Development Of Pharmacotherapies Research Articles

Large multicenter randomized trials in autism: key insights gained from the balovaptan clinical development program

BackgroundAutism spectrum disorder (ASD) is a common and heterogeneous neurodevelopmental condition that is characterized by the core symptoms of social communication difficulties and restricted and repetitive behaviors. At present, there is an unmet medical need for therapies to ameliorate these core symptoms in order to improve quality of life of autistic individuals. However, several challenges are currently faced by the ASD community relating to the development of pharmacotherapies, namely in the conduct of clinical trials. Balovaptan is a V1a receptor antagonist that has been investigated to improve social communication difficulties in individuals with ASD. In this viewpoint, we draw upon our recent first-hand experiences of the balovaptan clinical development program to describe current challenges of ASD trials.Discussion pointsThe balovaptan trials were conducted in a wide age range of individuals with ASD with the added complexities associated with international trials. When summarizing all three randomized trials of balovaptan, a placebo response was observed across several outcome measures. Placebo response was predicted by greater baseline symptom severity, online recruitment of participants, and less experienced or non-academic trial sites. We also highlight challenges relating to selection of outcome measures in ASD, the impact of baseline characteristics, and the role of expectation bias in influencing trial results.ConclusionTaken together, the balovaptan clinical development program has advanced our understanding of the key challenges facing ASD treatment research. The insights gained can be used to inform and improve the design of future clinical trials with the collective aim of developing efficacious therapies to support individuals with ASD.

Promotion of nonalcoholic steatohepatitis by RNA N6-methyladenosine reader IGF2BP2 in mice

AbstractNonalcoholic steatohepatitis (NASH) has emerged as the major cause of end-stage liver diseases. However, an incomplete understanding of its molecular mechanisms severely dampens the development of pharmacotherapies. In the present study, through systematic screening of genome-wide mRNA expression from three mouse models of hepatic inflammation and fibrosis, we identified IGF2BP2, an N6-methyladenosine modification reader, as a key regulator that promotes NASH progression in mice. Adenovirus or adeno-associated virus-mediated overexpression of IGF2BP2 could induce liver steatosis, inflammation, and fibrosis in mice, at least in part, by increasing Tab2 mRNA stability. Besides, hepatic overexpression of IGF2BP2 mimicked gene expression profiles and molecular pathways of human NASH livers. Of potential clinical significance, IGF2BP2 expression is significantly upregulated in the livers of NASH patients. Moreover, knockdown of IGF2BP2 substantially alleviated liver injury, inflammation, and fibrosis in diet-induced NASH mice. Taken together, our findings reveal an important role of IGF2BP2 in NASH, which may provide a new therapeutic target for the treatment of NASH.

Sex‐specific cholinergic regulation of dopamine release mechanisms through nicotinic receptors in the nucleus accumbens

Biological sex has been pinpointed as significant biological factor impacting the prevalence and prognosis of Substance Use Disorder (SUD). Despite the overwhelming utilization of male subjects in SUD research, epidemiological evidence shows that women are the most susceptible population. At the hub of female vulnerability to SUD is significant dysfunction in the mesolimbic dopamine system connecting the ventral tegmental area (VTA) to the nucleus accumbens (NAc). Importantly, an important characteristic of dopamine release from axon terminals in the NAc is that it is rapidly modulated by local regulatory microcircuit mechanisms independent of somatic activity in the VTA. In the NAc, dopamine is released in tonic (slow and regular) and phasic (short, burst/spikes) patterns that are subject to heavy modulation by cholinergic (ChAT) interneurons signaling through α4β2*‐containing nicotinic acetylcholine receptors (nAChRs) located directly on dopamine terminals. Previous work suggests that ChAT regulation of dopamine release through nAChRs is fundamentally different between males and females, yet the processes and mechanisms that underlie these sex differences are largely unknown. In this project, we took a multifaceted approach to determine sex‐dependent neurochemical mechanisms that underlie ChAT regulation of dopamine release through nAChRs in male, naturally cycling and ovariectomized (OVX) female mice. Using ex vivo fast scan cyclic voltammetry (FSCV) paired with pharmacological applications, we found that ChAT regulation of dopamine release through α4β2*‐nAChRs is not present in female mice under most conditions. Deficits in nAChR modulation of dopamine release in intact females were not affected by the estrous cycle; however, they were rescued by ovariectomy – indicating that ovarian hormones play significant a role in this process. Critically, we find that 17β−Estradiol (E2) increases dopamine release acutely, an effect that is blocked by antagonism of α4β2*‐nAChRs. Additionally, we observed reduced nAChR agonist effects on dopamine release in females; which is what would be expected for desensitized receptors. Finally, Gq‐DREADD behavior studies revealed that male mice learned at a faster rate than intact females when ChAT interneurons were activated. Overall, we show that circulating ovarian hormones, regardless of the hormone cycle, alter the ability of α4β2*‐nAChRs on dopamine terminals to modulate dopamine release in the NAc. This suggests that sex differences in ChAT regulation of dopamine neurotransmission underlies sex‐dependent differentiation in reward learning. Moving forward, it will be critical to directly link these sex differences to reward learning for the development of sex‐specific pharmacotherapies to treat SUD.

