Calcitonin Gene Research Articles

The comparative effectiveness of migraine preventive drugs: a systematic review and network meta-analysis

ObjectiveWhile there are several trials that support the efficacy of various drugs for migraine prophylaxis against placebo, there is limited evidence addressing the comparative safety and efficacy of these drugs. We conducted a systematic review and network meta-analysis to facilitate comparison between drugs for migraine prophylaxis.MethodsWe searched MEDLINE, EMBASE, CENTRAL, and clinicaltrials.gov from inception to August 13, 2022, for randomized trials of pharmacological treatments for migraine prophylaxis in adults. Reviewers worked independently and in duplicate to screen references, extract data, and assess risk of bias. We performed a frequentist random-effects network meta-analysis and rated the certainty (quality) of evidence as either high, moderate, low, or very low using the GRADE approach.ResultsWe identified 74 eligible trials, reporting on 32,990 patients. We found high certainty evidence that monoclonal antibodies acting on the calcitonin gene related peptide or its receptor (CGRP(r)mAbs), gepants, and topiramate increase the proportion of patients who experience a 50% or more reduction in monthly migraine days, compared to placebo. We found moderate certainty evidence that beta-blockers, valproate, and amitriptyline increase the proportion of patients who experience a 50% or more reduction in monthly migraine days, and low certainty evidence that gabapentin may not be different from placebo. We found high certainty evidence that, compared to placebo, valproate and amitriptyline lead to substantial adverse events leading to discontinuation, moderate certainty evidence that topiramate, beta-blockers, and gabapentin increase adverse events leading to discontinuation, and moderate to high certainty evidence that (CGRP(r)mAbs) and gepants do not increase adverse events.Conclusions(CGRP(r)mAbs) have the best safety and efficacy profile of all drugs for migraine prophylaxis, followed closely by gepants.

Evaluation of serum VIP and aCGRP during pulmonary exacerbation in cystic fibrosis: A longitudinal pilot study of patients undergoing antibiotic therapy.

Objective monitoring of improvement during treatment of pulmonary exacerbation can be difficulty in children when pulmonary function testing cannot be obtained. Thus, the identification of predictive biomarkers to determine the efficacy of drug treatments is of high priority. The major aim of the current study was to investigate the serum levels of vasoactive intestinal peptide (VIP) and alpha calcitonin gene related peptide (aCGRP) of cystic fibrosis pediatric patients during pulmonary exacerbation and post-antibiotic therapy, and possible associations of their levels with different clinicopathological parameters. 21 patients with cystic fibrosis were recruited at onset of pulmonary exacerbation. Serum was collected at time of admission, three days post-antibiotic therapy, and two weeks post-antibiotic therapy (end of antibiotic therapy). Serum VIP and aCGRP levels were measured using ELISA. Overall least square means of serum aCGRP level but not VIP changed from time of exacerbation to completion of antibiotic therapy (p = 0.005). Serum VIP was significantly associated with the presence of diabetes mellitus (p = 0.026) and other comorbidities (p = 0.013), and with type of antibiotic therapy (p = 0.019). Serum aCGRP level was significantly associated with type of antibiotic therapy (p = 0.012) and positive Staphylococcus aureus microbiology test (p = 0.046). This study could only show significant changes in serum aCGRP levels following treatment of pulmonary exacerbations. Future studies with larger sample size are required to investigate the clinical importance of VIP and aCGRP in cystic fibrosis patients.

Intestinal origins of Parkinson's Disease pathologies

Accumulating evidence suggests that Parkinson’s disease (PD) pathology may arise in the gut. This likely occurs through the enteric nervous system (ENS), which facilitates bidirectional communication between the brain and intestines. A hallmark of PD is neuronal accumulation of misfolded α-synuclein (aSyn) proteins which have been shown to travel from the ENS to the brain via the vagus nerve. The goal of this study was to connect related neural and immune phenotypes in ex vivo and in vivo mouse models of PD.Recent data suggests that enteric neuronal fibers containing calcitonin gene related peptide (CGRP) act as chemo-sensors that can be stimulated to release CGRP in response to bacterial and chemical signals. CGRP can activate receptors that influence goblet cells (GCs) and immune cells. GCs are responsible for secreting mucus to maintain mucosal barrier integrity. Deterioration of gut barrier integrity is hallmark of PD patients. We hypothesize that alterations in luminal contents modifies and disturbs GCs disrupting the gut barrier in PD. This may result in increased release of CGRP leading to alterations in mucus production, immune responses, and aSyn aggregation in enteric neurons. In this study, the pesticide rotenone was given to C57BL/6 mice to facilitate aggregation of misfolded aSyn. Lectin and immuno-histochemistry were performed on sections of ileum and colon. GC mucopolysaccharides were fluorescently labeled with the lectin Ulex Europaeus Agglutinin I (UEA) conjugated to rhodamine. UEA-1+ cells in crypts were 25% more prevalent (68.5 +/- 0.5 vs. 52.5 +/-2.5) with rotenone treatment but 53% less prevalent in the luminal portion of crypts (22.5 +/- 2.5 vs. 47.5 +/-2.5). Fewer GCs in luminal positions is consistent with decreased mucus seen in PD patients. T cells were identified by immunoreactive (ir) CD3. Approximately 50% fewer CD3+ cells were in rotenone treated lamina propria (17 +/- 1.4) compared to control (36.2 +/- 3.5) consistent with previous reports. The area of CGRP-ir fibers in the lamina propria was 114% higher in control (6.4%+/-1.3) compared to rotenone treated tissue (5.6%+/-0.6). Rotenone treatment resulted in a 217% increase in the area average of CGRP-ir fibers in the region just below the epithelial monolayer (12.8%+/-1.3) compared to control (5.8%+/-0.7). While we did not observe CGRP fibers beyond the epithelial cell layer, GC cell disruption that could allow luminal contents to access CGRP fibers was suggested by the potential failure of GCs to migrate toward luminal surfaces from crypts. Future studies are needed to test the hypothesis that rotenone disturbance of mitochondrial function in GCs causes intestinal wall failure that leads to altered neuroimmune function. Aggregation of aSyn in enteric neurons may thereby be mediated by altered immune to neural actions as exacerbated by alterations in CGRP containing fibers and T cell populations in the gut. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Real-world Adherence to Subsequent CGRP mAb Treatment Among Chronic Migraine (CM) Patients Initially Treated with OnabotulinumtoxinA: A Retrospective Claims Analysis (P10-12.004)

