ABSTRACT
BACKGROUND: Triptans are anti-migraine drugs with a potential central site of action. However, it is not known to what extent triptans cross the blood-brain barrier (BBB). The aim of this study was therefore to determine if triptans pass the brain capillary endothelium and investigate the possible underlying mechanisms with focus on the involvement of the putative proton-coupled organic cation (H+/OC) antiporter. Additionally, we evaluated whether triptans interacted with the efflux transporter, P-glycoprotein (P-gp). METHODS: We investigated the cellular uptake characteristics of the prototypical H+/OC antiporter substrates, pyrilamine and oxycodone, and seven different triptans in the human brain microvascular endothelial cell line, hCMEC/D3. Triptan interactions with P-gp were studied using the IPEC-J2 MDR1 cell line. Lastly, in vivo neuropharmacokinetic assessment of the unbound brain-to-plasma disposition of eletriptan was conducted in wild type and mdr1a/1b knockout mice. RESULTS: We demonstrated that most triptans were able to inhibit uptake of the H+/OC antiporter substrate, pyrilamine, with eletriptan emerging as the strongest inhibitor. Eletriptan, almotriptan, and sumatriptan exhibited a pH-dependent uptake into hCMEC/D3 cells. Eletriptan demonstrated saturable uptake kinetics with an apparent Km of 89 ± 38 µM and a Jmax of 2.2 ± 0.7 nmol·min-1·mg protein-1 (n = 3). Bidirectional transport experiments across IPEC-J2 MDR1 monolayers showed that eletriptan is transported by P-gp, thus indicating that eletriptan is both a substrate of the H+/OC antiporter and P-gp. This was further confirmed in vivo, where the unbound brain-to-unbound plasma concentration ratio (Kp,uu) was 0.04 in wild type mice while the ratio rose to 1.32 in mdr1a/1b knockout mice. CONCLUSIONS: We have demonstrated that the triptan family of compounds possesses affinity for the H+/OC antiporter proposing that the putative H+/OC antiporter plays a role in the BBB transport of triptans, particularly eletriptan. Our in vivo studies indicate that eletriptan is subjected to simultaneous brain uptake and efflux, possibly facilitated by the putative H+/OC antiporter and P-gp, respectively. Our findings offer novel insights into the potential central site of action involved in migraine treatment with triptans and highlight the significance of potential transporter related drug-drug interactions.
Subject(s)
Blood-Brain Barrier , Brain , Endothelial Cells , Mice, Knockout , Pyrrolidines , Tryptamines , Tryptamines/pharmacology , Tryptamines/metabolism , Tryptamines/pharmacokinetics , Animals , Endothelial Cells/metabolism , Endothelial Cells/drug effects , Humans , Blood-Brain Barrier/metabolism , Blood-Brain Barrier/drug effects , Brain/metabolism , Cell Line , Mice , Mice, Inbred C57BL , Biological Transport/physiology , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Male , Antiporters/metabolism , Pyrilamine/metabolism , Pyrilamine/pharmacology , ATP Binding Cassette Transporter, Subfamily B/metabolismABSTRACT
Migraine is a common, polygenic disorder that is characterized by moderate to severe headache attacks. Migraine attacks are commonly treated with triptans, i.e. serotonin receptor agonists. However, triptans are effective in ~ 60% of the population, and the mechanisms of triptans are debated. Here, we aim to expose the mechanisms of triptan using metabolomics and transcriptomics in spontaneous migraine attacks. We collected temporal multi-omics profiles on 24 migraine patients, using samples collected at a migraine attack, 2 h after treatment with a triptan, when headache-free, and after a cold-pressor test. Differential metabolomic analysis was performed to find metabolites associated with treatment. Their effect was further investigated using correlation analysis and a machine learning approach. We found three differential metabolites: cortisol, sumatriptan and glutamine. The change in sumatriptan levels correlated with a change in GNAI1 and VIPR2 gene expression, both known to regulate cAMP levels. Furthermore, we found fatty acid oxidation to be affected, a mechanism known to be involved in migraine but not previously found in relation to triptans. In conclusion, using an integrative approach we find evidence for a role of glutamine, cAMP regulation, and fatty acid oxidation in the molecular mechanisms of migraine and/or the effect of triptans.