Activation of a novel α2AAR‐spinophilin‐cofilin axis determines the effect of α2 adrenergic drugs on fear memory reconsolidation

Posttraumatic stress disorder (PTSD) after the pandemic has emerged as a major neuropsychiatric component of the post‐acute COVID‐19 syndrome, yet the current pharmacotherapy for PTSD is limited. The use of adrenergic drugs to treat PTSD has been suggested, yet hindered by conflicting clinical results and a lack of mechanistic understanding of drug actions. Our studies using both genetically modified mice and human induced pluripotent stem cell‐derived neurons reveals a novel α2A adrenergic receptor (α2AAR)‐spinophilin‐cofilin axis in the hippocampus that is critical for regulation of contextual fear memory reconsolidation. We have further found that two a2 ligands, clonidine and guanfacine, exhibit differential abilities in activating this signaling axis to disrupt fear memory reconsolidation. Stimulation of a2AAR with clonidine, but not guanfacine, promotes the interaction of cofilin, an actin binding protein, with the dendritic spine scaffolding protein spinophilin to induce cofilin activation at the synapse. Spinophilin‐dependent regulation of cofilin is required for clonidine‐induced disruption of contextual fear memory reconsolidation. Our results inform the interpretation of differential clinical observations of these two drugs on PTSD, and suggest that clonidine could provide immediate treatment for PTSD symptoms related to the current pandemic. Furthermore, our study indicates modulation of dendritic spine morphology may represent an effective strategy for development of new pharmacotherapies for PTSD.

A novel soluble epoxide hydrolase vaccine protects murine cardiac muscle against myocardial infarction

Myocardial infarction is still a life-threatening disease, even though its prognosis has been improved through the development of percutaneous coronary intervention and pharmacotherapy. In addition, heart failure due to remodeling after myocardial infarction requires lifelong management. The aim of this study was to develop a novel treatment suppressing the myocardial damage done by myocardial infarction. We focused on inhibition of soluble epoxide hydrolase to prolong the activation of epoxyeicosatrienoic acids, which have vasodilatory and anti-inflammatory properties. We successfully made a new vaccine to inactivate soluble epoxide hydrolase, and we have evaluated the effect of the vaccine in a rat myocardial infarction model. In the vaccinated group, the ischemic area was significantly reduced, and cardiac function was significantly preserved. Vaccine treatment clearly increased microvessels in the border area and suppressed fibrosis secondary to myocardial infarction. This soluble epoxide hydrolase vaccine is a novel treatment for improving cardiac function following myocardial infarction.

