Two-hour infusion of vasoactive intestinal polypeptide induces delayed headache and extracranial vasodilation in healthy volunteers

Cephalalgia ◽  
2020 ◽  
Vol 40 (11) ◽  
pp. 1212-1223 ◽  
Author(s):  
Lanfranco Pellesi ◽  
Mohammad Al-Mahdi Al-Karagholi ◽  
Basit Ali Chaudhry ◽  
Cristina Lopez Lopez ◽  
Josefin Snellman ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Intravenous Infusion ◽  
Superficial Temporal Artery ◽  
Area Under The Curve ◽  
Temporal Artery ◽  
Continuous Intravenous Infusion ◽  
Headache Intensity ◽  
Parasympathetic System ◽  
The Difference ◽  
Cranial Arteries

Background In recent years, vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptides (PACAPs) have gained special interest in headache science. VIP and PACAPs (two isoforms, PACAP27 and PACAP38) are related in structure and function, as are their receptors, but they show differences in vasodilating- and headache-inducing properties. Intravenous infusion of PACAP27 or PACAP38, but not VIP, induces a long-lasting dilation of cranial arteries and delayed headache. The relationship between the long-lasting cranial vasodilation and headache development is not fully clarified. Methods In a double-blinded, placebo-controlled, crossover study in 12 healthy volunteers, diameter changes of cranial arteries, occurrence of headache and the parasympathetic system were examined before, during and after a 2-hour continuous intravenous infusion of VIP and placebo. Primary endpoints were the differences in area under the curve for the superficial temporal artery diameter and headache intensity scores, as well as in headache incidence, between VIP and placebo. Results The superficial temporal artery diameter was significantly larger on the VIP day compared to placebo ( p < 0.001) and the dilation lasted for more than 2 h. The incidence of headache was higher ( p = 0.003) on the VIP day compared to the placebo day. The difference in headache intensity scores was more evident in the post-infusion period (120–200 min, p = 0.034) and in the post-hospital phase (4–12 h, p = 0.025). Cranial parasympathetic activity, measured through the production of tears, was higher during VIP compared to placebo ( p = 0.033). Conclusion Continuous intravenous infusion of VIP over 2 h induced a long-lasting cranial vasodilation, activation of the cranial parasympathetic system, and delayed mild headaches in healthy volunteers. Trial Registration: The study is registered at ClinicalTrials.gov (NCT03989817).

Opening of BKCa channels alters cerebral hemodynamic and causes headache in healthy volunteers

Cephalalgia ◽  
2020 ◽  
Vol 40 (11) ◽  
pp. 1145-1154
Author(s):  
Mohammad Al-Mahdi Al-Karagholi ◽  
Hashmat Ghanizada ◽  
Cherie Amalie Waldorff Nielsen ◽  
Camilla Skandarioon ◽  
Josefin Snellman ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Radial Artery ◽  
Superficial Temporal Artery ◽  
Area Under The Curve ◽  
Temporal Artery ◽  
Bkca Channels ◽  
Double Blind ◽  
Headache Intensity ◽  
The Difference

Introduction Preclinical data implicate large conductance calcium-activated potassium (BKCa) channels in the pathogenesis of headache and migraine, but the exact role of these channels is still unknown. Here, we investigated whether opening of BKCa channels would cause headache and vascular effects in healthy volunteers. Methods In a randomized, double-blind, placebo-controlled, cross-over study, 21 healthy volunteers aged 18–39 years were randomly allocated to receive an intravenous infusion of 0.05 mg/min BKCa channel opener MaxiPost and placebo on two different days. The primary endpoints were the difference in incidence of headache and the difference in area under the curve (AUC) for headache intensity scores (0–12 hours) and for middle cerebral artery blood flow velocity (VMCA) (0–2 hours) between MaxiPost and placebo. The secondary endpoints were the differences in area under the curve for superficial temporal artery and radial artery diameter (0–2 hours) between MaxiPost and placebo. Results Twenty participants completed the study. Eighteen participants (90%) developed headache after MaxiPost compared with six (30%) after placebo ( p = 0.0005); the difference of incidence is 60% (95% confidence interval 36–84%). The area under the curve for headache intensity (AUC0–12 hours, p = 0.0003), for mean VMCA (AUC0–2 hours, p = 0.0001), for superficial temporal artery diameter (AUC0–2 hours, p = 0.003), and for radial artery diameter (AUC0–2 hours, p = 0.03) were significantly larger after MaxiPost compared to placebo. Conclusion MaxiPost caused headache and dilation in extra- and intracerebral arteries. Our findings suggest a possible role of BKCa channels in headache pathophysiology in humans. ClinicalTrials.gov, ID: NCT03887325.