<h3>Objective:</h3> To examine adherence to calcitonin gene–related peptide monoclonal antibody (CGRP mAb) treatment among patients who initiated onabotulinumtoxinA (OnabotA) and subsequently added on or switched to a CGRP mAb. <h3>Background:</h3> The 2021 American Headache Society consensus statement and emerging clinical reports suggest that the combination of a CGRP mAb and OnabotA in patients with migraine is probably effective. However, real-world utilization of combination treatments relative to monotherapies among patients with chronic migraine (CM) has not been examined previously. <h3>Design/Methods:</h3> In this retrospective cohort study, adult patients with CM (ICD-10-CM G43.7X) treated with OnabotA and subsequently with a CGRP mAb were identified from IBM MarketScan® claims databases (05/17/2018 – 06/30/2021). The index date was the first CGRP mAb prescription. Patients were categorized into two cohorts: “addition” (concomitant OnabotA and index CGRP mAb usage ≥28 days) and “switch” (otherwise). Adherence (≥80% of days covered on medication) over a 6-month follow-up period was assessed using logistic regression to adjust for baseline characteristics during the 6-month pre-index period. <h3>Results:</h3> The study sample included 610 patients in the addition cohort and 680 in the switch cohort. Lower adherence to index CGRP mAb was observed in the addition versus switch cohorts (38.9% vs 48.2%; <i>P</i>&lt;0.001). After controlling for baseline characteristics, the switch cohort had 41% (95% CI: 1.12–1.77; <i>P</i>=0.003) higher odds of adherence versus the addition cohort. In the addition cohort, 60.2% (n=367) of patients were adherent to OnabotA alone or in combination with a CGRP mAb, and 19.3% (n=118) were adherent to combination use of the index CGRP mAb and OnabotA. <h3>Conclusions:</h3> During follow-up, patients who added a CGRP mAb to OnabotA had significantly lower adherence to the CGRP mAb versus patients who switched to a CGRP mAb. These findings suggest that usage of CGRP mAb as add-on to OnabotA occurs for a limited duration. <b>Disclosure:</b> Ms. DONG has received personal compensation for serving as an employee of AbbVie. Ms. DONG has stock in AbbVie. Ms. DONG has received research support from National Institutes of Health. Ms. Gusovsky has nothing to disclose. Ms. Shah has received personal compensation for serving as an employee of AbbVie. Ms. Shah has stock in AbbVie Inc. An immediate family member of Ms. Shah has received research support from National Institutes of Health. Mr. Park has received personal compensation for serving as an employee of AbbVie. Mr. Park has stock in AbbVie. Changgeng Zhao has received personal compensation for serving as an employee of AbbVie. Changgeng Zhao has stock in AbbVie.

Benefit-Risk Assessment of Atogepant: A Post Hoc Analysis of the ADVANCE Trial (P12-12.001)

Benefit-Risk Assessment of Atogepant: A Post Hoc Analysis of the ADVANCE Trial (P12-12.001)

Real-world Adherence to Subsequent Prophylactic Therapy Among Chronic Migraine (CM) Patients Initially Treated With a Calcitonin Gene–related Peptide Monoclonal Antibody (CGRP mAb) (P6-12.009)

