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Expert Opinion on Emerging Drugs Jun 2020While antipsychotics have been generally successful in treating psychosis in schizophrenia, there is a major treatment gap for negative symptoms and cognitive deficits.... (Review)
Review
INTRODUCTION
While antipsychotics have been generally successful in treating psychosis in schizophrenia, there is a major treatment gap for negative symptoms and cognitive deficits. Given that these aspects of the disease contribute to poor functional outcomes independently of positive symptoms, treatments would have profound implications for quality of life. The 5-HT- receptor has been considered a potential target for interventions aimed at negative and cognitive symptoms and multiple antagonists and inverse agonists of this receptor have been tested.
AREAS COVERED
Ritanserin and volinanserin, are historically important compounds in this area, while pimavanserin, roluperidone, and lumateperone are either newly approved, in late stages of development, or currently being tested for efficacy in schizophrenia-related features. The focus will be on their efficacy in the treatment of negative symptoms, with a limited secondary discussion of cognition.
EXPERT OPINION
In addition to their efficacy in treating negative symptoms and cognition, these compounds may also have a role in modulating antipsychotic-induced dopamine super-sensitivity and preventing relapse. They may also show efficacy in treating patients with milder symptoms such as patients with schizotypal personality disorder and attenuated psychosis syndrome. Their utility may also expand outside the spectrum of schizophrenia to encompass Parkinson's Disease psychosis, major depression, bipolar depression, and dementia-associated apathy.
Topics: Animals; Antipsychotic Agents; Cognition Disorders; Drug Design; Drug Development; Humans; Quality of Life; Schizophrenia; Serotonin Antagonists
PubMed: 32449404
DOI: 10.1080/14728214.2020.1773792 -
Journal of Clinical Anesthesia Nov 2016Palonosetron is a second-generation 5-HT3 receptor antagonist with proposed higher efficacy and sustained action for prophylaxis of postoperative nausea and vomiting... (Comparative Study)
Comparative Study Meta-Analysis Review
INTRODUCTION
Palonosetron is a second-generation 5-HT3 receptor antagonist with proposed higher efficacy and sustained action for prophylaxis of postoperative nausea and vomiting (PONV).
METHODS
Randomized controlled trials involving adult population undergoing elective surgery under general anesthesia comparing palonosetron to placebo, ramosetron, granisetron, and ondansetron were included. Data were extracted for vomiting incidence (VI), complete response (no nausea/vomiting; Complete Response [CR]), and rescue antiemetic need. This was categorized as early phase (24 hours postoperative for ramosetron and 6 hours for rest) and delayed phase (48 hours for ramosetron and 24 hours for rest). VI and CR were used as markers of drug efficacy. Any adverse effects were evaluated.
RESULTS
Twenty-two trials (4 with 3 groups) were included (comparing palonosetron to placebo in 5, ramosetron in 5, granisetron in 4, and ondansetron in 12 subgroups). Palonosetron demonstrated statistical superiority over placebo for VI and CR, both early/delayed PONV prevention. For delayed phase, palonosetron surpassed ramosetron in all 3 variables; however, none of the variables attained statistical significance during early phase. In early phase, palonosetron had better VI and CR than did granisetron; however, variables other than CR (better for palonosetron) failed to achieve statistical significance for delayed phase. All 3 outcomes were significantly better for palonosetron compared with ondansetron in delayed phase, but statistical superiority could only be demonstrated for VI in early phase. Being inconsistently documented across trials, nausea scores could not be evaluated.
CONCLUSION
Palonosetron is as safe as and more effective than placebo, ramosetron, granisetron, and ondansetron in preventing delayed PONV. For early PONV, it has higher efficacy over placebo, granisetron, and ondansetron.
Topics: Adult; Anesthesia, General; Antiemetics; Benzimidazoles; Granisetron; Humans; Isoquinolines; Ondansetron; Palonosetron; Postoperative Nausea and Vomiting; Quinuclidines; Randomized Controlled Trials as Topic; Serotonin Antagonists; Treatment Outcome
PubMed: 27687434
DOI: 10.1016/j.jclinane.2016.05.018 -
Current Pharmaceutical Design 2021Lurasidone is a novel azapirone derivative and atypical antipsychotic agent with a high binding affinity for dopaminergic (D), serotoninergic (5-HT), and 5-HT receptors...
