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 > 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.

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.

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.

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).

Carbon monoxide inhalation induces headache in a human headache model

Cephalalgia ◽  
2017 ◽  
Vol 38 (4) ◽  
pp. 697-706 ◽  
Author(s):  
Nanna Arngrim ◽  
Henrik Winther Schytz ◽  
Josefine Britze ◽  
Mark Bitsch Vestergaard ◽  
Mikael Sander ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Blood Flow ◽  
Healthy Volunteers ◽  
Skin Blood Flow ◽  
Rating Scale ◽  
Superficial Temporal Artery ◽  
Laser Speckle ◽  
Facial Skin ◽  
Contrast Imaging ◽  
Double Blind

Introduction Carbon monoxide (CO) is an endogenously produced signalling molecule that has a role in nociceptive processing and cerebral vasodilatation. We hypothesized that inhalation of CO would induce headache and vasodilation of cephalic and extracephalic arteries. Methods In a randomized, double-blind, placebo-controlled crossover design, 12 healthy volunteers were allocated to inhalation of CO (carboxyhemoglobin 22%) or placebo on two separate days. Headache was scored on a verbal rating scale from 0–10. We recorded mean blood velocity in the middle cerebral artery (VMCA) by transcranial Doppler, diameter of the superficial temporal artery (STA) and radial artery (RA) by high-resolution ultrasonography and facial skin blood flow by laser speckle contrast imaging. Results Ten volunteers developed headache after CO compared to six after placebo. The area under the curve for headache (0–12 hours) was increased after CO compared with placebo ( p = 0.021). CO increased VMCA ( p = 0.002) and facial skin blood flow ( p = 0.012), but did not change the diameter of the STA ( p = 0.060) and RA ( p = 0.433). Conclusion In conclusion, the study demonstrated that CO caused mild prolonged headache but no arterial dilatation in healthy volunteers. We suggest this may be caused by a combination of hypoxic and direct cellular effects of CO.

Safety evaluation of an antimalarial herbal product from Andrographis paniculata (AS201-01) in healthy volunteers

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Aty Widyawaruyanti ◽  
Arijanto Jonosewojo ◽  
Hilkatul Ilmi ◽  
Lidya Tumewu ◽  
Ario Imandiri ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Healthy Volunteers ◽  
Day Treatment ◽  
Phase 1 ◽  
Andrographis Paniculata ◽  
Control Group ◽  
Healthy Human ◽  
Double Blind ◽  
Random Blood Glucose ◽  
Significant Difference

Abstract Objectives Andrographis paniculata tablets (AS201-01) have previously been shown to have potent bioactivity as an antimalarial and to produce no unwanted side effects in animal models. Here, we present the phase 1 clinical trial conducted to evaluate the safety of AS201-01 tablets in healthy volunteers. Methods The study was a randomized, double-blind controlled cross-over, a placebo-controlled design consisting of a 4-day treatment of AS201-01 tablets. A total of 30 healthy human volunteers (16 males and 14 females) were divided into two groups, and each group was given 4 tablets, twice daily for 4 days. Group 1 received AS201-01, while group 2 received placebo tablets. Volunteers were given a physical examination before the treatment. The effects of AS201-01 on random blood glucose, biochemical, and hematological as well as urine profiles were investigated. Results There were no changes in observed parameters as a result of AS201-01 being administered. Statistical analysis showed no significant difference (p>0.05) between the test and control group regarding hematology profile, biochemical profile, and random blood glucose. Increased appetite and better sleep, which categorized as grade 1 adverse event was reported after treatment with AS201-01 tablet Conclusions The outcome supports our previous observation that the AS201-01 tablet, given twice a day for 4 days, is safe and nontoxic.

scholarly journals Cerebral blood flow autoregulation in ischemic heart failure

2017 ◽  
Vol 312 (1) ◽  
pp. R108-R113 ◽  
Author(s):  
J. R. Caldas ◽  
R. B. Panerai ◽  
V. J. Haunton ◽  
J. P. Almeida ◽  
G. S. R. Ferreira ◽  
...  
Keyword(s):  
Heart Failure ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Healthy Volunteers ◽  
Neurological Complications ◽  
Ischemic Heart ◽  
Step Response ◽  
Ischemic Heart Failure ◽  
Arterial Blood ◽  
End Tidal