<h3>Objective:</h3> To examine adherence to branded preventive chronic migraine (CM) treatments among patients who initiated calcitonin gene–related peptide monoclonal antibody (CGRP mAb) treatment and subsequently added on or switched to another branded preventive treatment. <h3>Background:</h3> OnabotulinumtoxinA (OnabotA) and CGRP mAbs treat CM prophylactically. CM patients treated with a CGRP mAb may introduce a subsequent treatment, but little is known about adherence to the subsequent CM treatment. <h3>Design/Methods:</h3> This retrospective cohort study included adult CM patients (ICD-10-CM G43.7XX) treated with a CGRP mAb and a subsequent CM treatment from IBM MarketScan® claims databases (05/17/2018 – 06/30/2021). The index date was the first claim date of subsequent treatment. Patients were categorized into three cohorts: switch to another CGRP mAb, switch to OnabotA, and add-on OnabotA (concomitant with CGRP mAb ≥28 days immediately following index). Baseline characteristics were assessed during the 6-month pre-index period. Adherence was defined as ≥80% of days covered on index treatment over the 6-month follow-up period. Difference in adherence between cohorts was compared using a Chi-square test and adjusted for baseline characteristics using logistic regression. <h3>Results:</h3> A total of 1315 patients were included; 745 switched to a CGRP mAb, 449 switched to OnabotA, and 121 added OnabotA. Mean age was 41.9, 39.8, and 41.3 years, respectively, and all cohorts were ≥86% female. Adherence was highest for add-on OnabotA, followed by switch to OnabotA, and, lastly, switch to CGRP mAb (68.6% vs 61.5% vs 33.2%, respectively; <i>P</i>&lt;0.0001). After adjustment, switch to OnabotA and add-on OnabotA cohorts had 3.3 (95% CI: 2.5–4.2) and 4.6 (95% CI: 3.0–7.0) times higher odds of adherence compared with the switch to CGRP mAb cohort. <h3>Conclusions:</h3> Following a CGRP mAb, adding on or switching to OnabotA as a subsequent CM treatment was associated with significantly higher adherence over 6 months compared with switching to another CGRP mAb. <b>Disclosure:</b> Ms. Gusovsky has nothing to disclose. Ms. DONG has received personal compensation for serving as an employee of AbbVie. Ms. DONG has stock in AbbVie. Ms. DONG has received research support from National Institutes of Health. Changgeng Zhao has received personal compensation for serving as an employee of AbbVie. Changgeng Zhao has stock in AbbVie. Mr. Park has received personal compensation for serving as an employee of AbbVie. Mr. Park has stock in AbbVie. Ms. Shah has received personal compensation for serving as an employee of AbbVie. Ms. Shah has stock in AbbVie Inc. An immediate family member of Ms. Shah has received research support from National Institutes of Health.

Corticosterone mediates FKBP51 signaling and inflammation response in the trigeminal ganglion in chronic stress-induced corneal hyperalgesia mice

Stress-induced hyperalgesia is a health-threatening condition that lacks effective therapeutic intervention, impairing the quality of life. Interestingly, a high prevalence of corneal pain symptoms was also found in patients experienced severe stressors. Excessive secretion corticosterone in rodents has been shown to contribute to the development of visceral and mechanical hyperalgesia under stressful conditions. The co-chaperone protein FK506-binding protein 5 (FKBP5) was reported to modulate steroid sensitivity and inhibition of FKBP51 possessed anxiolytic and anti-hyperalgesic in the stressed-mice model. However, whether corticosterone and FKBP5 play a role in chronic stress-induced corneal hyperalgesia remains unknown. The aim of this study was to evaluate the corneal sensitivity after exposure to chronic restraint stress (CRS) and investigate the potential role of corticosterone and FKBP5 mediated proinflammatory cytokines release in trigeminal ganglion (TG) in corneal hyperalgesia under chronic stressful situations. Firstly, mice displayed increased corneal sensitivity without changes in tear production and corneal injury after CRS for 4 hours/day for 14 days. Meanwhile, corticosterone deficiency via adrenalectomy could prevent CRS-induced corneal hyperalgesia, whereas chronic corticosterone feeding increased the corneal sensitivity accompanied by increasing proinflammatory cytokines levels of phospho-NF-κB (p-NF-κB), tumor necrosis factor (TNF)-α and interleukin (IL)-1β in the TG on d14. Notably, we found that FKBP51 was significantly upregulated in the TG in the stressed-mice. Intraperitoneal injection of FKBP51 inhibitor significantly alleviated CRS-induced corneal hyperalgesia, and reversed calcitonin gene related peptide (CGRP) increase and proinflammatory cytokines production in the TG. Moreover, FKBP51 inhibitor could also exert its anti-hyperalgesic effect on corneal pain through intra-TG injection. Our study proves that CRS can induce corneal hyperalgesia in mice and uncovers the role of corticosterone and FKBP51 in modulating corneal sensitivity, providing a novel treatment strategy for stress-induced corneal hyperalgesia. Availability of data and materialsAll data and additional file are available upon request from the corresponding author.