Lurasidone is a novel azapirone derivative and atypical antipsychotic agent with a high binding affinity for dopaminergic (D), serotoninergic (5-HT), and 5-HT receptors (antagonist), a moderate affinity for 5- HT receptors (partial agonist), and no appreciable affinity for histaminergic (H) and muscarinic (M) receptors. It was recently included by the European Medication Agency among the in-label pharmacological treatments for children and adolescents affected by early onset schizophrenia. As a dopamine and serotonin antagonist, lurasidone acted on a variety of receptors and showed its efficacy both as an antipsychotic and an activating compound. Administered with food or within 30 minutes from a meal, it presents sufficient bioavailability and does not interact with most of the other drugs during metabolism. With little effects on hormones and weight gain, potential procognitive profile due to its 5-HT antagonism, and reduced extrapyramidal side effects, lurasidone could be a good choice in terms of both effectiveness and tolerability, particularly for patients headed towards a long-term treatment. This article aims to summarize the available scientific evidence from the literature on the use of lurasidone in children and adolescents and to provide recommendations for clinical management and future research.
Topics: Adolescent; Antipsychotic Agents; Child; Dopamine; Humans; Lurasidone Hydrochloride; Schizophrenia; Serotonin Antagonists
PubMed: 34348620
DOI: 10.2174/1381612827666210804110853 -
Annals of the Royal College of Surgeons... Jul 2016Introduction Shivering is one of the most frequent complications of operation during the postanaesthesia period. Ondansetron has been proved to be valid in preventing... (Meta-Analysis)
Meta-Analysis Review
Introduction Shivering is one of the most frequent complications of operation during the postanaesthesia period. Ondansetron has been proved to be valid in preventing postanaesthesia shivering (PAS) in several studies. However, its efficiency and safety are still disputable. We therefore performed an updated meta-analysis of randomised controlled trials (RCTs) for evaluation and to clarify this issue. Methods A literature search using the PubMed, Embase™ and Cochrane Library databases was performed (from inception to January 2015). RCTs that evaluated the efficiency and safety of ondansetron in the prevention of PAS were included in the meta-analysis. The primary outcome measure was incidence of PAS, and secondary outcomes included subgroup analysis and the side effects of ondansetron. Results A total of 8 RCTs containing 905 subjects were identified as suitable for this review. Compared with placebo, ondansetron was associated with a significant reduction of PAS (relative risk [RR]: 0.33, 95% confidence interval [CI]: 0.19-0.58, p=0.0001) while no difference was detected between ondansetron and pethidine (RR: 0.89, 95% CI: 0.41-1.94, p=0.78). There was no significant difference between ondansetron and placebo or pethidine in terms of risk of bradycardia but ondansetron was associated with a lower risk of hypotension (RR: 0.26, 95% CI: 0.08-0.79, p=0.020) than placebo. There was no difference in hypotension when ondansetron was compared with pethidine. Conclusions Ondansetron can prevent PAS effectively and reduce the risk of hypotension.
Topics: Anesthesia Recovery Period; Humans; Hypotension; Ondansetron; Postoperative Complications; Randomized Controlled Trials as Topic; Serotonin Antagonists; Shivering
PubMed: 27138855
DOI: 10.1308/rcsann.2016.0152 -
Expert Opinion on Pharmacotherapy Dec 2014Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life. The emetogenicity of the chemotherapeutic agents,... (Review)
Review
INTRODUCTION
Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles, and patient risk factors significantly influence CINV. The introduction of 5-hydroxytryptamine-3 (5-HT3) receptor antagonists has been a major factor in the improvement of the prevention of chemotherapy-induced acute and delayed emesis. Palonosetron , a second-generation 5-HT3 receptor antagonist with a different half-life, a different binding capacity, and a different mechanism of action than the first-generation 5-HT3 receptor antagonists appears to be the most effective agent in this drug class.
AREAS COVERED
Palonosetron's chemistry, pharmacodynamics, pharmacokinetics, metabolism, clinical efficacy, including comparison with other antiemetics, role in controlling nausea, potential role in multi-day chemotherapy and bone marrow transplantation, and overall safety are discussed.
EXPERT OPINION
The clinical data in the literature have established palonosetron as the 5-HT3 receptor antagonist of choice in terms of efficacy and safety for the prevention of CINV for patients receiving moderately or highly emetogenic chemotherapy. Three international guidelines have listed palonosetron as the preferred 5-HT3 receptor antagonist. Due to its higher efficacy, the use of palonosetron may be more cost effective compared to the generic first-generation 5-HT3 receptor antagonists. Clinical organizations' pharmacy and formulary committees should consider efficacy when making recommendations for agents for the prevention of CINV.
