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'''CT38''' is an experimental peptide (i.e., two or more amino acids linked in a chain) that acts as an agonist for [[corticotropin-releasing factor receptor type 2|CRFR2]] ([[corticotropin]] releasing factor receptor type 2).<ref name="NCT03613129">{{Cite web | url = https://clinicaltrials.gov/ct2/show/NCT03613129 | title = Clinical Trial to Investigate CT38 in the Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome | last = Bateman | first = Lucinda | author-link = Lucinda Bateman | website = clinicaltrials.gov|language=en|archive-url=|archive-date=|url-status= | access-date = 2019-03-06}}</ref> CT38 was developed as a synthetic analog of [[urocortin II]] by [[Cortene]].<ref name="HR2018">{{Cite web | url = https://www.healthrising.org/blog/2018/07/14/cortene-chronic-fatigue-syndrome-me-cfs-drug-trial-begins/ | title = The Cortene Chronic Fatigue Syndrome (ME/CFS) Drug Trial Begins | last = Johnson | first = Cort | author-link = Cort Johnson | date = Jul 14, 2018 | website = [[Health Rising]]|language=en-GB|archive-url=|archive-date=|url-status= | access-date = 2019-03-06}}</ref> ==Hypothesis== The primary hypothesis for the use of CT38 is that symptoms arise due to the [[CRFR2 upregulation hypothesis|CRFR2 upregulation]], leading to an oversensitive [[adrenocorticotropic hormone]] (ACTH) response to minor stimulation of the [[hypothalamus]],<ref name="NCT03613129" /> it is also suggested that this will lead to an increase in [[serotonin]] expression.<ref name="HR2018" /> It is proposed that CT38 therapy will stimulate [[CRFR2]], leading to a downregulation of receptor expression and thus normalisation of the response to corticotropin-releasing hormone (CRH) at the end of the therapy. Hypothetically, CT38 may increase symptoms while the peptide is being taken, if this is a key mechanism involved in ME/CFS. In animal models, increased [[CRFR2]] stimulation has been shown to lead to increased sympathetic nervous system activation. However, increased sympathetic nervous system activation is not consistently found in ME/CFS patients, with shifts in some patients to a sympathetic predominance instead explained by a reduction of parasympathetic nervous system activity.<ref name="Nelson2019">{{Cite journal | last = Nelson | first = Maximillian J. | last2 = Bahl | first2 = Jasvir S. | last3 = Buckley | first3 = Jonathan D. | last4 = Thomson | first4 = Rebecca L. | last5 = Davison | first5 = Kade | date = Oct 2019 | title = Evidence of altered cardiac autonomic regulation in myalgic encephalomyelitis/chronic fatigue syndrome: A systematic review and meta-analysis | url = https://journals.lww.com/md-journal/fulltext/2019/10250/Evidence_of_altered_cardiac_autonomic_regulation.36.aspx | journal = Medicine|language=en-US | volume = 98 | issue = 43| page = e17600 |doi=10.1097/MD.0000000000017600|issn=0025-7974|pmc=|pmid=|quote=|access-date=|via=}}</ref> Currently, there is a lack of evidence for the dysregulation of [[CRFR2]] expression in ME/CFS patients but if the trial is successful, this would increase research interest in this area. ==Evidence== ===InTiME=== Evidence is very limited, with only first clinical trial, an open-label phase 1/2 trial involving 14 [[ME/CFS]] patients published.<ref name="NCT03613129" /> The trial was successful, although after CT38 was given to the first two ME/CFS patients, the dose needed to be lowered for remaining patients. InTiME is the name of the initial CT38 trial.<ref name="InTiME-ct" /> ==Clinicians== [[Lucinda Bateman]] is the principal investigator for a current clinical trial of CT38 for [[ME/CFS]], it is only being tested on patients who meet the [[Canadian Consensus Criteria]] for [[myalgic encephalomyelitis]]/[[chronic fatigue syndrome]], the [[Fukuda criteria]] for [[chronic fatigue syndrome]] '''and''' the [[systemic exertion intolerance disease]] criteria. [[Suzanne Vernon]] is the study director.