Patients with ischemic heart failure (iHF) have a high risk of neurological complications such as cognitive impairment and stroke. We hypothesized that iHF patients have a higher incidence of impaired dynamic cerebral autoregulation (dCA). Adult patients with iHF and healthy volunteers were included. Cerebral blood flow velocity (CBFV, transcranial Doppler, middle cerebral artery), end-tidal CO2 (capnography), and arterial blood pressure (Finometer) were continuously recorded supine for 5 min at rest. Autoregulation index (ARI) was estimated from the CBFV step response derived by transfer function analysis using standard template curves. Fifty-two iHF patients and 54 age-, gender-, and BP-matched healthy volunteers were studied. Echocardiogram ejection fraction was 40 (20–45) % in iHF group. iHF patients compared with control subjects had reduced end-tidal CO2 (34.1 ± 3.7 vs. 38.3 ± 4.0 mmHg, P < 0.001) and lower ARI values (5.1 ± 1.6 vs. 5.9 ± 1.0, P = 0.012). ARI <4, suggestive of impaired CA, was more common in iHF patients (28.8 vs. 7.4%, P = 0.004). These results confirm that iHF patients are more likely to have impaired dCA compared with age-matched controls. The relationship between impaired dCA and neurological complications in iHF patients deserves further investigation.

Pharmacological Modulation of Cutaneous Reactivity to Histamine: A Double-Blind Acute Comparative Study between Cetirizine, Terfenadine and Astemizole

1989 ◽  
Vol 17 (1) ◽  
pp. 24-27 ◽  
Author(s):  
L. Ghys ◽  
J.-P. Rihoux
Keyword(s):  
Comparative Study ◽  
Healthy Volunteers ◽  
Inhibitory Effect ◽  
Blind Study ◽  
Double Blind Study ◽  
Single Administration ◽  
Double Blind ◽  
Pharmacological Modulation ◽  
The Difference ◽  
Cutaneous Reactivity

In a double-blind study performed in 81 healthy volunteers, 10 mg cetirizine and 60 mg terfenadine given orally in a single administration significantly inhibited skin reactivity to histamine. Astemizole (10 mg) was completely ineffective. The inhibitory effect of cetirizine was potent and regular whereas 6/28 (21%) volunteers did not respond to terfenadine. The difference observed beween cetirizine and terfenadine might be due to differences in the metabolism of the two drugs after administration: terfenadine is rapidly and extensively metabolized whereas cetirizine is directly active without the need for biotransformation and, indeed is poorly metabolized.

scholarly journals A double-blind randomized controlled trial of topical Curcuma xanthorrhiza Roxb. on mild psoriasis: clinical manifestations, histopathological features, and K6 expressions

2018 ◽  
Vol 27 (3) ◽  
pp. 178-84 ◽  
Author(s):  
Githa Rahmayunita ◽  
Tjut N.A. Jacoeb ◽  
Endi Novianto ◽  
Wresti Indriatmi ◽  
Rahadi Rihatmadja ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Clinical Manifestations ◽  
Effective Treatment Option ◽  
Psoriasis Area Severity Index ◽  
Double Blind ◽  
Old Patients ◽  
Mean Values ◽  
Significant Difference ◽  
Curcuma Xanthorrhiza ◽  
The Difference

Background: Curcuma xanthorrhiza Roxb. exerts its anti-inflammatory effects by reducing the concentration of IL-6, IL-8, and phosphorylase kinase, which has role in keratinocyte proliferation. Our study aimed to evaluate the efficacy of C. xanthorrhiza in psoriasis.Methods: From 18 to 59 year-old patients with mild psoriasis, 2 similar lesions were selected. The severity assessment was based on the psoriasis area severity index (PASI), Trozak score, and K6 expression. Using a double-blinded randomized method, lesion was treated with 1% C. xanthorrhiza ointment vs placebo for 4 weeks. The results were analyzed by the chi-square test using STATATM V.12 software (Stata Corp.).Results: The study was conducted in 2010 to 2012 with 17 subjects participated. The median of PASI score were reduced significantly in both lesions, either treated with 1% C. xanthorrhiza ointment vs placebo; however when compared between the group, it was not significant (p=0.520). The Trozak score were reduced in lesions treated with 1% C. xanthorrhiza ointment; but it was not significant (p = 0.306). In lesions treated with placebo, the Trozak score was increased significantly. The difference of Trozak score between lesions treated with C. xanthorrhiza and placebo was significant (p=0.024). There was no significant difference of K6 expression in lesions treated with 1% C. xanthorrhiza ointments or placebo as well as on the difference of mean values of K6 expression between the group (p=0.827).Conclusion: Based on the results, 1% C. xanthorrhiza ointment is effective treatment option for mild psoriasis, but longer follow-up period is suggested to confirm this results. C. xanthorrhiza ointment is safe for topical administration as there were no side effects reported in this study.