Pro-inflammatory and vasoconstricting prostanoid PGF2α causes no headache in man

Cephalalgia ◽  
2011 ◽  
Vol 31 (15) ◽  
pp. 1532-1541 ◽  
Author(s):  
Maria Antonova ◽  
Troels Wienecke ◽  
Jes Olesen ◽  
Messoud Ashina
Keyword(s):  
Healthy Volunteers ◽  
Rating Scale ◽  
Superficial Temporal Artery ◽  
Area Under The Curve ◽  
Temporal Artery ◽  
Human Model ◽  
Prostaglandin E ◽  
Signalling Molecules ◽  
Prostaglandin F

Background: During two decades of migraine provocation studies with naturally occurring signalling molecules, vasodilators such as prostaglandin E2, prostaglandin I2 (prostacyclin) and prostaglandin D2 were shown to be able to induce headache in man. To elucidate the role of inflammation and vasodilatation in the generation of headache, we investigated whether the pro-inflammatory and vasoconstricting prostanoid prostaglandin F2α (PGF2α) would cause headache in a human model of headache. Methods: Twelve healthy volunteers were randomly allocated to receive 3.5 µg/kg/min PGF2α or placebo over 20 min in a two-way crossover study. We recorded headache intensity on a verbal rating scale, middle cerebral artery blood flow velocity (VMCA) and the diameters of the superficial temporal artery (STA) and radial artery (RA). Results: We found no difference in the area under the curve (AUC) for immediate headache (0–90 min) between PGF2α and placebo ( p = 0.144). The McNemar's test showed no difference in the incidence of immediate and delayed headache between verum and placebo ( p = 0.500 and p = 1.000, respectively). There was no difference in VMCA ( p = 0.776) and in the diameter of the STA ( p = 0.460) or RA ( p = 0.780) between PGF2α and placebo. Conclusion: The present study shows that PGF2α, unlike vasodilating prostaglandins, does not provoke headache. We suggest that the vasodilating abilities of prostaglandins are important for the induction of experimental headache in healthy volunteers.

Effect of KATP channel blocker glibenclamide on levcromakalim-induced headache

Cephalalgia ◽  
2020 ◽  
Vol 40 (10) ◽  
pp. 1045-1054 ◽  
Author(s):  
Mohammad Al-Mahdi Al-Karagholi ◽  
Hashmat Ghanizada ◽  
Lili Kokoti ◽  
Joachim S Paulsen ◽  
Jakob Møller Hansen ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Potassium Channel ◽  
Healthy Volunteers ◽  
Channel Blocker ◽  
Area Under The Curve ◽  
Mean Difference ◽  
Double Blind ◽  
Headache Intensity ◽  
Primary Endpoints ◽  
The Difference

Introduction Administration of ATP-sensitive potassium channel opener levcromakalim triggers headache in healthy volunteers and migraine attacks in migraine patients. Here, we investigated the effect of ATP-sensitive potassium channel blocker glibenclamide on levcromakalim-induced headache in healthy volunteers. Methods In a randomized, double-blind, placebo-controlled, three-way cross-over study, 15 healthy volunteers aged 18–40 years were randomly allocated to receive glibenclamide and levcromakalim (day 1), glibenclamide and placebo (day 2), and placebo and placebo (day 3) on three different days separated by at least 1 week. The primary endpoints were the difference in incidence of headache and the difference in area under the curve for headache intensity scores (0–12 hours) between the days. Results Fifteen healthy volunteers completed the 3 days of the study. More participants (12/15, 80%) developed headache on the glibenclamide-levcromakalim day compared to the glibenclamide-placebo day (5/15, 33%) ( p = 0.01; mean difference 47%; 95% confidence interval 18–75%) and compared to the placebo-placebo day (1/15, 7%) ( p = 0.001; mean difference 73%; 95% confidence interval 48–99%). We found no difference in headache incidence between glibenclamide-placebo day and placebo-placebo day ( p = 0.12; mean difference 27%; 95% confidence interval 1.3–52%). The area under the curve for headache intensity was significantly larger on the glibenclamide-levcromakalim day compared to the glibenclamide-placebo day ( p = 0.003); and compared to the placebo-placebo day ( p = 0.001). We found no difference in the area under the curve between the glibenclamide-placebo day compared to the placebo-placebo day ( p = 0.07). The median time to onset for headache after levcromakalim infusion with glibenclamide pretreatment was delayed (180 min) compared to levcromakalim without pretreatment (30 min) from a previously published study. Conclusion Glibenclamide administration did not cause headache, and glibenclamide pretreatment did not prevent levcromakalim-induced headache. However, glibenclamide delayed the onset of levcromakalim-induced headache. More selective blockers are needed to further elucidate the role of the ATP-sensitive potassium channel in headache initiation. Trial Registration: ClinicalTrials.gov NCT03886922.