Topics: Antiemetics; Antineoplastic Agents; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Isoquinolines; Nausea; Palonosetron; Quality of Life; Quinuclidines; Serotonin 5-HT3 Receptor Antagonists; Vomiting
PubMed: 25323946
DOI: 10.1517/14656566.2014.972366 -
Expert Opinion on Investigational Drugs 2015Alzheimer's disease (AD) is the most common cause of dementia in the elderly. Pharmacological treatment of AD involves acetylcholinesterase inhibitors (AChEIs) for... (Review)
Review
INTRODUCTION
Alzheimer's disease (AD) is the most common cause of dementia in the elderly. Pharmacological treatment of AD involves acetylcholinesterase inhibitors (AChEIs) for mild-to-moderate AD and memantine for severe AD. These drugs provide mainly symptomatic short-term benefits without clearly counteracting the progression of the disease. Idalopirdine is an antagonist of the serotonin 6 (5-HT6) receptor, which is expressed in areas of the CNS involved with memory. Given that there is evidence suggesting that the blockade of 5-HT6 receptors induces acetylcholine release, it became reasonable to consider that 5-HT6 antagonism could also be a promising approach for restoring acetylcholine levels in a deteriorated cholinergic system.
AREAS COVERED
This review discusses the history leading to the discovery of idalopirdine, its pharmacokinetics and pharmacodynamics profile and safety issues, together with an overview of clinical trials carried out so far. A literature search was performed with PubMed using the keywords idalopirdine, AD and 5-HT6 antagonists. The article is also based on information derived from the ClinicalTrials.gov site for clinical trials with idalopirdine.
EXPERT OPINION
Idalopirdine is safe and well tolerated. It could be used as add-on therapy to potentiate the effect of available AChEIs in AD. Nevertheless, results from ongoing Phase III trials are needed to verify whether this drug has a significant clinical effect on cognition in association with AChEIs.
Topics: Alzheimer Disease; Animals; Benzylamines; Humans; Indoles; Receptors, Serotonin; Serotonin Antagonists
PubMed: 26022777
DOI: 10.1517/13543784.2015.1052402 -
Journal of Alzheimer's Disease : JAD May 2016Lack of efficacy of many new highly selective and specific drug candidates in treating diseases with poorly understood or complex etiology, as are many of central... (Review)
Review
Lack of efficacy of many new highly selective and specific drug candidates in treating diseases with poorly understood or complex etiology, as are many of central nervous system (CNS) diseases, encouraged an idea of developing multi-modal (multi-targeted) drugs. In this manuscript, we describe molecular pharmacology, in vitro ADME, pharmacokinetics in animals and humans (part of the Phase I clinical studies), bio-distribution, bioavailability, in vivo efficacy, and safety profile of the multimodal drug candidate, AVN-101. We have carried out development of a next generation drug candidate with a multi-targeted mechanism of action, to treat CNS disorders. AVN-101 is a very potent 5-HT7 receptor antagonist (Ki = 153 pM), with slightly lesser potency toward 5-HT6, 5-HT2A, and 5HT-2C receptors (Ki = 1.2-2.0 nM). AVN-101 also exhibits a rather high affinity toward histamine H1 (Ki = 0.58 nM) and adrenergic α2A, α2B, and α2C (Ki = 0.41-3.6 nM) receptors. AVN-101 shows a good oral bioavailability and facilitated brain-blood barrier permeability, low toxicity, and reasonable efficacy in animal models of CNS diseases. The Phase I clinical study indicates the AVN-101 to be well tolerated when taken orally at doses of up to 20 mg daily. It does not dramatically influence plasma and urine biochemistry, nor does it prolong QT ECG interval, thus indicating low safety concerns. The primary therapeutic area for AVN-101 to be tested in clinical trials would be Alzheimer's disease. However, due to its anxiolytic and anti-depressive activities, there is a strong rational for it to also be studied in such diseases as general anxiety disorders, depression, schizophrenia, and multiple sclerosis.
Topics: Animals; Central Nervous System Diseases; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Excitatory Amino Acid Antagonists; Humans; Maze Learning; Neuroprostanes; Protein Binding; Receptors, Serotonin; Serotonin Antagonists; Time Factors
PubMed: 27232215
DOI: 10.3233/JAD-151146 -
Medicinal Research Reviews Sep 2020Serotonin (5-hydroxytryptophan [5-HT]) is a biologically active amine expressed in platelets, in gastrointestinal (GI) cells and, to a lesser extent, in the central... (Review)
Review
Serotonin (5-hydroxytryptophan [5-HT]) is a biologically active amine expressed in platelets, in gastrointestinal (GI) cells and, to a lesser extent, in the central nervous system (CNS). This biogenic compound acts through the activation of seven 5-HT receptors (5-HT Rs). The 5-HT R is a ligand-gated ion channel belonging to the Cys-loop receptor family. There is a wide variety of 5-HT R modulators, but only receptor antagonists (known as setrons) have been used clinically for chemotherapy-induced nausea and vomiting and irritable bowel syndrome treatment. However, since the discovery of the setrons in the mid-1980s, a large number of studies have been published exploring new potential applications due their potency in the CNS and mild side effects. The results of these studies have revealed new potential applications, including the treatment of neuropsychiatric disorders such as schizophrenia, depression, anxiety, and drug abuse. In this review, we provide information related to therapeutic potential of 5-HT R antagonists on GI and neuropsychiatric disorders. The major attention is paid to the structure, function, and pharmacology of novel 5-HT R modulators developed over the past 10 years.
