Delayed Migraine-Like Headache in Healthy Volunteers After a Combination of Acetazolamide and Glyceryl Trinitrate

Cephalalgia ◽  
2009 ◽  
Vol 29 (12) ◽  
pp. 1294-1300 ◽  
Author(s):  
D Daugaard ◽  
LL Thomsen ◽  
HK Iversen ◽  
J Olesen
Keyword(s):  
Glyceryl Trinitrate ◽  
Healthy Volunteers ◽  
Rating Scale ◽  
Cerebral Arteries ◽  
The Body ◽  
Sensory Nerves ◽  
Pharmacological Intervention ◽  
Genetic Trait ◽  
Double Blind ◽  
Headache Diary

Glyceryl trinitrate (GTN) is a pro-drug dissociating nitric oxide throughout the body. It dilates cephalic arteries without increasing cerebral blood flow (CBF). GTN induces headache in healthy volunteers and migraine attacks in migraineurs. Acetazolamide (Az) increases CBF but does not dilate cerebral arteries. The hypothesis tested here was that Az, by dilating cerebral arterioles but not arteries and thereby decreasing pulsatile stretching of the wall of the large arteries and their perivascular sensory nerves, would reduce or prevent the GTN-induced headache We tested this hypothesis in 14 healthy volunteers. In a randomized, double-blind, cross-over study, they were pretreated with Az or placebo followed on both study days by a GTN infusion of 0.5 μg kg-1 min-1 for 20 min. Headache was scored on a verbal rating scale and a headache diary was kept for 12 h. Mean blood velocity of the middle cerebral artery was measured (transcranial Doppler). Our hypothesis was disproved, as Az did not decrease GTN-induced headache. Unexpectedly but interestingly, GTN combined with Az induced more delayed headache than GTN alone. Furthermore, a migraine-like headache was observed in three volunteers, who did not develop migraine after GTN alone. The fact that a suitable pharmacological intervention may trigger migraine in individuals with no prior migraine may suggest that the ability to develop migraine without aura is a quantitative genetic trait.

Calcitonin gene-related peptide (CGRP) levels during glyceryl trinitrate (GTN)-induced headache in healthy volunteers

Cephalalgia ◽  
2009 ◽  
Vol 30 (4) ◽  
pp. 467-474 ◽  
Author(s):  
C Kruuse ◽  
HK Iversen ◽  
I Jansen-Olesen ◽  
L Edvinsson ◽  
J Olesen
Keyword(s):  
Glyceryl Trinitrate ◽  
Healthy Volunteers ◽  
Rating Scale ◽  
Calcitonin Gene Related Peptide ◽  
Trigeminovascular System ◽  
Double Blind ◽  
No Donor ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Before And After

The role of nitric oxide (NO) in migraine has been studied in the experimental glyceryl trinitrate (GTN)-infusion headache model. We hypothesized that GTN-induced headache may activate the trigeminovascular system and be associated with increased levels of sensory neuropeptides, including calcitonin gene-related peptide (CGRP). CGRP, vasoactive intestinal peptide (VIP), neuropeptide Y (NPY) and somatostatin plasma levels were measured before and after placebo/sumatriptan injection and during GTN-induced headache. Following a double-blind randomized cross-over design, 10 healthy volunteers received subcutaneous sumatriptan 6 mg or placebo. This was succeeded by 20 min of GTN (0.12 µg kg−1 min−1) infusion. At baseline no subject reported headache (using verbal rating scale from 0 to 10) and the jugular CGRP-like immunoreactivity (-LI) level was 18.6 ± 2.5 pmol/l. After a 20-min intravenous infusion of GTN 0.12 µg kg−1 min−1, median peak headache intensity was 4 (range 2–6) ( P < 0.05), while jugular CGRP-LI levels were unchanged (19.0 ± 2.8 pmol/l; P > 0.05). There were no changes in VIP-, NPY- or somatostatin-LI. In conclusion, the NO donor GTN appears not to induce headache via immediate CGRP release.