Rifapentine is an entry and replication inhibitor against yellow fever virus both in vitro and in vivo

ABSTRACT Yellow fever virus (YFV) infection is a major public concern that threatens a large population in South America and Africa. No specific anti-YFV drugs are available till now. Here, we report that rifapentine is a potent YFV inhibitor in various cell lines by high-throughput drugs screening, acting at both cell entry and replication steps. Kinetic test and binding assay suggest that rifapentine interferes the viral attachment to the target cells. The application of YFV replicon and surface plasmon resonance assay indicates that rifapentine suppresses viral replication by binding to the RNA-dependent RNA polymerase (RdRp) domain of viral nonstructural protein NS5. Further molecular docking suggests that it might interact with the active centre of RdRp. Rifapentine significantly improves the survival rate, alleviates clinical signs, and reduces virus load and injury in targeted organs both in YFV-infected type I interferon receptor knockout A129−/− and wild-type C57 mice. The antiviral effect in vivo is robust during both prophylactic intervention and therapeutic treatment, and the activity is superior to sofosbuvir, a previously reported YFV inhibitor in mice. Our data show that rifapentine may serve as an effective anti-YFV agent, providing promising prospects in the development of YFV pharmacotherapy.

Acute intermittent hypoxia drives hepatic de novo lipogenesis in humans and rodents

Background and aimsNon-alcoholic fatty liver disease (NAFLD) is the most common chronic liver condition. It is tightly associated with an adverse metabolic phenotype (including obesity and type 2 diabetes) as well as with obstructive sleep apnoea (OSA) of which intermittent hypoxia is a critical component. Hepatic de novo lipogenesis (DNL) is a significant contributor to hepatic lipid content and the pathogenesis of NAFLD and has been proposed as a key pathway to target in the development of pharmacotherapies to treat NAFLD. Our aim is to use experimental models to investigate the impact of hypoxia on hepatic lipid metabolism independent of obesity and metabolic disease. MethodsHuman and rodent studies incorporating stable isotopes and hyperinsulinaemic euglycaemic clamp studies were performed to assess the regulation of DNL and broader metabolic phenotype by intermittent hypoxia. Cell-based studies, including pharmacological and genetic manipulation of hypoxia-inducible factors (HIF), were used to examine the underlying mechanisms. ResultsHepatic DNL increased in response to acute intermittent hypoxia in humans, without alteration in glucose production or disposal. These observations were endorsed in a prolonged model of intermittent hypoxia in rodents using stable isotopic assessment of lipid metabolism. Changes in DNL were paralleled by increases in hepatic gene expression of acetyl CoA carboxylase 1 and fatty acid synthase. In human hepatoma cell lines, hypoxia increased both DNL and fatty acid uptake through HIF-1α and -2α dependent mechanisms. ConclusionsThese studies provide robust evidence linking intermittent hypoxia and the regulation of DNL in both acute and sustained in vivo models of intermittent hypoxia, providing an important mechanistic link between hypoxia and NAFLD.

New Directions in the Development of Pharmacotherapy for Osteoarthrosis Based on Modern Concepts of the Disease Pathogenesis (A Review)

New Directions in the Development of Pharmacotherapy for Osteoarthrosis Based on Modern Concepts of the Disease Pathogenesis (A Review)

Bladder cancer: what's new in 2020-2021

This article aims to give an up-to-date review of studies on the diagnosis and treatment of patients with bladder cancer (BCa). We emphasize that the assessment of treatment and prognosis using specific markers is a promising method. However, clinical data currently outpace the results of molecular testing. Patients with luminal BCa demonstrate worse response to pharmacotherapy than those with other BCa types. The implementation of new drugs such as avelumab, enfortumab, and new drug combinations into clinical practice raised hopes to improve treatment outcomes of patients with locally advanced and metastatic bladder cancer. The development of new pharmacotherapy and immunotherapy regimens will improve treatment outcomes. We describe the experience of some foreign countries with the treatment and outpatient follow-up of patients after radical cystectomy. The article also contains the guidelines by the European Association of Urology on the treatment of patients with urinary tract cancers during the COVID-19 pandemic.