Subject(s)
Migraine Disorders , Tryptamines , Humans , Tryptamines/therapeutic use , Sumatriptan/therapeutic use , Glutamine , Multiomics , Migraine Disorders/drug therapy , Migraine Disorders/genetics , Serotonin 5-HT1 Receptor Agonists , Fatty AcidsABSTRACT
PURPOSE: In four large controlled trials with lasmiditan and ubrogepant placebo was administered in the first step to demonstrate an effect on migraine attack. In the same trials the investigators also asked the question: is a second dose of the drug effective in non-responders to the first dose? In this phase patients who received placebo in the first phase of the trial again after 2 hours received another dose of placebo. CONCLUSION: To be ethical, clinical research requires balancing rigorous science with the protection of human subjects; and it is, in our view, questionable whether placebo was used with "scientific rigor" in the second step of these trials, and this design is not recommended.
Subject(s)
Migraine Disorders , Pyridines , Benzamides , Controlled Clinical Trials as Topic , Humans , Migraine Disorders/drug therapy , Piperidines , Pyridines/therapeutic use , PyrrolesABSTRACT
BACKGROUND: Naratriptan, marketed in a low oral dose of 2.5 mg, is generally regarded as a less-effective triptan with a slower onset of action than most other triptans in the treatment of migraine attacks. In this review, naratriptan will be compared with sumatriptan, the standard triptan. METHODS: Papers on pharmacodynamics and pharmacokinetics and results from comparative clinical trials with oral and subcutaneous naratriptan versus other triptans were retrieved from PubMed. RESULTS: Naratriptan and sumatriptan have similar effects in relevant animal models. In a randomized controlled trial, oral naratriptan 2.5 mg is less effective than oral sumatriptan 100 mg after both 2 h and 4 h. In contrast, oral naratriptan 10 mg has a similar time-effect curve as oral sumatriptan 100 mg, in both its steepness and the efficacy at 2 h and 4 h. Subcutaneous naratriptan 10 mg (88% pain free at 2 h) was in one trial superior to subcutaneous sumatriptan 6 mg (55% pain free at 2 h). CONCLUSION: Naratriptan was marketed for the treatment of migraine attacks as the "gentle triptan" in a low oral dose of 2.5 mg, a dose with no more adverse events than placebo. This low dose results in the slow onset of action and low efficacy of oral naratriptan, but in high doses oral naratriptan is similar to oral sumatriptan. Based on one randomized controlled trial, subcutaneous naratriptan has probably the greatest effect of any triptan.
Subject(s)
Migraine Disorders , Sumatriptan , Animals , Migraine Disorders/drug therapy , Piperidines , Randomized Controlled Trials as Topic , Serotonin Receptor Agonists , TryptaminesABSTRACT
BACKGROUND: This post-hoc analysis was conducted to evaluate the effect of erenumab on monthly migraine days, monthly migraine attacks, and attack duration in patients with episodic migraine to investigate whether erenumab actually prevents the occurrence of migraine attacks and/or shortens them. METHODS: We conducted a post-hoc analysis of the data from the STRIVE study, in 955 patients with episodic migraine. Relative changes from baseline to mean over months 4, 5 and 6 of the double-blind treatment phase in monthly migraine days, monthly migraine attacks and mean migraine attack duration were assessed. RESULTS: Erenumab reduced monthly migraine days and monthly migraine attacks compared with placebo in a similar way. Erenumab had only a minor impact on shortening the duration of migraine attacks. CONCLUSION: These post-hoc analyses demonstrate that the decrease in monthly migraine days by erenumab is mainly driven by a reduction in the frequency of monthly migraine attacks and to a much lesser extent by shortening the duration of migraine attacks.Trial registration: This study is registered at ClinicalTrials.gov (NCT02456740).