Evaluation of serum calcitonin gene related peptide (CGRP) Level in HIV infected patients as an indicator of disease activity

Human immunodeficiency virus (HIV) infection is under global attention due to its rapid spread and high rate of morbidity and mortality. HIV gets an access into the mucosa of genital epithelium through binding to Langerhans cells. While viral load and CD4+ cell count are the main parameters to detect disease activity, new biomarkers are introduced as a potential parameter for monitoring of disease activity in HIV infected patients. Calcitonin Gene Related Peptide (CGRP) is a neuropeptide that is secreted by peripheral neurons at genital epithelia and plays an important role in limitation of HIV transmission and spread to infected CD4+ cells through its effect onto Langerhans cells. This study aimed to evaluate the serum level of CGRP in HIV infected patients and to determine whether CGRP can serve as an indicator of HIV infection activity. The study included 104 HIV patients and 24 normal controls. Patients were divided into four groups. Serum levels of CGRP were measured by ELISA and correlated to viral load and CD4+ cells count for patients in the four groups: primary HIV infection (PHI), chronic HIV infection (CHI) before combinational antiretroviral therapy (cART-naïve), chronic HIV infection after one year of cART-initiation, and chronic HIV infection after two years of cART. Serum levels of CGRP were also measured in sera of controls and compared to patients' groups. Serum levels of CGRP were significantly lower in cART naïve PHI and CHI patients in comparison with normal controls (p < 0.05), Also, serum CGRP levels were positively correlated with CD4+ cells count (p < 0.01), but negatively correlated with viral load (p>0.05). In conclusion, CGRP could be proposed as an indicator of disease activity in HIV patients.

Yuhong ointment ameliorates inflammatory responses and wound healing in scalded mice.

Yuhong ointment (YHO) is famous for its efficacy in clearing away heat and dampness, reducing swelling and relieving pain, and it has been used for more than 600 years. Scalding damages the skin's defense function, resulting in a large number of necrotic tissues and cells on the wound surface, which favors bacterial growth and inflammation. If the inflammation reaction is not controlled on time, it may lead to reduced immunity and cause complications such as infection. Yuhong ointment can promote wound healing in scalded mice, but its potential pharmacological mechanism is still unclear. This study focused on identifying the active ingredients of YHO and on investigating the performance of YHO in terms of anti-inflammatory activity and scald wound healing activity. High-performance liquid chromatography (HPLC) and high-performance liquid chromatography-mass spectrometry (HPLC-MS) were performed to identify the active ingredients of YHO. The performance of transdermal delivery of YHO was studied via HPLC for analyzing the ingredients of the exposed skin liquid of mice. Enzyme-linked immunosorbent assay (ELISA) analysis, immunohistochemistry, and real-time fluorescence quantitative PCR (qRT-PCR) were used to investigate the anti-inflammatory and scald wound healing activity of YHO. A total of 41 components of YHO were identified via HPLC and HPLC-MS for the first time. In the transdermal delivery experiment, the cumulative amounts of chlorogenic acid, sesamol, ferulic acid, and L-shikonin were calculated to be 342.28, 567.89, 384.54, and 528.67 μg/cm2, respectively. Pharmacological activity experiments indicated that these four kinds of drugs exhibited different degrees of therapeutic effects on scald. Specifically, YHO high-dose (YHO-H) group showed better therapeutic ability (P < 0.01) than FN and MB group. Furthermore, the immune function of the YHO group was enhanced due to the continuous increment of the levels of Hydroxyproline (HYP), Immunoglobulin G (IgG), and vascular endothelial growth factor (VEGF) and simultaneous decrement of the levels of TNF-α, TNF-β, IL-10, and IL-6 in the skin wound. Histological results showed that the thickening of skin tissue was alleviated after treatment with YHO. Moreover, the expression of substance P (SP), calcitonin gene related peptide (CGRP) and transient receptor potential vanilloid-1 (TRPV1) was inhibited, and the expression of VEGF was promoted by YHO (P < 0.01). The qRT-PCR test results indicated that the YHO group exhibited better inhibitory effect on interleukin 6 (IL-6), interleukin 10 (IL-10), transforming growth factor-beta (TGF-β), and Smad-3 mRNA expression levels than the other groups. In this work, the active ingredients of YHO were identified via HPLC and HPLC-MS analysis. Importantly, YHO showed great advantages in transdermal delivery and scald wound healing, which can be attributed to the both anti-inflammatory and tissue regeneration mechanisms. Therefore, this work not only identified the active ingredients of YHO but also revealed the potential pharmacological mechanism of YHO for the healing of scald.

Calcitonin gene relating peptide inhibitors in combination for migraine treatment: A mini-review.

The discovery of calcitonin gene-related peptide (CGRP) and its role in migraine pathophysiology has led to advances in the treatment of migraine. Since 2018, the Food and Drug Administration (FDA) has approved four monoclonal antibody (mab) therapies targeting either the CGRP ligand or receptor and 3 oral small molecule CGRP receptor antagonists. These targeted therapies have been shown to be safe and effective for either preventive or acute treatment of migraine in adults. Given their efficacy and tolerability profile, CGRP inhibitors have revolutionized the approach to migraine treatment. Theoretically, combining therapies within this therapeutic class could lead to more CGRP blockade and, subsequently, improved patient outcomes. There are providers currently combining CGRP therapies in clinical practice. However, limited data are available regarding the efficacy and safety of this practice. This mini-review provides a summary of available data and poses important considerations when combining CGRP therapies for migraine treatment.