The Effect of Propranolol on Glyceryltrinitrate-Induced Headache and Arterial Response

Cephalalgia ◽  
2004 ◽  
Vol 24 (12) ◽  
pp. 1076-1087 ◽  
Author(s):  
JF Tvedskov ◽  
LL Thomsen ◽  
LL Thomsen ◽  
HK Iversen ◽  
P Williams ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Migraine Without Aura ◽  
Rating Scale ◽  
No Reduction ◽  
International Headache Society ◽  
Cerebral Arteries ◽  
Superficial Temporal Artery ◽  
New Drugs ◽  
Prophylactic Effect ◽  
Double Blind

Prophylactic drug trials in migraine are long-lasting and expensive and require long-term toxicology information. A human migraine model would therefore be helpful in testing new drugs. Immediate headache and delayed migraine after glyceryltrinitrate (GTN) has been well characterized. We have recently shown that sodium valproate has prophylactic effect in the GTN model. Here we report our experience with propranolol in this model. Nineteen subjects with migraine without aura and 16 sex- and aged-matched healthy subjects were included in a two-centre randomized double-blind cross-over study. Fourteen migraine subjects and 14 healthy subjects completed the study and results from comparison of the 28 subjects are reported. Randomly propranolol 160 mg or placebo were each given daily for 14 days to both migraine and healthy subjects. A 20-min intravenous infusion of GTN 0.25 mg/kg per min was administered on a study day at the end of both pretreatment periods. Headache was registered for 12 h after GTN infusions. Its intensity was scored on a numerical verbal rating scale from 0 to 10. Fulfilment of International Headache Society (HIS) criteria was recorded for 24 h. Radial and superficial temporal artery diameters and blood velocity of both middle cerebral arteries were measured. All migraine subjects developed headache after GTN. No reduction of overall peak headache was found after propranolol (median 5, range 0-7) compared with placebo (median 5, range 0-10) ( P = 0.441). Eight of the 14 completing migraine subject developed IHS 1.1 migraine after GTN, two subjects on both days, three subjects only after placebo, and three subjects only after propranolol. No reduction of GTN-induced migraine was found after propranolol compared with placebo (5 vs. 5, P = 1.000). All healthy subjects developed headache after GTN. No reduction of overall peak headache was found after propranolol (median 2, range 1-5) compared with placebo (median 1, range 1-7) ( P = 0.315). Two subjects fulfilled IHS criteria 1.1 for migraine without aura after propranolol but not after placebo. The fulfilment was short lasting and did not require rescue medication. Headache after GTN was more pronounced in migraine subjects than in healthy subjects both with ( P = 0.003) and without pretreatment with propranolol ( P = 0.017). We found that 2 weeks of propranolol constricted the radial artery in healthy subjects but not in migraine subjects. GTN-induced vasodilatation abolished this difference. Mean maximum blood flow velocity in the middle cerebral artery was higher in healthy subjects than in migraine patients ( P = 0.003-0.033) and unaffected by propranolol. We observed no effect of propranolol on GTN-induced headache and migraine. This could indicate that GTN induces migraine at a deeper level of the pathophysiological cascade of migraine than the prophylactic effect of propranolol. Propranolol does not constrict cerebral arteries, which therefore cannot be part of its mechanism of action in migraine.

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.

scholarly journals Treatment of Levodopa-induced dyskinesia with Vitamin D: A Randomized, double-blind, placebo-controlled trial

2018 ◽  
Vol 10 (3) ◽  
Author(s):  
Amir Hassan Habibi ◽  
Arezo Anamoradi ◽  
Gholam Ali Shahidi ◽  
Saeed Razmeh ◽  
Elham Alizadeh ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Vitamin D ◽  
Parkinson's Disease ◽  
Parkinson Disease ◽  
Rating Scale ◽  
Involuntary Movement ◽  
Controlled Trial ◽  
The Body ◽  
Double Blind ◽  
Double Blind Clinical Trial

Dyskinesia refers to any involuntary movement, such as chorea, dystonia, ballism that affect any part of the body. Levodopa-induced dyskinesia is a neurological disorder that afflicts many patients with Parkinson disease usually 5 years after the onset of levodopa therapy and can cause severe disability. The pathophysiology of this dyskinesia is complex and not fully understood. However, the association between vitamin D and Parkinson disease is interesting. The present study was conducted to evaluate the effect of vitamin D on levodopa induced dyskinesia in patients with Parkinson’s disease .In this Double blind clinical trial, 120 patients with PD divided into two groups randomly, vitamin D and placebo group. A dose of 1000 IU/d was selected, Demographic information is registered. In the first visit, three variables have been measured which were the duration, severity of dyskinesia and unified Parkinson’s disease rating scale (UPDRS). These variables were measured again after 3 months and the data was analyzed using SPSS 22. There are no differences between two groups after 3 months. This study revealed, vitamin D has no effects on improvement of levodopa induced dyskinesia.

