scholarly journals Emergence of Ketamine as a Rapid Acting Antidepressant: Mechanistic Insights and Future Directions

2021 ◽  
Author(s):  
Atamjit Singh ◽  
Preet Mohinder Singh Bedi
Keyword(s):  
Clinical Trials ◽  
Adverse Effects ◽  
Receptor Antagonist ◽  
Mechanism Of Action ◽  
Antidepressant Activity ◽  
Future Directions ◽  
Aspartate Receptor ◽  
Resistant Depression ◽  
Significant Attention ◽  
Shed Light

Ketamine is a phencyclidine derivative and N-methyl-D-aspartate receptor antagonist, widely popular as a dissociative anesthetic. Its use as an anesthetic in humans was progressively fallen out due to its associated adverse effects and the emergence of newer and safer anesthetics. In recent few decades, various reports related to its efficacy in the treatment of resistant depression with anti-suicidal potential draw significant attention from researchers around the globe. The rapid clinical effect of ketamine within hours as compared to traditional antidepressants that take several weeks makes it a hot topic in antidepressant research. Studies conducted in the recent past suggest its mechanism of action through glutamate modulation via receptors like NMDA, AMPA as well as downregulation of BDNF etc. This chapter will shed light on the various mechanisms of ketamine related to antidepressant activity. Along with that its pharmacokinetics, toxicology and ongoing clinical trials will also be discussed.

Pharmacotherapy of anxiety and related disorders

2020 ◽  
pp. 147-164
Author(s):  
Dan J. Stein
Keyword(s):  
Clinical Trials ◽  
Anxiety Disorder ◽  
Mental Disorders ◽  
Randomized Clinical Trials ◽  
Generalized Anxiety ◽  
Obsessive Compulsive ◽  
Future Directions ◽  
Compulsive Disorder ◽  
Translational Models ◽  
Shed Light

Anxiety disorders are the most prevalent of the mental disorders, and good translational models of these conditions encourage pharmacotherapy studies. This chapter discusses six randomized clinical trials that have contributed significantly to the pharmacotherapy of anxiety and related disorders, including generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, and social anxiety disorder. Although any such list is necessarily incomplete, these selections may shed light on early and ongoing challenges in the field and on key advances to date. After reviewing these foundational papers, the advances they represent, and the work that they have given impetus to, the chapter closes by considering future directions in work on the pharmacotherapy of anxiety and related disorders.

Granisetron: The Second Serotonin-Receptor Antagonist

1995 ◽  
Vol 29 (12) ◽  
pp. 1240-1251 ◽  
Author(s):  
Val R Adams ◽  
Amy W Valley
Keyword(s):  
Clinical Trials ◽  
Adverse Effects ◽  
Receptor Antagonist ◽  
Serotonin Receptor ◽  
English Language ◽  
Data Extraction ◽  
Optimal Dose ◽  
Nausea And Vomiting ◽  
Cost Comparison ◽  
Antiemetic Agents

Objective: To review the pharmacology, pharmacokinetics, clinical efficacy, and adverse effects of granisetron, focusing on critical analysis of published clinical trials and comparison with other antiemetic agents, including ondansetron. Data Sources: MEDLINE (1966–1995) and CANCERLIT (1991–1995) searches of English-language literature using the terms “granisetron” and “granisetron (m)” were performed. Study Selection And Data Extraction: All articles were considered for possible inclusion in this review. Abstracts of clinical trials were included only when they were judged to add critical information not otherwise available in the medical literature. For studies published more than once, the most recent publication was cited. Data Synthesis: Nausea and vomiting are rated by patients as the most distressing chemotherapy-related adverse effects and may produce potentially life-threatening complications. The discovery of the role of serotonin in nausea and vomiting and the development of selective serotonin3-receptor (5-HT3) antagonists has significantly diminished the incidence and consequences of chemotherapy-related nausea and vomiting. Granisetron is the second 5-HT3-receptor antagonist to be marketed in the US. Granisetron has been compared with other antiemetic agents, including ondansetron, against highly and moderately emetogenic chemotherapy. The results of these trials have shown granisetron to be superior to conventional antiemetics and as effective as ondansetron in the prevention of chemotherapy-induced nausea and vomiting. The optimal dose of granisetron has yet to be determined. Formulary decisions should be based on a cost comparison among the 5-HT3-receptor antagonists at individual institutions. Conclusions: Granisetron is a safe, effective antiemetic agent for the management of nausea and vomiting caused by cancer chemotherapy.