Switching anti-CGRP(R) monoclonal antibodies in multi-assessed non-responder patients and implications for ineffectiveness criteria: A retrospective cohort study.

A pharmacological class effect was initially proposed for monoclonal antibodies against the calcitonin gene related peptide pathway. However, preliminary evidence shows that switching patients who were non-responding to one monoclonal antibody to another could provide some benefit. Herein, we assess treatment response to an anti-calcitonin gene related peptide/receptor monoclonal antibody in patients who have failed to respond to anti-calcitonin gene related peptide/ligand monoclonal antibodies calcitonin gene related peptide/ligand monoclonal antibodies and vice versa. In addition, we select non-responders to the first anti- monoclonal antibody by three or five more stringent variables. Retrospective cohort study including outpatients treated consecutively with two anti-calcitonin gene related peptide monoclonal antibodies. Ineffectiveness to the first monoclonal antibody was assessed using three (MIDAS score, monthly headache days, and analgesic monthly days) variables or five (monthly headache days, MIDAS score, analgesic monthly days, analgesic monthly number and HIT-6 score) variables in the same cohort of patients. The primary endpoints were the absolute change from baseline in monthly headache days, response rate, and persistence in medication overuse at three months of treatment with the second anti-CGRP mAb. In patients selected by three variables, a sustained reduction in monthly headache days, analgesic monthly days, MIDAS and HIT-6 scores was observed at month-3 of treatment with the second monoclonal antibody. Ten (45.4%) patients achieved at least a ≥30% response rate. No difference was reported switching anti-CGRP mAb against ligand or receptor. In the patient subgroup selected by five variables, only HIT-6 was reduced from baseline at month-3. However, a trend toward a reduction in monthly headache days, analgesic monthly days, and MIDAS score was observed at month-3. Switching anti-calcitonin gene related peptide monoclonal antibodies in selected patients might be an option to achieve or improve clinical benefit. More studies are required to establish the effectiveness of switching these treatments.

Role of adrenomedullin2/ intermedin in pregnancy induced vascular and metabolic adaptation in mice.

Introduction: Adrenomedullin2 (AM2) shares its receptor with Calcitonin gene related peptide and adrenomedullin with overlapping but distinct biological functions. Goal of this study was to assess the specific role of Adrenomedullin2 (AM2) in pregnancy induced vascular and metabolic adaptation using AM2 knockout mice (AM2 -/-). Method : The AM2 -/- mice were successfully generated using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Nuclease Cas nine system. Phenotype of pregnant AM2 -/- mice was assessed with respect to its fertility, blood pressure regulation, vascular health and metabolic adaptations and compared to the wild type littermates (AM2 +/+). Results : Current data shows that AM2 -/- females are fertile with no significant difference in number of pups/litter compared to the AM2 +/+. However, ablation of AM2 decreases the gestational length and the total number of pups born dead or that die after birth is greater in AM2 -/- mice compared to AM2 +/+ mice (p < 0.05). Further AM2 -/- mice exhibit elevated blood pressure and elevated vascular sensitivity for the contractile responses to angiotensin two and higher serum sFLT-1 trigylcerides levels compared to AM2 +/+(p < 0.05). In addition, AM2 -/- mice develop glucose intolerance with elevated serum levels of Insulin during pregnancy compared to the AM2 +/+mice. Discussion: Current data suggests a physiological role for AM2 in pregnancy induced vascular and metabolic adaptations in mice.

Acute herpes zoster treated with surrounding fire needling combined with electroacupuncture at Jiājĭ (夹脊EX-B2): A randomized controlled trial: 火针围刺联合夹脊电针治疗急性期带状疱疹:随机对照试验