<ref name="NCT03613129" /> ==Risks and safety== In healthy subjects, adverse effects Dr [[Lucinda Bateman]] reported (as part of the clinical trial protocol), were that escalating doses caused hypotension and tachycardia, with one subject reporting a heart rate of 160 BPM at a dose of 1.667 ฮผg/kg. The expected maximum tolerable dose is expected to be to be 0.833 ฮผg/kg, causing "mild" hypotension without signficant tachycardia. <ref name="InTiME-ct">{{Cite web | url = https://www.clinicaltrials.gov/ProvidedDocs/29/NCT03613129/Prot_SAP_000.pdf | title=Pilot phase 1/2 Open-label, clinical trial to Investigate CT38 in the Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (InTiME) | last = Bateman | first = Lucinda | author-link = Lucinda Bateman | date = Dec 7, 2018 | website = | archive-url = | archive-date = |url-status = | access-date=June 6, 2020}}</ref> Overall Safety in humans is currently unknown due to insufficient study, however Urocortin 2 stimulation of [[CRFR2]] has been shown to cause cardiac dysfunction and can increase risk of heart failure in mice. <ref name="Tsuda2017">{{Cite journal | last = Tsuda | first = Takuma | last2 = Takefuji | first2 = Mikito | last3 = Wettschureck | first3 = Nina | last4 = Kotani | first4 = Kazuhiko | last5 = Morimoto | first5 = Ryota | last6 = Okumura | first6 = Takahiro | last7 = Kaur | first7 = Harmandeep | last8 = Eguchi | first8 = Shunsuke | last9 = Sakaguchi | first9 = Teruhiro | date = 2017-07-03 | title = Corticotropin releasing hormone receptor 2 exacerbates chronic cardiac dysfunction | url =https://rupress.org/jem/article/214/7/1877/52167/Corticotropin-releasing-hormone-receptor-2 | journal = Journal of Experimental Medicine|language=en | volume = 214 | issue = 7 | pages = 1877โ1888|doi=10.1084/jem.20161924|issn=0022-1007|pmc = 5502432|pmid=28550160}}</ref> ==Costs and availability== CT38 is not yet approved for use, so it is unavailable outside clinical trials. CT38 is administered by subcutaneous infusion. Costs in future are unknown. == Articles, talks and interviews == * 2018, [https://www.healthrising.org/blog/2018/07/14/cortene-chronic-fatigue-syndrome-me-cfs-drug-trial-begins/ The Cortene Chronic Fatigue Syndrome (ME/CFS) Drug Trial Begins]<ref name="HR2018" /> == Notable studies == *2021, Acute Corticotropin-Releasing Factor Receptor Type 2 Agonism Results in Sustained Symptom Improvement in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome<ref name="Pereira2021">{{Cite journal | last = Pereira | first = Gerard | last2 = Gillies | first2 = Hunter | last3 = Chanda | first3 = Sanjay | last4 = Corbett | first4 = Michael | last5 = Vernon | first5 = Suzanne D. | last6 = Milani | first6 = Tina | last7 = Bateman | first7 = Lucinda | date = 2021 | title=Acute Corticotropin-Releasing Factor Receptor Type 2 Agonism Results in Sustained Symptom Improvement in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | url =https://www.frontiersin.org/article/10.3389/fnsys.2021.698240 | journal = Frontiers in Systems Neuroscience | volume = 15 | pages = 84|doi=10.3389/fnsys.2021.698240|issn=1662-5137|pmc=PMC8441022|pmid=34539356}}</ref> [https://doi.org/10.3389/fnsys.2021.698240 (Full text)] ==Learn more== *[https://clinicaltrials.gov/ct2/show/NCT03613129 Clinical Trial to Investigate CT38 in the Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome] *[http://corteneinc.com/science Hypothesis behind CT38] - Cortene *Sep 2021, [https://batemanhornecenter.org/cortene-plans-to-study-ct38-in-me-cfs-and-long-covid/ Cortene Weighs-In on Future Plans for CT38] - Bateman Horne Center *Sep 2021, [https://batemanhornecenter.org/september-message-cortene-study-published/ Cortene study published] *Sep 2021, [https://batemanhornecenter.org/dr-bateman-on-cortene-and-ct38/ Dr Bateman on Cortene and CT38] ==See also== *[[Cortene]] *[[Corticotropin-releasing factor receptor type 2]] (CRFR2) *[[Bateman Horne Center]] ==References== {{reflist}} [[Category:Potential treatments]] [[Category:Peptides]]
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