Інновації в стратегії фармакотерапії ранніх стадій когнітивних розладів

Стаття присвячена проблемі корекції когнітивних розладів, що супроводжують порушення мозкового кровообігу. Наголошено, що застосування адекватної фармакопрофілактичної стратегії при синдромі помірних когнітивних розладів більш ефективне, ніж при клініці деменції, що вже маніфестувала. Провідним компонентом такої стратегії є вплив на фундаментальні нейромедіаторні механізми розвитку цього синдрому — холін-, ГАМК- та дофамінергічні. До останнього часу в неврологічній практиці комбіновані препарати були представлені, як правило, або полікомпонентними рослинними седативними засобами, або комбінацією двох ноотропних складових, що далеко не завжди дозволяла забезпечити клінічний вплив на всі ланки патогенезу синдрому. Нещодавно в Україні з’явився принципово новий, інноваційний комбінований препарат (Когніфен), що містить у своєму складі два абсолютно різні за хімічною структурою та фармакологічними властивостями компоненти, які оптимально доповнюють один одного із точки зору клініко-фармакологічних ефектів, — фенібут (300 мг) та іпідакрин (5 мг). Появу Когніфену можна розглядати як новий етап у розвитку клінічної нейрофармакології та фармакотерапії когнітивних розладів на ранніх стадіях.

The Use of Bioactive Compounds in Hyperglycemia- and Amyloid Fibrils-Induced Toxicity in Type 2 Diabetes and Alzheimer's Disease.

It has become increasingly apparent that defective insulin signaling may increase the risk for developing Alzheimer’s disease (AD), influence neurodegeneration through promotion of amyloid formation or by increasing inflammatory responses to intraneuronal β-amyloid. Recent work has demonstrated that hyperglycemia is linked to cognitive decline, with elevated levels of glucose causing oxidative stress in vulnerable tissues such as the brain. The ability of β-amyloid peptide to form β-sheet-rich aggregates and induce apoptosis has made amyloid fibrils a leading target for the development of novel pharmacotherapies used in managing and treatment of neuropathological conditions such as AD-related cognitive decline. Additionally, deposits of β-sheets folded amylin, a glucose homeostasis regulator, are also present in diabetic patients. Thus, therapeutic compounds capable of reducing intracellular protein aggregation in models of neurodegenerative disorders may prove useful in ameliorating type 2 diabetes mellitus symptoms. Furthermore, both diabetes and neurodegenerative conditions, such as AD, are characterized by chronic inflammatory responses accompanied by the presence of dysregulated inflammatory biomarkers. This review presents current evidence describing the role of various small bioactive molecules known to ameliorate amyloidosis and subsequent effects in prevention and development of diabetes and AD. It also highlights the potential efficacy of peptide–drug conjugates capable of targeting intracellular targets.

Substance abuse and neurotransmission.

The number of people who suffer from a substance abuse disorder has continued to rise over the last decade; particularly, the number of drug-related overdose deaths has sharply increased during the COVID-19 pandemic. Converging lines of clinical observations, supported by imaging and neuropsychological performance testing, have demonstrated that substance abuse-induced dysregulation of neurotransmissions in the brain is critical for development and expression of the addictive properties of abused substances. Recent scientific advances have allowed for better understanding of the neurobiological processes that mediates drugs of abuse and addiction. This chapter presents the past classic concepts and the recent advances in our knowledge about how cocaine, amphetamines, opioids, alcohol, and nicotine alter multiple neurotransmitter systems, which contribute to the behaviors associated with each drug. Additionally, we discuss the interactive effects of HIV-1 or COVID-19 and substance abuse on neurotransmission and neurobiological pathways. Finally, we introduce therapeutic strategies for development of pharmacotherapies for substance abuse disorders.

Current Perspectives on Selective Dopamine D3 Receptor Antagonists/Partial Agonists as Pharmacotherapeutics for Opioid and Psychostimulant Use Disorders.