ObjectivesTo investigate the clinical efficacy of surrounding fire needling combined with electroacupuncture (EA) at Jiājĭ (夹脊EX-B2) on acute herpes zoster, and explore the potential mechanism of this combined treatment by measuring the changes of serum inflammatory cytokines and pain mediators. MethodsSixty patients with acute herpes zoster were randomly assigned to either acupuncture plus western medicine group or western medicine group. In the western medicine group, the patients took orally mecobalamin and ganciclovir for 14 consecutive days. In the acupuncture plus western medicine group, on the base of the western medicine, the surrounding fire needling (fire needling was operated swiftly toward the center of skin lesions.) combined with EA at EX-B2 was provided. Acupoints of EX-B2 were selected based on the nerve ganglion corresponding to the skin lesions, as well as two adjacent nerve ganglions(one level upwards and one downwards) to the lesions, and were stimulated with EA once daily for 14 days. The change of symptoms from the blister eruption to scabbing and decrustation were observed. The score of visual analogue scale (VAS), serum inflammatory cytokines (interleukin-1β, interleukin-6, tumor necrosis factor-α) and pain mediators (calcitonin gene related peptide, substance P) before and after treatment, the scores of Pittsburgh sleep quality index (PSQI) and Hamilton depression scale (HAMD) before and after treatment as well as at 1 month of follow-up, and the overall effective rate and the incidence of post-hepatic neuralgia at 1 month of follow-up were assessed and compared between two groups, respectively. ResultsAfter treatment completion, the time of blister relief, scabbing and decrustation in the acupuncture plus western medicine group was significantly shorter when compared with that of the western medicine group (all P < 0.05). After treatment, VAS score, PSQI score and HAMD score were all reduced significantly when compared with that before treatment within group (P < 0.05). These scores in the acupuncture plus western medicine were reduced significantly compared with the western medicine group at the same time point (all P < 0.05). After treatment, the incidence of post-hepatic neuralgia was 6.89%, lower than that in western medicine group (50.00%, P < 0.05). After treatment, the values of serum inflammatory cytokines (IL-1β, IL-6, TNT-a) and pain mediators (CGRP, SP) were reduced when compared with the those before treatment within group (P < 0.05), and the reduction in the acupuncture plus western medicine group was larger than that in the western medicine group (P < 0.05). The total effective rate was 96.67% in the acupuncture plus western medicine group, higher than western medicine group (86.67%, P < 0.05). ConclusionsSurrounding fire needling therapy combined with EA at EX-B2 on the base of western medicine obtained better therapeutic effect on acute herpes zoster when compared with western medicine. This combined treatment may effectively relieve pain and depressive emotions, improve sleep quality and reduce the incidence of post-hepatic neuralgia. The underlying mechanism may related to regulation of pain mediators and reduction of inflammatory cytokines.

Human salivary concentrations of brain derived neurotrophic factor correlates with subjective pain intensity associated with initial orthodontic therapy

Current study aimed to evaluate presence & concentration of salivary molecular pain biomarkers Calcitonin Gene Related Peptide (CGRP) and Brain-Derived Neurotrophic Factor (BDNF) during initial stages of orthodontic treatment and correlation with subjective pain scales, Numerical Rating Scale (NRS), Visual Analogue Scale (VAS), Verbal Rating Scale (VRS) and McGill Pain Questionnaire (MPQ). Consented, healthy-pain free patients (n = 40) undergoing orthodontic therapy, having moderate crowding with pre-molar extraction were recruited. Unstimulated whole saliva was collected and stored at -80 °C in cryotubes. Levels of CGRP & BDNF in salivary samples was assessed by enzyme–linked immunosorbent assay. Samples were collected under stipulated 5 time periods using saliva collection tube by passive drooling method: immediately after bonding but before wire placement (T0-baseline), after 24 h (T1), 48 h (T2), 72 h (T3) & 168 h (T4) after wire placement. Consolidated subjective pain scales were administered concurrently. Regression value (R2 > 0.9) confirmed BDNF & CGRP in saliva. Significant change was observed from baseline to 168 h in all subjective parameters (p < 0.05). CGRP did not correlate with subjective pain scales statistically (p > 0.05). BDNF levels correlated with all the subjective pain scales, NRS (T3-p = 0.0092&T4-p = 0.0064), VRS (T3-p = 0.0112&T4-p = 0.0500), VAS (T3-p = 0.0092 &T4-p = 0.0064) &MPQ (T1-p = 0.0255). Mean BDNF & median subjective pain scale graphs were similar. BDNF correlated with all the subjective pain scales warranting further investigation.Trial registration; Clinical Trial Registry—India (CTRI) Reg No: CTRI/2018/12/016571; Registered 10th December, 2018 (10/12/2018) prospectively; http://ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=29640&EncHid=&userName=Dr%20Sagar%20S%20Bhat.

P087 Calcitonin gene related peptide beta (CGRPβ): a new player in inflammatory bowel disease pathophysiology