Subject(s)
Calcitonin Gene-Related Peptide Receptor Antagonists , Migraine Disorders , Antibodies, Monoclonal, Humanized , Double-Blind Method , Humans , Migraine Disorders/prevention & control , Treatment OutcomeABSTRACT
AIM OF STUDY: When the biceps tendon is tapped, a contraction is elicited in the biceps muscle. This also occurs with tapping of the radial bone, and it has been suggested that vibration is a stimulus for deep tendon reflexes. We investigated whether the normal stimulus for the deep tendon reflex is a sudden stretch, a phasic vibration, or both. Furthermore, we investigated the importance of forearm position for the reflex response in controls and stroke patients. METHODS: We investigated 50 neurological outpatients without clinical signs of neurological disorders in the arms. The biceps tendon and distal radius were tapped with the forearm in the midway (90°), supinated, and pronated positions. In 10 of these patients, the two reflexes were also investigated with quantitative electromyography (EMG) measurements in the 3 positions. Another 10 patients were investigated clinically when stretch of elbow was eliminated and 17 patients were examined when prestretching of the biceps tendon was avoided. Finally, we examined 32 patients that had experienced stroke. RESULTS: In 94% (47/50) of patients, after a radial tap, the biceps contraction disappeared in the supinated forearm, and the median peak-to-peak amplitude of the surface EMG response (n = 10) decreased from 1.1 to 0.2 mV (p < .01). Elimination of elbow stretch as well as pressure on the biceps tendon did not change the reflex response. In 84% (27/32) of stroke patients, after a radial tap, the biceps contraction persisted in supination in the arm with hyperreflexia. CONCLUSION: The combined clinical and EMG results are consistent with the concept that the deep tendon reflexes in man can be elicited by both stretch and phasic vibration. Clinicians should be aware that the brachioradial reflex depends on the forearm position.
Subject(s)
Reflex, Stretch , Vibration , Electromyography , Forearm , Humans , TendonsABSTRACT
INTRODUCTION: Migraine patients prioritize early complete relief of headache and associated symptoms, sustained freedom of pain, and good tolerability. One major obstacle for the successful use of drug treatment of migraine attack is that the speed of action of triptans, 5-HT1B/1D receptor agonists, is delayed. AREAS COVERED: In this review, the author discusses the following features of acute migraine drugs: pharmacology; pharmacokinetics, and absorption of drugs during migraine attacks. Next, dose-response curves for effect; and the delayed onset of action is reviewed. In the more clinical part of the review, the following items are discussed: overall clinical judgments; comparison of triptans; comparison of triptans with NSAIDs; early intervention with triptans; medication-overuse headache; comments on the effect of gepants; and the general principle of acute migraine therapy. EXPERT OPINION: The delay in the onset of effect of acute migraine drugs is likely due to a complex antimigraine system involving more than one site of action. Investigations into the mechanisms of the delay should have a high priority, both in studies with animals, migraine models, and in migraine patients during attacks. Non-oral administration of antimigraine drugs resulting in early absorption of drugs should be developed as they possibly also can increase Emax.