Over three decades of evidence indicate that dopamine (DA) D3 receptors (D3R) are involved in the control of drug-seeking behavior and may play an important role in the pathophysiology of substance use disorders (SUD). The expectation that a selective D3R antagonist/partial agonist would be efficacious for the treatment of SUD is based on the following key observations. First, D3R are distributed in strategic areas belonging to the mesolimbic DA system such as the ventral striatum, midbrain, and ventral pallidum, which have been associated with behaviors controlled by the presentation of drug-associated cues. Second, repeated exposure to drugs of abuse produces neuroadaptations in the D3R system. Third, the synthesis and characterization of highly potent and selective D3R antagonists/partial agonists have further strengthened the role of the D3R in SUD. Based on extensive preclinical and preliminary clinical evidence, the D3R shows promise as a target for the development of pharmacotherapies for SUD as reflected by their potential to (1) regulate the motivation to self-administer drugs and (2) disrupt the responsiveness to drug-associated stimuli that play a key role in reinstatement of drug-seeking behavior triggered by re-exposure to the drug itself, drug-associated environmental cues, or stress. The availability of PET ligands to assess clinically relevant receptor occupancy by selective D3R antagonists/partial agonists, the definition of reliable dosing, and the prospect of using human laboratory models may further guide the design of clinical proof of concept studies. Pivotal clinical trials for more rapid progression of this target toward regulatory approval are urgently required. Finally, the discovery that highly selective D3R antagonists, such as R-VK4-116 and R-VK4-40, do not adversely affect peripheral biometrics or cardiovascular effects alone or in the presence of oxycodone or cocaine suggests that this class of drugs has great potential in safely treating psychostimulant and/or opioid use disorders.

Involvement of the ghrelin system in the maintenance and reinstatement of cocaine-motivated behaviors: a role of adrenergic action at peripheral β1 receptors

Cocaine addiction is a significant medical and public concern. Despite decades of research effort, development of pharmacotherapy for cocaine use disorder remains largely unsuccessful. This may be partially due to insufficient understanding of the complex biological mechanisms involved in the pathophysiology of this disorder. In the present study, we show that: (1) elevation of ghrelin by cocaine plays a critical role in maintenance of cocaine self-administration and cocaine-seeking motivated by cocaine-conditioned stimuli; (2) acquisition of cocaine-taking behavior is associated with the acquisition of stimulatory effects of cocaine by cocaine-conditioned stimuli on ghrelin secretion, and with an upregulation of ghrelin receptor mRNA levels in the ventral tegmental area (VTA); (3) blockade of ghrelin signaling by pretreatment with JMV2959, a selective ghrelin receptor antagonist, dose-dependently inhibits reinstatement of cocaine-seeking triggered by either cocaine or yohimbine in behaviorally extinguished animals with a history of cocaine self-administration; (4) JMV2959 pretreatment also inhibits brain stimulation reward (BSR) and cocaine-potentiated BSR maintained by optogenetic stimulation of VTA dopamine neurons in DAT-Cre mice; (5) blockade of peripheral adrenergic β1 receptors by atenolol potently attenuates the elevation in circulating ghrelin induced by cocaine and inhibits cocaine self-administration and cocaine reinstatement triggered by cocaine. These findings demonstrate that the endogenous ghrelin system plays an important role in cocaine-related addictive behaviors and suggest that manipulating and targeting this system may be viable for mitigating cocaine use disorder.

LncRNA HOTAIR mediates OGD/R-induced cell injury and angiogenesis in a EZH2-dependent manner.

Long non-coding RNAs (lncRNA) serve an important role in neonatal hypoxic-ischemic encephalopathy (HIE) have been reported to regulate the activity of HIE-associated proteins. The present study aimed to elucidate the role of Hox transcript antisense intergenic RNA (HOTAIR) in oxygen-glucose deprivation/reperfusion (OGD/R)-induced injury in human brain microvascular endothelial cells (hBMVECs). The levels of HOTAIR were evaluated in the serum of neonatal patients with HIE, and the effects of HOTAIR were evaluated using in vitro assays, such as reverse transcription-quantitative PCR to detect lncRNA and mRNA levels and western blot analysis to determine protein levels. Moreover, RNA immunoprecipitation assays were used to evaluate the association between HOTAIR and enhancer of zeste homolog 2 (EZH2), Cell Counting Kit-8 was used to detect cell viability, an endothelial monolayer cell permeability assay was used to analyze cell viability, TUNEL staining was used to detect the levels of apoptosis, a Transwell assay was used to evaluate cell invasion and a tube formation assay was used to analyze tube formation ability. In addition, the effects of HOTAIR and EZH2 on cell apoptosis and the invasive and tube formation abilities of hBMVECs were investigated using TUNEL, Transwell and tube formation assays, respectively. The results showed that the expression levels of HOTAIR were markedly increased both in neonatal HIE patients and in the OGD/R injury in vitro model. HOTAIR knockdown reduced hBMVEC viability, enhanced cell permeability and apoptosis, in addition to decreasing the expression levels of tight junction-related proteins, such as zonula occludens-1, occluden, Claudin5 and vascular endothelial-cadherin. However, EZH2 overexpression reversed the effects of HOTAIR silencing on hBMVECs. Additionally, HOTAIR knockdown enhanced the migratory and tube formation abilities of OGD/R-induced hBMVECs, which were also reversed by EZH2 overexpression. Overall, the present study revealed an association between the HOTAIR/EZH2 axis and brain microvascular endothelial cell injury and angiogenesis, which provides a novel insight into the molecular mechanism underlying stroke or the development of new pharmacotherapies.