Abstract Background Calcitonin gene related peptide (CGRP) is mainly present in the central nervous system (α isoform) and enteric nervous system (β isoform). CGRP is known to be the most potent vasodilator of the body, and it promotes migration of inflammatory cells. Although its function in the gut is not well established yet, CGRPβ is postulated to have a protective role against inflammation in the gut, promoting migration of inflammatory cells, regulating nociception, motility and gut microbioma. The aim of the study is to analyse serum levels of CGRPβ in patients newly diagnosed with inflammatory bowel disease (IBD), to unravel its potential role in the disease. Methods CGRPβ levels were measured by ELISA (CUSABIO, China) in early morning samples of newly diagnosed patients with IBD. Classification of the disease (ulcerative colitis- UC, Crohn’s disease- CD or unclassified inflammatory bowel disease- U-IBD), demographic data and treatment during sample collection were also collected. The results were compared with healthy controls (HC) stratified by age and sex. Statistical analysis was performed using SPSS and CGRPβ levels were compared with Mann-Whitney and Dunn’s tests. Results Seventy-one patients with newly diagnosed IBD (mean age 48.3±16.5 years, 63.4% females) were matched with 71 HC (mean age= 48.2±16.7 years-64.8% females). Samples were collected between 0 and 249 days after IBD diagnosis was established (median 49 days, interquartile range 29-66 days). Thirty patients were diagnosed as CD, 36 as UC and 5 as U-IBD. Most patients with CD had ileal location and inflammatory behaviour. One of these patients was on methotrexate due to a prior diagnosis of rheumatoid arthritis; the rest were either with no treatment, aminosalicylates, steroids or budesonide, or some combination of these. Half of the patients with UC had proctitis. Six had no treatment, and the rest were prescribed aminosalicylates, seven of them in combination with steroids. These characteristics are shown in table 1. Serum CGRPβ levels in patients with IBD were significantly decreased (2.95±1.68 pg/mL) compared to HC (4.65±2.59 pg/mL), (p&amp;lt;0.0001). These results stayed significant, in both CD (3.15±2.08 pg/mL; p&amp;lt;0.05), and UC (2.83±12.7 pg/mL; p &amp;lt;0.01), but not in IBD-U (2.56±1.73 pg/mL), though the number of U-IBD cases was low. CGRPβ concentrations did not differ significantly in patients with CD and UC. The results are illustrated in figures 1 and 2. Conclusion The consistent decrease in CGRPβ levels in IBD shown here strongly supports a protective role of this peptide in the homeostasis of the intestinal mucosa. This work was supported by a grant from the Instituto de Salud Carlos III (PI20/01358).

P114 Increased serum levels of the migraine biomarker calcitonin gene related peptide alpha in a newly diagnosed inflammatory bowel disease population: a new mediator for the gut-brain-axis

Abstract Background Calcitonin gene related peptide (CGRP) is known to be the most potent vasodilator of the body, and it promotes migration of inflammatory cells. CGRPβ isoform is located along the enteric nervous system, and CGRPα is mainly present in the central nervous system. CGRPα is known to be the key molecule in migraine, an entity with digestive symptoms. It has been suggested that migraine prevalence is increased in inflammatory bowel disease (IBD). The aim of the study was to assess CGRPα serum levels in patients with newly diagnosed of IBD, stratified by migraine diagnosis, to unravel its potential role in the disease. Methods CGRPα serum concentrations were measured by ELISA (CUSABIO, China) in early morning samples of newly diagnosed patients with IBD. Classification of the disease (ulcerative colitis- UC, Crohn’s disease- CD or unclassified inflammatory bowel disease- U-IBD), demographic data and treatment during sample collection were also collected. To establish a migraine diagnosis, patients were interviewed about prior migraine diagnosis and validated ID-migraine questionnaire was used to diagnose patients with migraine. The results were compared with healthy controls (HC) matched by age and sex. Statistical analysis was performed using SPSS and CGRPα levels were compared with Mann-Whitney and Dunn’s tests. Results Sixty-two patients with newly diagnosed IBD (mean age 47.9±16.3 years, 62.5% females) were matched with 71 HC (mean age 48.2±16.7 years, 64.8% females). Samples were collected between 0 and 249 days after IBD diagnosis was stablished (median 50.5 days, interquartile range 26.75-64.5 days). We included 27 patients with CD, 31 with UC and 4 with U-IBD. Baseline characteristics are shown in table 1. Fifteen female patients met migraine criteria (22.7%). Serum CGRPα levels in patients with IBD were significantly increased (59.7±26.3 pg/mL), compared to HC (43.6±25.3 pg/mL, p&amp;lt;0.0001). CGRPα remained significantly elevated as compared to HC both in IBD patients with migraine (74.8±27.3 pg/mL, p&amp;lt; 0.001) and without migraine (58.6±24.4 pg/mL, p&amp;lt;0.05), though those with migraine were significantly increased as compared to IBD patients without migraine (p&amp;lt;0.05). These results are shown in figures 1 and 2. Conclusion Serum CGRPα levels are increased in patients with IBD, regardless of migraine diagnosis, which could indicate a role of this peptide in the pathophysiology of IBD. These results, and especially the higher levels in IBD patients with migraine, suggest a bidirectional, shared pathophysiology between migraine and IBD, which could be a further example of the clinical relevance of the gut-brain axis. Supported by Instituto de Salud Carlos III (PI20/01358).

Periglomerular afferent innervation of the mouse renal cortex.