scholarly journals Baloxavir Marboxil: A New Antiviral for Acute Influenza

2020 ◽  
Vol 66 (4) ◽  
pp. 33-38
Author(s):  
Stephen Selvanayagam ◽  
Amy Kang ◽  
David Ha
Keyword(s):  
Clinical Trials ◽  
Single Dose ◽  
Adverse Effects ◽  
Mechanism Of Action ◽  
Age Groups ◽  
Viral Titer ◽  
Dependent Endonuclease ◽  
Dose Oral ◽  
Endonuclease Enzyme ◽  
Viable Treatment

Baloxavir is a newly approved, single-dose, oral influenza antiviral indicated for acute uncomplicated influenza in patients 12 years and older if symptomatic for less than 48 hours. The purpose of this article is to review currently available literature on the mechanism of action, pharmacokinetics, safety, and clinical and virologic efficacy of baloxavir. Its novel mechanism of action prevents influenza replication by targeting the viral cap-dependent endonuclease enzyme. In clinical trials baloxavir was shown to be superior to placebo and comparable to oseltamivir with regard to time to alleviation of symptoms and viral titer reduction and was well tolerated with minimal adverse effects. Baloxavir is a viable treatment option for acute uncomplicated influenza in certain age groups.

Atovaquone: A Review with Emphasis on its Role in the Treatment of Pneumocystis Carinii Pneumonia

1994 ◽  
Vol 10 (4) ◽  
pp. 151-155
Author(s):  
Daniel S. Maddix
Keyword(s):  
Clinical Trials ◽  
Adverse Effects ◽  
Mechanism Of Action ◽  
Pneumocystis Carinii Pneumonia ◽  
Pneumocystis Carinii ◽  
Plasmodium Species ◽  
Double Blind ◽  
Medline Search

Objective: To discuss the mechanism of action, in vitro and in vivo activity, pharmacokinetics, clinical trials, adverse effects, drug interactions, and dosage guidelines of atovaquone. Data Sources: Pertinent literature published since 1988 was identified via a MEDLINE search. Published proceedings of selected conferences were also used. Study Selection: All basic science, microbiologic, and pharmacokinetic articles were evaluated. Since only limited data regarding atovaquone are available in the literature, all clinical trials involving the use of atovaquone in the treatment of Pneumocystis carinii pneumonia were reviewed. Data Synthesis: Atovaquone is an antiprotozoal agent that was recently approved for the treatment of mild to moderate P. carinii pneumonia (PCP) in patients who are intolerant of trimethoprim/sulfamethoxazole (TMP/SMX). The exact mechanism of action of atovaquone against P. carinii has not been determined. The drug has in vitro and in vivo activity against P. carinii, Toxoplasma gondii, and Plasmodium species. The bioavailability of oral atovaquone is highly variable. The drug must be administered with food to enhance absorption. In a double-blind comparative trial in AIDS patients with mild to moderate PCP, those who were treated with atovaquone had a significantly higher mortality rate than those treated with TMP/SMX. More patients who received TMP/SMX experienced adverse effects that resulted in discontinuation of therapy. Conclusions: Because of concerns of increased mortality in atovaquone recipients, the drug should be reserved for the treatment of mild to moderate PCP in patients who are unable to tolerate TMP/SMX and trimethoprim-dapsone.