FGF2 is an endogenous regulator of alcohol reward and consumption.

Alcohol use disorder (AUD) is a chronic, relapsing disorder, characterized by escalating alcohol drinking and loss of control, with very limited available treatments. We recently reported that the expression of fibroblast growth factor 2 (Fgf2) is increased in the striatum of rodents following long-term excessive alcohol drinking and that the systemic or intra-striatal administration of recombinant FGF2 increases alcohol consumption. Here, we set out to determine whether the endogenous FGF2 plays a role in alcohol drinking and reward, by testing the behavioural phenotype of Fgf2 knockout mice. We found that Fgf2 deficiency resulted in decreased alcohol consumption when tested in two-bottle choice procedures with various alcohol concentrations. Importantly, these effects were specific for alcohol, as a natural reward (sucrose) or water consumption was not affected by Fgf2 deficiency. In addition, Fgf2 knockout mice failed to show alcohol-conditioned place preference (CPP) but showed normal fear conditioning, suggesting that deletion of the growth factor reduces alcohol's rewarding properties. Finally, Fgf2 knockout mice took longer to recover from the loss of righting reflex and showed higher blood alcohol concentrations when challenged with an intoxicating alcohol dose, suggesting that their ethanol metabolism might be affected. Together, our results show that the endogenous FGF2 plays a critical role in alcohol drinking and reward and indicate that FGF2 is a positive regulator of alcohol-drinking behaviours. Our findings suggest that FGF2 is a potential biomarker for problem alcohol drinking and is a potential target for pharmacotherapy development for AUD.

Potential of Ligands for Trace Amine-Associated Receptor 1 (TAAR1) in the Management of Substance Use Disorders.

Trace amines, including β-phenylethylamine (β-PEA), p-tyramine (TYR), tryptamine (TRP), and p-octopamine (OCT), represent a group of amines expressed at low levels in the mammalian brain. Given the close structural similarities to traditional monoamines, links between trace amines and the monoaminergic system have long been suspected. Trace amine-associated receptor 1 (TAAR1), the most well characterized receptor in the TAAR family, has been shown to be potently activated by trace amines such as TYR and PEA. Further, catecholamine metabolites and amphetamine analogs are also potent agonists of TAAR1, implicating the receptor in mediating the monoaminergic system and in substance use disorders. In the central nervous system, TAAR1 is expressed in brain regions involved in dopaminergic, serotonergic, and glutamatergic transmission, and genetic animal models and electrophysiological studies have revealed that TAAR1 is a potent modulator of the monoaminergic system. Selective and potent engineered TAAR1 ligands, including full (RO5166017 and RO5256390) and partial (RO5203648, RO5263397 and RO5073012) agonists and the antagonist EPPTB (N-(3-ethoxyphenyl)-4-(1-pyrrolidinyl)-3-(trifluoromethyl) benzamide, RO5212773), serve as invaluable tools for the investigation of TAAR1 functions and display significant potential for the development of TAAR1-based pharmacotherapies for the treatment of substance use disorders. Despite a number of advances that have been made, more clinical studies are warranted in order to test the potential and efficacy of TAAR1 ligands in the treatment of psychiatric disorders, including substance use disorders.