Recent studies using a novel method for targeted ablation of afferent renal nerves have demonstrated their importance in the development and maintenance of some animal models of hypertension. However, relatively little is known about the anatomy of renal afferent nerves distal to the renal pelvis. Here, we investigated the anatomical relationship between renal glomeruli and afferent axons identified based on transient receptor potential vanilloid 1 channel (TRPV1) lineage or calcitonin gene related peptide (CGRP) immunolabeling. Analysis of over 6,000 (10,000 was accurate prior to the removal of the TH data during the review process) glomeruli from wildtype C57BL/6J mice and transgenic mice expressing tdTomato in TRPV1 lineage cells indicated that approximately half of all glomeruli sampled were closely apposed to tdTomato+ or CGRP+ afferent axons. Glomeruli were categorized as superficial, midcortical, or juxtamedullary based on their depth within the cortex. Juxtamedullary glomeruli were more likely to be closely apposed by afferent axon subtypes than more superficial glomeruli. High-resolution imaging of thick, cleared renal slices and subsequent distance transformations revealed that CGRP+ axons closely apposed to glomeruli were often found within 2 microns of nephrin+ labeling of glomerular podocytes. Furthermore, imaging of thick slices suggested that CGRP+ axon bundles can closely appose multiple glomeruli that share the same interlobular artery. Based on their expression of CGRP or tdTomato, prevalence near glomeruli, proximity to glomerular structures, and close apposition to multiple glomeruli within a module, we hypothesize that periglomerular afferent axons may function as mechanoreceptors monitoring glomerular pressure. These anatomical findings highlight the importance of further studies investigating the physiological role of periglomerular afferent axons in neural control of renal function in health and disease.

PACAP-PAC1 receptor inhibition is effective in opioid induced hyperalgesia and medication overuse headache models

Opioids prescribed for pain and migraine can produce opioid-induced hyperalgesia (OIH) or medication overuse headache (MOH). We previously demonstrated that pituitary adenylate cyclase activating polypeptide (PACAP) is upregulated in OIH and chronic migraine models. Here we determined if PACAP acts as a bridge between opioids and pain chronification. We tested PACAP-PAC1 receptor inhibition in novel models of opioid-exacerbated trigeminovascular pain. The PAC1 antagonist, M65, reversed chronic allodynia in a model which combines morphine with the migraine trigger, nitroglycerin. Chronic opioids also exacerbated cortical spreading depression, a correlate of migraine aura; and M65 inhibited this augmentation. In situ hybridization showed MOR and PACAP co-expression in trigeminal ganglia, and near complete overlap between MOR and PAC1 in the trigeminal nucleus caudalis and periaqueductal gray. PACAPergic mechanisms appear to facilitate the transition to chronic headache following opioid use, and strategies targeting this system may be particularly beneficial for OIH and MOH.

Nutrition and Calcitonin Gene Related Peptide (CGRP) in Migraine.

Targeting calcitonin gene-related peptide (CGRP) and its receptor by antibodies and antagonists was a breakthrough in migraine prevention and treatment. However, not all migraine patients respond to CGRP-based therapy and a fraction of those who respond complain of aliments mainly in the gastrointestinal tract. In addition, CGRP and migraine are associated with obesity and metabolic diseases, including diabetes. Therefore, CGRP may play an important role in the functioning of the gut-brain-microflora axis. CGRP secretion may be modulated by dietary compounds associated with the disruption of calcium signaling and upregulation of mitogen-activated kinase phosphatases 1 and 3. CGRP may display anorexigenic properties through induction of anorexigenic neuropeptides, such as cholecystokinin and/or inhibit orexigenic neuropeptides, such as neuropeptide Y and melanin-concentrating hormone CH, resulting in the suppression of food intake, functionally coupled to the activation of the hypothalamic 3',5'-cyclic adenosine monophosphate. The anorexigenic action of CGRP observed in animal studies may reflect its general potential to control appetite/satiety or general food intake. Therefore, dietary nutrients may modulate CGRP, and CGRP may modulate their intake. Therefore, anti-CGRP therapy should consider this mutual dependence to increase the efficacy of the therapy and reduce its unwanted side effects. This narrative review presents information on molecular aspects of the interaction between dietary nutrients and CGRP and their reported and prospective use to improve anti-CGRP therapy in migraine.

Efficacy of Vonoprazan Fumarate Tablets in Refractory Reflux Esophagitis

To evaluate the efficacy of vonoprazan fumarate tablets in refractory reflux esophagitis and to provide new insights into the clinical management of refractory reflux esophagitis. A total of 60 refractory reflux esophagitis E patients meeting the inclusion criteria were recruited and assigned via random number table method to receive either conventional treatments (control group) or vonoprazan fumarate plus conventional treatments (treatment group), with 30 cases in each group. Traditional Chinese medicine decoction was administered for adjuvant therapy. Outcome measures included clinical symptom score, gastroesophageal reflux disease healthrelated quality of life scores, esophageal mucosal damage, serum inflammatory factors, serum calcitonin gene related peptide, 5-hydroxytryptamine levels and relapse. Vonoprazan fumarate resulted in milder esophageal mucosal damage and symptoms, and a lower incidence of recurrence vs. conventional treatment alone (p<0.05). Patients with vonoprazan fumarate showed higher quality of life and lower inflammatory factor levels vs. those without (p<0.05). No documented safety events were found during the administration of vonoprazan fumarate. Vonoprazan fumarate tablets are effective in acid suppression, reducing serum calcitonin gene related peptide and 5-hydroxytryptamine levels in refractory reflux esophagitis patients, alleviating the inflammatory response and promoting esophageal mucosal healing with a high safety profile. Vonoprazan fumarate tablets supplemented with traditional Chinese medicine decoction offers a viable option for the treatment of refractory reflux esophagitis. Further studies are required prior to clinical promotion.