Early treatment with sumatriptan prevents PACAP38-induced migraine: A randomised clinical trial

Cephalalgia ◽  
2021 ◽  
pp. 033310242097539
Author(s):  
Nita Katarina Frifelt Wienholtz ◽  
Casper Emil Christensen ◽  
Ditte Georgina Zhang ◽  
Hande Coskun ◽  
Hashmat Ghanizada ◽  
...  
Keyword(s):  
Early Treatment ◽  
Intravenous Infusion ◽  
Migraine Without Aura ◽  
Superficial Temporal Artery ◽  
Area Under The Curve ◽  
Temporal Artery ◽  
Randomised Clinical Trial ◽  
Trigeminovascular System ◽  
Double Blind ◽  
Nociceptive Transmission

Objective To determine whether early treatment with sumatriptan can prevent PACAP38-induced migraine attacks. Methods A total of 37 patients with migraine without aura were enrolled between July 2018 to December 2019. All patients received an intravenous infusion of 10 picomole/kg/min of PACAP38 over 20 min followed by an intravenous infusion of 4 mg sumatriptan or placebo over 10 min on two study days in a randomised, double-blind, placebo-controlled, crossover study. Results Of 37 patients enrolled, 26 (70.3%) completed the study and were included in analyses. Of the 26 patients, four (15%) developed a PACAP38-induced migraine attack on sumatriptan and 11 patients (42%) on placebo ( p = 0.016). There were no differences in area under the curve for headache intensity between sumatriptan (mean AUC 532) and placebo (mean AUC 779) ( p = 0.35). Sumatriptan significantly constricted the PACAP38-dilated superficial temporal artery immediately after infusion (T30) compared with infusion of placebo ( p < 0.001). Conclusions and relevance: Early treatment with intravenously administered sumatriptan prevented PACAP38-induced migraine. Prevention of migraine attacks was associated with vasoconstriction by sumatriptan in the earliest phases of PACAP provocation. These results suggest that sumatriptan prevents PACAP38-induced migraine by modulation of nociceptive transmission within the trigeminovascular system. Trial Registration: ClinicalTrials.gov (NCT03881644).

scholarly journals The Effect of KATP Channel Blocker Glibenclamide on CGRP-Induced Headache and Hemodynamic in Healthy Volunteers

2021 ◽  
Vol 12 ◽  
Author(s):  
Hande Coskun ◽  
Fatima Azzahra Elbahi ◽  
Mohammad Al-Mahdi Al-Karagholi ◽  
Hashmat Ghanizada ◽  
Majid Sheykhzade ◽  
...  
Keyword(s):  
Blood Flow ◽  
Healthy Volunteers ◽  
Channel Blocker ◽  
Superficial Temporal Artery ◽  
Sulfonylurea Receptor ◽  
Double Blind ◽  
Headache Intensity ◽  
Arterial Blood ◽  
Significant Difference ◽  
The Difference