Topics: Gastrointestinal Diseases; Humans; Nausea; Receptors, Serotonin, 5-HT3; Serotonin; Serotonin Antagonists
PubMed: 32115745
DOI: 10.1002/med.21666 -
Expert Opinion on Investigational Drugs 2015There are significant efforts invested into the discovery and development of novel treatments for Alzheimer's disease. While current discovery efforts and most... (Review)
Review
INTRODUCTION
There are significant efforts invested into the discovery and development of novel treatments for Alzheimer's disease. While current discovery efforts and most scientific discussions seem to focus on disease-modifying therapy, there are several symptomatic therapy approaches that are being actively pursued. The goal of this review is to summarize the recent developments in the field of 5-HT6 receptor antagonists, a principle that has been extensively characterized preclinically and is now undergoing critical phases of clinical development.
AREAS COVERED
The article covers the current status of 5-HT6 receptor antagonists in clinical development. It also discusses the underlying mechanisms for the observed procognitive effects. The article is based on a search for investigational drugs using the key words '5-HT6', 'cognition', 'dementia', 'Alzheimer's disease', 'Phase II' and 'Phase III' in various databases and from conference abstracts.
EXPERT OPINION
After some period of little or no development activities, the field of 5-HT6 receptor antagonists attracted a lot of attention with three companies (GSK, Pfizer and Lundbeck) confirming aggressive development plans and initiating pivotal Phase II and III studies. These studies will be critical to prove that 5-HT6 receptor antagonists have a symptomatic efficacy profile that can be differentiated from that of currently used agents (cholinesterase inhibitors and the NMDA-antagonist memantine). Furthermore, there are several sets of data that point at a disease-modifying potential of this class of agents and these effects are likely to receive critical exploration if the ongoing symptomatic trials bring 5-HT6 antagonists closer to clinical use.
Topics: Alzheimer Disease; Animals; Cognition; Drug Design; Drugs, Investigational; Humans; Receptors, Serotonin; Serotonin Antagonists
PubMed: 26548316
DOI: 10.1517/13543784.2015.1102884 -
Identification and Pharmacological Characterization of Two Serotonin Type 7 Receptor Isoforms from .International Journal of Molecular... Dec 2022Serotonin (5-hydroxytryptamine, 5-HT) is an important neuroactive molecule, as neurotransmitters regulate various biological functions in vertebrates and invertebrates...
Serotonin (5-hydroxytryptamine, 5-HT) is an important neuroactive molecule, as neurotransmitters regulate various biological functions in vertebrates and invertebrates by binding and activating specific 5-HT receptors. The pharmacology and tissue distribution of 5-HT receptors have been investigated in several model insects, and these receptors are recognized as potential insecticide targets. However, little is known about the pharmacological characterization of the 5-HT receptors in important agricultural pests. In this study, we investigated the sequence, pharmacology, and tissue distribution of receptors from oriental armyworm (Walker) (Lepidoptera: Noctuidae), an important migratory and polyphagous pest species. We found that the receptor gene encodes two molecularly distinct transcripts, and , by the mechanism of alternative splicing in . Msep5-HT7S differs from Msep5-HT7L based on the deletion of 95 amino acids within the third intracellular loop. Two Msep5-HT7 receptor isoforms were activated by 5-HT and synthetic agonists α-methylserotonin, 8-hydroxy-DPAT, and 5-methoxytryptamine, resulting in increased intracellular cAMP levels in a dose-dependent manner, although these agonists showed much poorer potency and efficacy than 5-HT. The maximum efficacy of 5-HT compared to the two 5-HT isoforms was equivalent, but 5-HT exhibited 2.63-fold higher potency against the Msep5-HT7S than the Msep5-HT7L receptor. These two isoforms were also blocked by the non-selective antagonist methiothepin and the selective antagonists WAY-100635, ketanserin, SB-258719, and SB-269970. Moreover, two distinct mRNA transcripts were expressed preferentially in the brain and chemosensory organs of adults, as determined by qPCR assay. This study is the first comprehensive characterization of two splicing isoforms of 5-HT7 receptors in , and the first to demonstrate that alternative splicing is also the mechanism for producing multiple 5-HT7 isoforms in insects. Pharmacological and gene expression profiles offer important information that could facilitate further exploration of their function in the central nervous system and peripheral chemosensory organs, and may even contribute to the development of new selective pesticides.
Topics: Animals; Serotonin; Serotonin Antagonists; Receptors, Serotonin; Moths; Protein Isoforms
PubMed: 36614100
DOI: 10.3390/ijms24010655