Toward a pragmatic migraine model for drug testing: 1. Cilostazol in healthy volunteers

Cephalalgia ◽  
2015 ◽  
Vol 36 (2) ◽  
pp. 172-178 ◽  
Author(s):  
Emma Katrine Hansen ◽  
Song Guo ◽  
Messoud Ashina ◽  
Jes Olesen
Keyword(s):  
Physical Activity ◽  
Healthy Volunteers ◽  
Migraine Headache ◽  
Drug Testing ◽  
Rescue Medication ◽  
No Reduction ◽  
Healthy Individuals ◽  
Double Blind ◽  
Headache Intensity ◽  
Accompanying Symptoms

Background A model for the testing of novel antimigraine drugs should ideally use healthy volunteers for ease of recruiting. Cilostazol provokes headache in healthy volunteers with some migraine features such as pulsating pain quality and aggravation by physical activity. Therefore, this headache might respond to sumatriptan, a requirement for validation. The hypothesis of the present study was that sumatriptan but not placebo is effective in cilostazol-induced headache in healthy individuals. Methods In a double-blind, randomized, cross-over design, 30 healthy volunteers of both sexes received cilostazol 200 mg on two separate days, each day followed by oral self-administered placebo or sumatriptan 50 mg. Headache response and accompanying symptoms were registered in a questionnaire by the participants themselves. Results Cilostazol induced a reproducible headache in 90% of the participants. The headache had several migraine-like features in most individuals. Median peak headache score was 2 on the sumatriptan day and 3 on the placebo day ( p = 0.17). There was no reduction in headache intensity two hours after sumatriptan ( p = 0.97) and difference in AUC 0 to four hours between two experimental days was not significant ( p = 0.18). On the placebo day eight participants took rescue medication compared to 3 on the sumatriptan day ( p = 0.13). Conclusion Despite similarities with migraine headache, cilostazol-induced headache in healthy volunteers does not respond to sumatriptan.

scholarly journals The post-lunch effect of regular and decaffeinated coffee on psychomotor performance: a randomized double-blind cross-over study

2021 ◽  
Vol 10 (8) ◽  
pp. 954
Author(s):  
Suganthi S. Ramachandran ◽  
Vijay L. Kumar ◽  
S. N. Dwivedi ◽  
Vishwajeet Singh ◽  
Pooja Gupta
Keyword(s):  
Healthy Volunteers ◽  
Psychomotor Performance ◽  
Subjective Ratings ◽  
Double Blind ◽  
Flicker Fusion Frequency ◽  
Female Ratio ◽  
Cardiovascular Parameters ◽  
Significant Difference ◽  
Decaffeinated Coffee ◽  
The Mean

Background: This study aimed to compare the effect of regular coffee and decaffeinated coffee on psychomotor performance in healthy volunteers during post-lunch period.Methods: In this randomized double-blind cross-over study, adult healthy volunteers were given hot coffee (3 g each of regular or decaffeinated coffee) during post-lunch period. Psychomotor functions (critical flicker-fusion frequency (CFF), choice reaction time (CRT) and error count in hand-steadiness test (HST)), blood pressure and heart rate were measured pre-lunch, pre-coffee (1-hour post-lunch) and 1-hour post-coffee consumption. Subjective ratings of sleepiness and mood were also assessed during post-lunch sessions.Results: The mean age of the participants (n=16) was 27.4±2.7 years with a male: female ratio of 7:9. There was no significant deterioration in psychomotor performance post-lunch when compared to pre-lunch on both the days. The mean CFF, CRT, errors committed in HST and cardiovascular parameters did not differ significantly between regular coffee and decaffeinated groups during post-lunch sessions. There was no significant difference in values of cardiovascular parameters as well as subjective ratings of sleep and mood between two groups.Conclusions: In healthy adult individuals’ consumption of both regular coffee and decaffeinated coffee during the post-lunch period did not affect psychomotor performance.

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