BackgroundCalcitonin gene-related peptide (CGRP) dilates cranial arteries and triggers headache. The CGRP signaling pathway is partly dependent on activation of ATP-sensitive potassium (KATP) channels. Here, we investigated the effect of the KATP channel blocker glibenclamide on CGRP-induced headache and vascular changes in healthy volunteers.MethodsIn a randomized, double-blind, placebo-controlled, cross-over study, 20 healthy volunteers aged 18–27 years were randomly allocated to receive an intravenous infusion of 1.5 μg/min CGRP after oral pretreatment with glibenclamide (glibenclamide-CGRP day) or placebo (placebo-CGRP day). The primary endpoints were the difference in incidence of headache and the difference in area under the curve (AUC) for headache intensity scores (0–14 h) between glibenclamide and placebo. The secondary endpoints were the difference in AUC for middle cerebral artery blood flow velocity (VMCA), superficial temporal artery (STA) and radial artery (RA) diameter, facial flushing, heart rate (HR) and mean arterial blood pressure (MAP) (0–4 h) between glibenclamide and placebo.ResultsWe found no significant difference in the incidence of headache between glibenclamide-CGRP day (14/20, 70%) and placebo-CGRP day (19/20, 95%) (P = 0.06). The AUC for headache intensity, VMCA, STA, RA, facial skin blood flow, HR, and MAP did not differ between glibenclamide-CGRP day compared to placebo-CGRP day (P &gt; 0.05).ConclusionPretreatment with a non-selective KATP channel inhibitor glibenclamide did not attenuate CGRP-induced headache and hemodynamic changes in healthy volunteers. We suggest that CGRP-induced responses could be mediated via activation of specific isoforms of sulfonylurea receptor subunits of KATP channel.

The Cholinomimetic Agent Carbachol Induces Headache in Healthy Subjects

Cephalalgia ◽  
2009 ◽  
Vol 29 (2) ◽  
pp. 258-268 ◽  
Author(s):  
HW Schytz ◽  
T Wieneckey ◽  
PS Oturai ◽  
J Olesen ◽  
M Ashina
Keyword(s):  
Healthy Subjects ◽  
Rating Scale ◽  
Parasympathetic Nervous System ◽  
Superficial Temporal Artery ◽  
Area Under The Curve ◽  
Temporal Artery ◽  
Double Blind ◽  
Migraine Pathogenesis ◽  
Blind Crossover Study ◽  
Double Blind Crossover Study

The parasympathetic nervous system is likely to be involved in migraine pathogenesis. We hypothesized that the cholinomimetic agonist carbachol would induce headache and vasodilation of cephalic and radial arteries. Carbachol (3 μg/kg) or placebo was randomly infused into 12 healthy subjects in a double-blind crossover study. Headache was scored on a verbal rating scale from 0–10. Velocity in the middle cerebral artery (Vmca) and diameter of the superficial temporal artery (STA) and radial artery (RA) were recorded. Nine participants developed headache after carbachol compared with three after placebo. The area under the curve for headache was increased after carbachol compared with placebo both during infusion (0–30 min) ( P = 0.042) and in the postinfusion period (30–90 min) ( P = 0.027). Carbachol infusion caused a drop in Vmca ( P = 0.003) and an increase in STA diameter ( P = 0.006), but no increase in the RA diameter ( P = 0.200). In conclusion, the study demonstrated that carbachol caused headache and dilation of cephalic arteries in healthy subjects.

Phase I and Pharmacokinetic Study of Irinotecan Administered as a Low-Dose, Continuous Intravenous Infusion Over 14 Days in Patients With Malignant Solid Tumors

1999 ◽  
Vol 17 (6) ◽  
pp. 1897-1897 ◽  
Author(s):  
Virginie M.M. Herben ◽  
Jan H.M. Schellens ◽  
Martha Swart ◽  
Gabriela Gruia ◽  
Laurent Vernillet ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Intravenous Infusion ◽  
High Performance ◽  
Infusion Pump ◽  
Area Under The Curve ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Continuous Intravenous Infusion ◽  
Infusion Schedule ◽  
Grade 3

PURPOSE: To evaluate the feasibility of administering irinotecan as a continuous intravenous infusion for 14 to 21 days. PATIENTS AND METHODS: Patients with solid tumors refractory to standard therapy received continuous infusions of irinotecan by means of an ambulatory infusion pump. The starting dosage was 12.5 mg/m2/d for 14 days every 3 weeks. After identification of the maximum-tolerated dose for the 14-day infusion schedule, the protocol was amended to prolong the infusion duration to 17 and 21 days. Pharmacokinetics of irinotecan and SN-38 and its glucuronide were determined using high-performance liquid chromatography and noncompartmental modeling. RESULTS: Thirty-three patients received 85+ courses. At the first dose level (12.5 mg/m2/d), cumulative grade 3 or 4 diarrhea and grade 3 or 4 neutropenia occurred in three of five patients. At a dosage of 10 mg/m2/d, 14-day administration resulted in grade 4 diarrhea in two of six patients and one episode of grade 4 vomiting occurred, whereas with 17-day administration, one episode of grade 3 nausea and two episodes of grade 3 or 4 diarrhea were observed in six patients. Increasing the number of days of infusion to 21 days was not feasible because of cumulative diarrhea. Hematologic toxicity was rare. The mean metabolic SN-38 area under the curve/irinotecan area under the curve ratio was 16% ± 6% compared with 3% to 5% after short infusion schedules involving therapeutic dosages. Partial responses were observed in two patients with extraovarian and colorectal cancer. CONCLUSION: The recommended dosage is 10 mg/m2/d for 14 days, repeated every 3 weeks. Enhanced metabolism of irinotecan to SN-38 may explain in part the low recommended dose for this schedule.