Influence of Subanesthetic Dose of Ketamine on Theta Cordance in Healthy Volunteers: Implications for Antidepressant Effect

2009 ◽  
Vol 24 (S1) ◽  
pp. 1-1
Author(s):  
M. Brunovsky ◽  
J. Horacek ◽  
M. Bares ◽  
T. Novak ◽  
B. Tislerova ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Rating Scale ◽  
Antidepressant Effect ◽  
Double Blind ◽  
Ketamine Infusion ◽  
Downstream Signaling ◽  
Theta Frequency ◽  
Psychiatric Rating ◽  
Left And Right ◽  
Psychiatric Rating Scale

Aims:A series of clinical studies demonstrated that QEEG prefrontal theta cordance value decreases after one week of treatment in responders to antidepressants and precedes clinical improvement. Ketamine, a non-competitive antagonist of NMDA receptors, has a unique rapid antidepressant effect but its influence on theta cordance is still unknown.Methods:In a double-blind, cross-over, placebo-controlled experiment we studied the influence of ketamine (0.54 mg/kg) on theta cordance in a group of 20 right-handed healthy volunteers. Participants were evaluated with the Brief Psychiatric Rating Scale before infusion and after 10 and 30 min. Three EEG segments obtained at baseline and prior to BPRS examinations at 10 and 30 min after dosing were entered into spectral analyses and QEEG cordance values in theta frequency band were calculated for four regions (prefrontal, central, left and right temporal).Results:Ketamine infusion induced a decrease in prefrontal theta cordance at 10 (p=0.04) and 30 min (p=0.02) and a significant increase of theta cordance in central region at both time points (p=0.01). We observed no significant effect on cordance values in the left and right temporal regions.Conclusions:Our data indicate that ketamine infusion immediately induces similar changes as monoaminergic-based antidepressants do gradually after a series of downstream signaling steps. The reduction in theta prefrontal cordance could serve as a marker of fast antidepressant effect of ketamine, a hypothesis that should be tested in antidepressants-refractory patients.This study was supported by a grant of IGA MHCR NR/9330-3 and by a project of MEYS CR VZ0021620816.

Extracranial activation of ATP-sensitive potassium channels induces vasodilation without nociceptive effects

Cephalalgia ◽  
2019 ◽  
Vol 39 (14) ◽  
pp. 1789-1797 ◽  
Author(s):  
Mohammad Al-Mahdi Al-Karagholi ◽  
Hashmat Ghanizada ◽  
Jakob Møller Hansen ◽  
Sameera Aghazadeh ◽  
Lene Theil Skovgaard ◽  
...  
Keyword(s):  
Potassium Channels ◽  
Healthy Volunteers ◽  
Local Effect ◽  
Intradermal Injection ◽  
The Body ◽  
Controlled Study ◽  
Double Blind ◽  
Head Pain ◽  
Peripheral Neurons ◽  
Intramuscular Injections

Introduction Levcromakalim opens ATP-sensitive potassium channels (KATP channel) and induces head pain in healthy volunteers and migraine headache in migraine patients, but no pain in other parts of the body. KATP channels are expressed in C- and Aδ-fibers, and these channels might directly activate nociceptors and thereby evoke pain in humans. Methods To assess the local effect of KATP channel opening in trigeminal and extra-trigeminal regions, we performed a crossover, double-blind, placebo-controlled study in healthy volunteers. Participants received intradermal and intramuscular injections of levcromakalim and placebo in the forehead and the forearms. Results Intradermal and intramuscular injections of levcromakalim did not evoke more pain compared to placebo in the forehead ( p > 0.05) and the forearms ( p > 0.05). Intradermal injection of levcromakalim caused more flare ( p < 0.001 ), skin temperature increase ( p < 0.001), and skin blood flow increase ( p < 0.001) compared to placebo in the forehead and the forearms. Conclusion These findings suggest that it is unlikely that levcromakalim induces head pain by direct activation of peripheral neurons.

Does Fentanyl Lead to Opioid-induced Hyperalgesia in Healthy Volunteers?