The impact of social variables in preclinical models of cocaine abuse.

At present, there are no US Food and Drug Administration–approved treatments for cocaine use disorders. One consideration for this lack of treatment efficacy stems from the appropriate use of animal models. The premise of this commentary is that social behavior needs to be incorporated in animal models of cocaine use disorder. The goal of this commentary is to describe some of the strengths and limitations of recent preclinical animal models of cocaine abuse which have incorporated social behavior. There are many ways to include social variables into preclinical research, and the study design will depend on the questions asked. Four general types of studies incorporating social factors are described: those involving aggression (that is, maternal neglect and social defeat), modeling, social reward, and social housing, including social isolation. The inclusion of social variables into preclinical research will help identify biobehavioral markers that may lead to an individualized treatment approach that more effectively decreases cocaine use. These studies will aid in the development of novel pharmacotherapies as well as non-pharmacological interventions (for example, punishment, alternative reinforcers, and environmental enrichment) that would be critical for informing policy decisions.

Adverse Impact of Environmental Chemicals on Developmental Origins of Kidney Disease and Hypertension.

Chronic kidney disease (CKD) and hypertension are becoming a global health challenge, despite developments in pharmacotherapy. Both diseases can begin in early life by so-called “developmental origins of health and disease” (DOHaD). Environmental chemical exposure during pregnancy can affect kidney development, resulting in renal programming. Here, we focus on environmental chemicals that pregnant mothers are likely to be exposed, including dioxins, bisphenol A (BPA), phthalates, per- and polyfluoroalkyl substances (PFAS), polycyclic aromatic hydrocarbons (PAH), heavy metals, and air pollution. We summarize current human evidence and animal models that supports the link between prenatal exposure to environmental chemicals and developmental origins of kidney disease and hypertension, with an emphasis on common mechanisms. These include oxidative stress, renin-angiotensin system, reduced nephron numbers, and aryl hydrocarbon receptor signaling pathway. Urgent action is required to identify toxic chemicals in the environment, avoid harmful chemicals exposure during pregnancy and lactation, and continue to discover other potentially harmful chemicals. Innovation is also needed to identify kidney disease and hypertension in the earliest stage, as well as translating effective reprogramming interventions from animal studies into clinical practice. Toward DOHaD approach, prohibiting toxic chemical exposure and better understanding of underlying mechanisms, we have the potential to reduce global burden of kidney disease and hypertension.

P001 Safety, tolerability, and efficacy of 1 month of atomoxetine plus oxybutynin in obstructive sleep apnoea

Abstract Introduction Single-night studies with noradrenergic and anti-muscarinics have recently been shown to improve upper-airway function and reduce obstructive sleep apnoea (OSA) severity. This study aimed to determine the safety, tolerability, and efficacy profile of longer-term use of different doses of the noradrenergic agent atomoxetine combined with the anti-muscarinic oxybutynin (ato-oxy) in people with OSA. Methods Thirty-nine people with predominantly severe OSA received either 80/5mg ato-oxy, 40/5mg ato-oxy, 40/2.5mg ato-oxy or placebo nightly for 30 days according to a double-blind, randomised, parallel design. Safety and tolerability were assessed via weekly phone calls for adverse events, vital signs and objective measures of alertness and memory. Participants completed 3 in-laboratory sleep studies (baseline, night 1 and night 30) to assess efficacy. Results Side effects were generally mild and consistent with the known side-effect profile of each drug alone (e.g. dose-dependent increases in dry mouth with oxybutynin). Heart rate increased by night 30 in two of the drug arms versus placebo (e.g. 80/5mg ~9 beats/min, p=0.01). Blood pressure and measures of alertness and memory did not change between conditions. AHI4 and hypoxic burden decreased by ~50% in the 80/5mg arm on night 1 with similar magnitude reductions at night 30. ~50% of participants indicated willingness to continue taking the medication post-study. Discussion 1 month of nightly noradrenergic and anti-muscarinic combination therapy is generally well-tolerated with a side effect profile consistent with each agent alone. These findings also further highlight the potential to target noradrenergic and anti-muscarinic mechanisms for OSA pharmacotherapy development.