Lack of correlation between vasodilatation and pharmacologically induced immediate headache in healthy subjects

Cephalalgia ◽  
2011 ◽  
Vol 31 (6) ◽  
pp. 683-690 ◽  
Author(s):  
Messoud Ashina ◽  
Peer Tfelt-Hansen ◽  
Peter Dalgaard ◽  
Jes Olesen
Keyword(s):  
Healthy Subjects ◽  
Rating Scale ◽  
Superficial Temporal Artery ◽  
Experimental Studies ◽  
Temporal Artery ◽  
Arterial Diameter ◽  
Mean Velocity ◽  
Headache Intensity ◽  
Scatter Plots ◽  
The Mean

Background: The causal relationship between experimental headache and vasodilatation has not been fully clarified. In the present study, we combined headache and vascular data from eight experimental studies and conducted detailed statistical analyses. Given that substances used in all these experiments were vasodilators we examined a possible correlation between headache scores and increases in arterial diameter. Methods: We identified nine studies and retrieved raw data in 89 healthy subjects (46 females, 43 males), mean age 27 years (range 18–59 years). The following variables were collected: maximal median headache intensity scores on a verbal rating scale (VRS) during immediate headache (0–120 minutes); the mean velocity of blood flow in the middle cerebral artery (VmeanMCA); and the diameter of the frontal branch of the superficial temporal artery (STA) during the maximal median headache intensity. Results: The scatter plots show no relationship between maximal headache score and the relative changes in VmeanMCA and diameter of the STA. The main analyses of covariance showed a significant effect only of heart rate on headache ( p = .014). The interaction tests were insignificant for all variables. Conclusions: The major outcome is a finding of no linear relationship between experimental immediate headache and dilatation of the MCA or STA.

Vasoactive Intestinal Peptide Causes Marked Cephalic Vasodilation, but does not Induce Migraine

Cephalalgia ◽  
2008 ◽  
Vol 28 (3) ◽  
pp. 226-236 ◽  
Author(s):  
A Rahmann ◽  
T Wienecke ◽  
JM Hansen ◽  
J Fahrenkrug ◽  
J Olesen ◽  
...  
Keyword(s):  
Vasoactive Intestinal Peptide ◽  
Rating Scale ◽  
Superficial Temporal Artery ◽  
Temporal Artery ◽  
High Frequency Ultrasound ◽  
Double Blind ◽  
Vascular Origin ◽  
Cranial Arteries ◽  
To Receive ◽  
Double Blind Crossover Study

We hypothesized that intravenous infusion of the parasympathetic transmitter, vasoactive intestinal peptide (VIP), might induce migraine attacks in migraineurs. Twelve patients with migraine without aura were allocated to receive 8 pmol kg-1 min-1 VIP or placebo in a randomized, double-blind crossover study. Headache was scored on a verbal rating scale (VRS), mean blood flow velocity in the middle cerebral artery ( Vmean mca) was measured by transcranial Doppler ultrasonography, and diameter of the superficial temporal artery (STA) by high-frequency ultrasound. None of the subjects reported a migraine attack after VIP infusion. VIP induced a mild immediate headache (maximum 2 on VRS) compared with placebo ( P = 0.005). Three patients reported delayed headache (3-11 h after infusion) after VIP and two after placebo ( P = 0.89). Vmean mca decreased (16.3 ± 5.9%) and diameter of STA increased significantly after VIP (45.9 ± 13.9%). VIP mediates a marked dilation of cranial arteries, but does not trigger migraine attacks in migraineurs. These data provide further evidence against a purely vascular origin of migraine.

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