Subject(s)
Migraine Disorders , Serotonin Receptor Agonists , Adult , Animals , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Calcitonin Gene-Related Peptide Receptor Antagonists/therapeutic use , Humans , Migraine Disorders/drug therapy , Serotonin Receptor Agonists/therapeutic use , Tryptamines/therapeutic useABSTRACT
BACKGROUND: Migraine patients want acute treatment to provide complete relief of the migraine attack within 30 minutes. Traditionally, "speed of onset of effect" is evaluated by estimating the time-point for first statistical separation of drug and placebo. The estimated onset of effect can be a few percent difference of patients being pain free in very large randomised, controlled trials. This difference, however, can be clinically irrelevant. METHODS: Placebo-controlled randomised, controlled trials with pain freedom results from 30 min to 2-4 hours were retrieved from the literature. For each time-point, the therapeutic gain (drug minus placebo) (TG) was calculated. Therapeutic gain for being pain free of 5% was chosen for the definition of "onset of action", since this is approximately 1/3 of the 16% TG and 1/4 of 21% of TG for sumatriptan 50 mg and 100 mg, respectively. RESULTS: A total of 22 time-effect curves based on randomised, controlled trials were analysed. Based on the "onset of action" of 5% pain freedom, the evaluated drugs and administration forms can be classified as follows: i) Early time to onset, ≤30 min (three randomised, controlled trials); ii) medium time to onset, 60 min (nine randomised, controlled trials); iii) delayed time to onset, 90-120 min (10 randomised, controlled trials). CONCLUSION: Only three non-oral administration forms with a triptan (subcutaneous sumatriptan and nasal zolmitriptan) resulted in an "onset of action" at ≥30 min; in the future, early onset of action should be a priority in the development of new drugs or new administration-forms for the treatment of acute migraine attacks.
Subject(s)
Migraine Disorders , Humans , Migraine Disorders/drug therapy , Pain , Pharmaceutical Preparations , Randomized Controlled Trials as Topic , Serotonin 5-HT1 Receptor Agonists , Sumatriptan/therapeutic use , Tryptamines/therapeutic useABSTRACT
Monoclonal antibodies against the calcitonin gene-related peptide (CGRP) receptor (Erenumab) or against CGRP (Eptinezumab, Fremanezumab, Galcanezumab) are new substances for the preventive treatment of migraine. They represent an extension of the therapeutic options, which already exist in migraine prevention. In randomized, placebo-controlled studies, the efficacy and good tolerability of these specific substances have been demonstrated in patients with episodic and chronic migraine. The following treatment recommendation presents a summary of the pivotal studies. Recommendations are provided for the targeted selection of patients as well as for the evaluation of therapeutic success and the duration of treatment. Finally, possible restrictions on the use of this new substance group are discussed. This guideline is an abridged and translated version of the guideline published by Diener H-C, May A et al., Prevention of migraine with monoclonal antibodies against CGRP or the CGRP receptor, Supplement to S1 Guideline Therapy of Migraine Attack and Prevention of Migraine, 2019, Deutsche Gesellschaft für Neurologie (eds.), Guidelines for Diagnostics and Therapy in Neurology. A complete version of this guideline can be found on the website of the Deutsche Gesellschaft für Neurologie (www.dgn.org/leitlinien) and the AWMF (Arbeitsgemeinschaft wissenschaftlicher Medizinischer Gesellschaften). This guideline has been approved by the German Neurological Society (DGN) and the German Migraine and Headache Society (GMHS) and was reviewed by the two societies.
ABSTRACT
BACKGROUND: Pain freedom after 2 hours is the recommended primary endpoint by the International Headache Society in randomized trials investigating drug treatment of acute migraine attacks. In order to demonstrate an early effect of a drug, some drug companies, however, have promoted headache relief (improvement from severe or moderate pain to mild or no pain) at earlier time points than 2 hours as outcome parameter. METHODS AND RESULTS: We analyzed the relationship between pain freedom and headache relief in acute migraine trials and observed that persistent mild headache constituted 90% of headache relief after 0.5 hour and 40% of headache relief after 2 hours. CONCLUSION: Headache relief at 2 hours should in our view only be used as an outcome measure for comparison with historic data. Prior to 2 hours, headache relief varies with time from intake and the therapeutic gain is very small. Therefore, pain freedom should be used at these early time points.
