Studies report a significant association between antenatal depression and an increased risk of preterm birth (less than 37 wk of gestation) and low birth weight of the baby (especially when the mother lives in a low-income country). . It was also suggested that the level of risk depends on the severity of depressive symptoms.
Children of these mothers have been shown to be at increased risk for child neglect, abuse, attachment problems, delayed growth and motor development, emotional problems and a range of negative early childhood cognitive outcomes. In addition, these children are at increased risk of clinical depression in late adolescence while experiencing the effects of stress related to caring for their mentally ill parent/s.
PREVENTION AND DIAGNOSIS
Rates of pregnancy and postnatal health complications and interventions are higher among women with perinatal mental illness, and their infants require a higher level of intensive care[18,19]. Nutritional neglect, severe hunger and malnutrition are also other huge problems in these children, most of whom are female and under five years of age[20-22]. These problems have resulted in increased concerns regarding the well-being of the child in the family and have brought a large number of families to the attention of child protection authorities[23-26].
TREATMENT
MENTAL HEALTH INITIATIVES
Research on mental health problems in the United States and other countries has shown that, despite high rates of mental illness in these countries, many people do not seek professional counseling and support or delay seeking help as long as they can. For example, the World Health Initiative of the World Health Organization[38] examined data from 28 countries and found that in both developed and developing countries only a small proportion of the population received treatment for their mental disorders such as mood or anxiety disorders. The results of the survey showed that 43.6% of the participants believed that postnatal depression was the most common health problem for women after giving birth.
Approximately two-thirds of participants considered postnatal depression to have a biological rather than a psychosocial etiology. It was also revealed that more than 80% of adult Australians believed all new mothers should have routine assessments for depression.
CONCLUSION AND DIRECTION FOR FUTURE RESEARCH
They can identify women at risk, provide them with an effective pathway and help alleviate postpartum mental health problems for most women[36,37]. Intimate partner abuse before and during pregnancy as risk factors for postpartum mental health problems. Postnatal mental health findings of women giving birth in Australia from the National Postnatal Depression Program beyond Blue.
WPA Guidelines for the Protection and Promotion of Mental Health in Children of Persons with Severe Mental Disorders. Evaluating the clinical efficacy of a liaison model of primary care focused, nurse-led perinatal mental health consultation.