Olmesartan Medoxomil: The Seventh Angiotensin Receptor Antagonist

2003 ◽  
Vol 37 (1) ◽  
pp. 99-105 ◽  
Author(s):  
Stephanie F Gardner ◽  
Amy M Franks
Keyword(s):  
Blood Pressure ◽  
Clinical Trials ◽  
Angiotensin Ii ◽  
Adverse Effects ◽  
Receptor Antagonist ◽  
Olmesartan Medoxomil ◽  
Data Sources ◽  
Angiotensin Receptors ◽  
Angiotensin Receptor ◽  
Angiotensin Ii Receptor

OBJECTIVE To review the pharmacology, pharmacokinetics, efficacy, and adverse effects of olmesartan medoxomil, an angiotensin II receptor antagonist for the treatment of hypertension. DATA SOURCES Information was obtained from MEDLINE searches (1996–April 2002) of English-language medical literature. Search terms included CS-866, olmesartan, olmesartan medoxomil, RNH-6270 (active metabolite of olmesartan), Benicar, angiotensin receptors, and antihypertensive agents. In addition, references from relevant articles were reviewed for additional citations. The authors independently reviewed literature identified in the searches. Studies evaluating olmesartan (i.e., abstracts, clinical trials, data on file with manufacturer) were considered for inclusion. STUDY SELECTION All articles identified from data sources with pertinent information regarding olmesartan medoxomil were evaluated, and all information deemed relevant was included in this review. DATA SYNTHESIS Olmesartan medoxomil is a competitively priced addition to the class of angiotensin II receptor antagonists. Monotherapy with olmesartan medoxomil in once-daily doses of 20–40 mg has produced significant reductions in systolic and diastolic blood pressure in hypertensive patients. Adverse effects have been minimal with olmesartan medoxomil, with dizziness being the only adverse effect occurring more often than with placebo in clinical trials. Additionally, animal studies indicate that olmesartan medoxomil may prove to be useful treatment for diabetic nephropathy, as well as atherosclerosis. CONCLUSIONS Olmesartan medoxomil has a favorable safety and efficacy profile, with blood pressure–lowering effects comparable to those of other angiotensin receptor blockers (i.e., losartan, valsartan, irbesartan). At this time, formulary decisions will be driven primarily by economic issues. Theoretical benefits of olmesartan medoxomil in reducing atherogenesis and lowering angiotensin II concentrations better than the alternative agents will be determined only with more extensive research. THIS ARTICLE IS APPROVED FOR CONTINUING EDUCATION CREDIT ACPE UNIVERSAL PROGRAM NUMBER: 407-000-03-002-H01

scholarly journals Ketamine: A tale of two enantiomers

2020 ◽  
pp. 026988112095964
Author(s):  
Luke A Jelen ◽  
Allan H Young ◽  
James M Stone
Keyword(s):  
Side Effects ◽  
Receptor Antagonist ◽  
The United States ◽  
Receptor Activation ◽  
Racemic Mixture ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Aspartate Receptor ◽  
Antidepressant Effects ◽  
Resistant Depression

The discovery of the rapid antidepressant effects of the dissociative anaesthetic ketamine, an uncompetitive N-Methyl-D-Aspartate receptor antagonist, is arguably the most important breakthrough in depression research in the last 50 years. Ketamine remains an off-label treatment for treatment-resistant depression with factors that limit widespread use including its dissociative effects and abuse potential. Ketamine is a racemic mixture, composed of equal amounts of (S)-ketamine and (R)-ketamine. An (S)-ketamine nasal spray has been developed and approved for use in treatment-resistant depression in the United States and Europe; however, some concerns regarding efficacy and side effects remain. Although (R)-ketamine is a less potent N-Methyl-D-Aspartate receptor antagonist than (S)-ketamine, increasing preclinical evidence suggests (R)-ketamine may have more potent and longer lasting antidepressant effects than (S)-ketamine, alongside fewer side effects. Furthermore, a recent pilot trial of (R)-ketamine has demonstrated rapid-acting and sustained antidepressant effects in individuals with treatment-resistant depression. Research is ongoing to determine the specific cellular and molecular mechanisms underlying the antidepressant actions of ketamine and its component enantiomers in an effort to develop future rapid-acting antidepressants that lack undesirable effects. Here, we briefly review findings regarding the antidepressant effects of ketamine and its enantiomers before considering underlying mechanisms including N-Methyl-D-Aspartate receptor antagonism, γ-aminobutyric acid-ergic interneuron inhibition, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor activation, brain-derived neurotrophic factor and tropomyosin kinase B signalling, mammalian target of rapamycin complex 1 and extracellular signal-regulated kinase signalling, inhibition of glycogen synthase kinase-3 and inhibition of lateral habenula bursting, alongside potential roles of the monoaminergic and opioid receptor systems.