Subject(s)
Analgesics/therapeutic use , Migraine Disorders/drug therapy , Randomized Controlled Trials as Topic/standards , Treatment Outcome , HumansABSTRACT
BACKGROUND: In trials of monoclonal antibodies against calcitonin gene-related peptide or its receptor for prevention of episodic migraine, we observed two problematic aspects: a) The graphic presentations; b) the methods of calculating "response rates" (≥50% decrease of monthly migraine days from baseline). OBSERVATIONS: Decrease in monthly migraine days is presented, over time, in figures on a downward (negative) scale from zero at baseline, with the ordinate stopped just beyond the maximum effect of the active drugs. In one trial, decreases in monthly migraine days were -1.8 after placebo, -3.2 after erenumab 70 mg and -3.7 after erenumab 140 mg, with the ordinate stopped at -4.5. The reader can perceive only a relative 2-fold benefit of erenumab versus placebo. If, however, treatment periods are compared with baseline in bar charts, MMDs persisting after treatment in the same trial can be illustrated as follows, creating a different perception: 78% for placebo, 61% for erenumab 70 mg, and 55% for erenumab 140 mg. In the nine trials, "response rates" defined as above were calculated in five different ways, taking different numbers of treatment months into account in comparisons with the one-month baseline. This makes comparisons impossible. SUGGESTIONS FOR IMPROVEMENTS: Mean monthly migraine days before and after treatment should be presented in a bar chart. Such figures, presenting persisting MMDs, are more clinically relevant and less misleading than decreases from baseline. The definition and methods of calculating and presenting "50% response rates" should be standardized by the Drug Trial Committee of the International Headache Society.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Calcitonin Gene-Related Peptide Receptor Antagonists/therapeutic use , Calcitonin Gene-Related Peptide/antagonists & inhibitors , Migraine Disorders/drug therapy , Antibodies, Monoclonal/pharmacology , Calcitonin Gene-Related Peptide/metabolism , Calcitonin Gene-Related Peptide Receptor Antagonists/pharmacology , Humans , Migraine Disorders/metabolism , Randomized Controlled Trials as Topic/methods , Treatment OutcomeABSTRACT
In randomised controlled trials (RCTs) of oral drug treatment of migraine attacks, efficacy is evaluated after 2 hours. The effect of oral naratriptan 2.5 mg with a maximum blood concentration (Tmax ) at 2 hours increases from 2 to 4 hours in RCTs. To check whether such a delayed effect is also present for other oral antimigraine drugs, we hand-searched the literature for publications on RCTs reporting efficacy. Two triptans, 3 nonsteroidal anti-inflammatory drugs (NSAIDs), a triptan combined with an NSAID and a calcitonin gene-related peptide receptor antagonist were evaluated for their therapeutic gain with determination of time to maximum effect (Emax ). Emax was compared with known Tmax from pharmacokinetic studies to estimate the delay to pain-free. The delay in therapeutic gain varied from 1-2 hours for zolmitriptan 5 mg to 7 hours for naproxen 500 mg. An increase in effect from 2 to 4 hours was observed after eletriptan 40 mg, frovatriptan 2.5 mg and lasmiditan 200 mg, and after rizatriptan 10 mg (Tmax = 1 h) from 1 to 2 hours. This strongly indicates a general delay of effect in oral antimigraine drugs. A review of 5 possible effects of triptans on the trigemino-vascular system did not yield a simple explanation for the delay. In addition, Emax for triptans probably depends partly on the rise in plasma levels and not only on its maximum. The most likely explanation for the delay in effect is that a complex antimigraine system with more than 1 site of action is involved.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Calcitonin Gene-Related Peptide Receptor Antagonists/pharmacokinetics , Migraine Disorders/drug therapy , Randomized Controlled Trials as Topic , Serotonin 5-HT1 Receptor Agonists/pharmacokinetics , Administration, Oral , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Arteries/drug effects , Arteries/innervation , Calcitonin Gene-Related Peptide Receptor Antagonists/administration & dosage , Humans , Migraine Disorders/physiopathology , Nociception/drug effects , Nociception/physiology , Serotonin 5-HT1 Receptor Agonists/administration & dosage , Thalamus/drug effects , Thalamus/physiopathology , Time Factors , Treatment Outcome , Trigeminal Ganglion/drug effects , Trigeminal Ganglion/physiopathology , Vasoconstriction/drug effectsABSTRACT
The aim of this study was to evaluate the pharmacokinetic variability of beta-adrenergic blocking agents used in cardiology by reviewing single-dose and steady-state pharmacokinetic studies from the literature. PubMed was searched for pharmacokinetic studies of beta-adrenergic blocking agents, both single-dose and steady-state studies. The studies included reported maximum plasma concentration (Cmax) and/or area under the concentration curve (AUC). The coefficient of variation (CV%) was calculated for all studies, and a CV% <40% was considered low or moderate variability, and a CV% >40% was considered high variability. The Cmax and AUC were reported a total of 672 times in 192 papers. Based on AUC, metoprolol, propranolol, carvedilol, and nebivolol showed high pharmacokinetic variability (highest first), whereas bisoprolol, atenolol, sotalol, labetalol, nadolol, and pindolol showed low to moderate variability (lowest first). We have shown a high interindividual pharmacokinetic variability that varies markedly in different beta-adrenergic blocking agents; the extreme being steady state ratios as high as 30 in metoprolol. A more personalized approach to the medical treatment of patients may be obtained by combining known pharmacokinetic information about variability, pharmaco-genetics and -dynamics, and patient characteristics, to avoid adverse events or lack of treatment effect.