2016 ◽  
Vol 124 (2) ◽  
pp. 453-463 ◽  
Author(s):  
Eckhard Mauermann ◽  
Joerg Filitz ◽  
Patrick Dolder ◽  
Katharina M. Rentsch ◽  
Oliver Bandschapp ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Pain Perception ◽  
Rating Scale ◽  
Cold Pressor ◽  
High Dose ◽  
Double Blind ◽  
Additional Measure ◽  
Pain Scores ◽  
Cold Pressor Pain ◽  
Fentanyl Administration

Abstract Background Although opioids in general and remifentanil in particular have been shown to induce hyperalgesia, data regarding fentanyl are scarce. Thus, the authors investigated the effect of fentanyl dosing on pain perception and central sensitization in healthy volunteers using established pain models. Methods Twenty-one healthy, male volunteers were included in this randomized, double-blind, crossover study and received either intravenous low-dose (1 μg/kg) or high-dose (10 μg/kg) fentanyl. Pain intensities and hyperalgesia were assessed by intracutaneous electrical stimulation, and cold pressor pain was used as an additional measure of acute pain. The primary outcome was hyperalgesia from 4.5 to 6.5 h after fentanyl administration. Results A higher dose of fentanyl led to significantly decreased pain scores as measured by the numeric rating scale (0.83 units lower [95% CI, 0.63 to 1.02]; P &lt; 0.001) but increased areas of hyperalgesia (+30.5% [95% CI, 16.6 to 44.4%]; P &lt; 0.001) from 4.5 to 6.5 h after fentanyl administration. Allodynia did not differ between groups (+4.0% [95% CI, −15.4 to 23.5%]; P = 0.682).The high dose also led to both increased cold pressor pain threshold (+43.0% [95% CI, 29.7 to 56.3%]; P &lt; 0.001) and tolerance (+32.5% [95% CI, 21.7 to 43.4%]; P &lt; 0.001) at 4.5 to 6.5h. In the high-dose group, 19 volunteers (90%) required reminders to breathe, 8 (38%) required supplemental oxygen, and 12 (57%) experienced nausea. Conclusions A higher dose of fentanyl increased hyperalgesia from 4.5 to 6.5 h in healthy volunteers while simultaneously decreasing pain scores.

scholarly journals Assessment the equivalence of the bioanalogue insulin lizpro biphasic 25 (Geropharm-bio, Russia) and Humalog® Mix 25 (Lilly France, France) using the euglycemic hyperinsulinum clamp method on healthy volonters

2019 ◽  
Vol 21 (6) ◽  
pp. 462-471 ◽  
Author(s):  
Alexander Y. Mayorov ◽  
Ekaterina O. Koksharova ◽  
Ekaterina E. Mishina ◽  
Roman V. Drai ◽  
Olga I. Avdeeva ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Insulin Lispro ◽  
Geometric Mean ◽  
Subcutaneous Administration ◽  
Modern Medicine ◽  
The Body ◽  
Double Blind ◽  
Clinical Safety ◽  
Biphasic Insulin ◽  
Patients With Diabetes

Background: Modern medicine requires use of effective antidiabetic drugs that can imitate the natural profile of insulin in the body of patients with diabetes mellitus. Examples of such preparations include biphasic insulin lispro, which is a mixture of insulin lispro ultra-short action and insulin lispro protamine suspension with prolonged effect. The clinical trials (CT) program for biosimilar insulins contains pharmacology studies: pharmacokinetics (PK), pharmacodynamics (PD) and clinical safety studies. Aims: To demonstrate Biphasic Insulin Lispro 25, suspension for subcutaneous administration, 100 U/ml (GEROPHARM-Bio, Russia) and Humalog Mix 25, suspension for subcutaneous administration, 100 U/ml (Lilly France, France) have comparable pharmacokinetic profiles under conditions of hyperinsulinemic euglycemic clamp (HEC) in healthy volunteers. Materials and methods: The study was conducted on 48 healthy men aged between 18 to 50 years. This was a double-blind, randomized, crossover study of comparative pharmacokinetics of drugs. The investigational products (IP) were administered before the clamp in a single dose of 0.4 U/kg subcutaneously in the abdominal wall. Regular blood sampling was performed during the study. The insulin concentrations in the samples were determined using an ELISA method. The results of the determination were used to calculate the PK parameters and construct the concentration-time curves. Adjust glucose infusion rates were based on blood glucose measurements. These data were used to calculate the PD parameters. Results: Our results demonstrated that Biphasic Insulin Lispro 25 and Humalog Mix 25 have comparable PK and PD profiles under conditions of HEC in healthy volunteers. The confidence intervals for the ratio of the geometric mean for Cins.max and AUCins.012 were 87.7599.90% and 83.7696.98% respectively, which were well within 80125% limits for establishing comparability. Conclusions: Biphasic Insulin Lispro 25 and Humalog Mix 25 are equivalent based on this CT applying the HEC technique in healthy volunteers.

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