scholarly journals Drugs used in viral diseases – their mechanism of action, selected adverse effects and safety during pregnancy and lactation

2019 ◽  
Vol 73 ◽  
pp. 491-507
Author(s):  
Kamil Dyrka ◽  
Miłosz Miedziaszczyk ◽  
Edyta Szałek ◽  
Katarzyna Łącka
Keyword(s):  
Clinical Trials ◽  
Adverse Effects ◽  
Mechanism Of Action ◽  
Antiviral Drugs ◽  
Patient Treatment ◽  
Viral Diseases ◽  
Efficacy And Safety ◽  
Treatment Results ◽  
Pregnancy And Lactation

Viruses cause many diseases in humans, from self-resolving diseases to acute fatal diseases. New antiviral drugs are registered and the efficacy and safety of other medicines are evaluated in clinical trials. Antiviral therapy significantly reduces the morbidity and mortality of patients, but may cause numerous adverse effects. The aim of this study is to discuss the mechanism, selected adverse effects of available antivirals and their safety during pregnancy and lactation. The authors refer to the classification of drugs used during pregnancy and recommendations for breastfeeding, which, for example, definitely prohibit the use of ribavirin. The authors also pay attention to the monitoring of selected diagnostic parameters to improve the treatment results. Clinicians should limit adverse effects through an individual, specific to the patient treatment regimen. Physicians should pay special attention to the use of antiviral drugs in pregnant and breast-feeding women. Clinical trials should be continued to increase knowledge about the adverse effects of antiviral medicines.

scholarly journals A Randomized Trial of the N-Methyl-d-Aspartate Receptor Glycine Site Antagonist Prodrug 4-Chlorokynurenine in Treatment-Resistant Depression

2020 ◽  
Vol 23 (7) ◽  
pp. 417-425 ◽  
Author(s):  
Lawrence T Park ◽  
Bashkim Kadriu ◽  
Todd D Gould ◽  
Panos Zanos ◽  
Deanna Greenstein ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Adverse Effects ◽  
Rating Scale ◽  
Secondary Outcome ◽  
Treatment Resistant Depression ◽  
Glycine Site ◽  
Treatment Resistant ◽  
Aspartate Receptor ◽  
Antidepressant Effects ◽  
Resistant Depression

Abstract Background Ketamine has rapid-acting antidepressant effects but is associated with psychotomimetic and other adverse effects. A 7-chlorokynurenic acid is a potent and specific glycine site N-methyl-d-aspartate receptor antagonist but crosses the blood-brain barrier inefficiently. Its prodrug, L-4-chlorokynurenine (4-Cl-KYN), exerts acute and sustained antidepressant-like effects in rodents and has no reported psychotomimetic effects in either rodents or healthy volunteers. This study examined whether 4-Cl-KYN has rapid antidepressant effects in individuals with treatment-resistant depression. Methods After a 2-week drug-free period, 19 participants with treatment-resistant depression were randomized to receive daily oral doses of 4-Cl-KYN monotherapy (1080 mg/d for 7 days, then 1440 mg/d for 7 days) or placebo for 14 days in a randomized, placebo-controlled, double-blind, crossover manner. The primary outcome measure was the Hamilton Depression Rating Scale score, assessed at several time points over a 2-week period; secondary outcome measures included additional rating scale scores. Pharmacokinetic measures of 7-chlorokynurenic acid and 4-Cl-KYN and pharmacodynamic assessments were obtained longitudinally and included 1H-magnetic resonance spectroscopy brain glutamate levels, resting-state functional magnetic resonance imaging, and plasma and cerebrospinal fluid measures of kynurenine metabolites and neurotrophic factors. Results Linear mixed models detected no treatment effects, as assessed by primary and secondary outcome measures. No difference was observed for any of the peripheral or central biological indices or for adverse effects at any time between groups. A 4-Cl-KYN was safe and well-tolerated, with generally minimal associated adverse events. Conclusions In this small crossover trial, 4-Cl-KYN monotherapy exerted no antidepressant effects at the doses and treatment duration studied. ClinicalTrials.gov identifier: NCT02484456.

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