Subject(s)
Adrenergic beta-Antagonists/pharmacokinetics , Adrenergic beta-Antagonists/administration & dosage , Area Under Curve , Biological Availability , Carvedilol/administration & dosage , Carvedilol/pharmacokinetics , Healthy Volunteers , Humans , Male , Metoprolol/administration & dosage , Metoprolol/pharmacokinetics , Propranolol/administration & dosage , Propranolol/pharmacokineticsABSTRACT
Background In 2008, the International Headache Society published guidelines on the "evaluation and registration of adverse events in clinical drug trials on migraine". They listed seven recommendations for reporting adverse events in randomized controlled trials on migraine. The present study aimed to evaluate adherence to these recommendations, and based on the results, to recommend improvements. Methods We searched the PubMed/MEDLINE database to identify controlled trials on migraine drugs published from 2010 to 2015. For each trial, we noted whether five of the recommended parameters were presented. In addition, we noted whether adverse events were reported in abstracts. Results We identified 73 trials; 51 studied acutely administered drugs and 22 studied prophylactic drugs for migraine. The number of patients with any adverse events were reported in 74% of acute-administration and 86% of prophylactic drug trials. Only 30 (41%) of the 73 studies reported adverse events with data in the abstracts, and 27 (37%) abstracts did not mention adverse events. Conclusion Adverse events, both frequency and symptoms, should be reported to allow a fair judgement of benefit/tolerability ratio when randomized controlled trials in migraine treatment are published. Clinically significant adverse events should be included in the abstract of every randomized controlled trial in migraine treatment.
Subject(s)
Drug-Related Side Effects and Adverse Reactions , Migraine Disorders/drug therapy , Randomized Controlled Trials as Topic/standards , HumansABSTRACT
In this review, we evaluate the variability in the pharmacokinetics of 11 drugs with established prophylactic effects in migraine to facilitate 'personalized medicine' with these drugs. PubMed was searched for 'single-dose' and 'steady-state' pharmacokinetic studies of these 11 drugs. The maximum plasma concentration was reported in 248 single-dose and 115 steady-state pharmacokinetic studies, and the area under the plasma concentration-time curve was reported in 299 single-dose studies and 112 steady-state pharmacokinetic studies. For each study, the coefficient of variation was calculated for maximum plasma concentration and area under the plasma concentration-time curve, and we divided the drug variability into two categories; high variability, coefficient of variation >40%, or low or moderate variability, coefficient of variation <40%. Based on the area under the plasma concentration-time curve in steady-state studies, the following drugs have high pharmacokinetic variability: propranolol in 92% (33/36), metoprolol in 85% (33/39), and amitriptyline in 60% (3/5) of studies. The following drugs have low or moderate variability: atenolol in 100% (2/2), valproate in 100% (15/15), topiramate in 88% (7/8), and naproxen and candesartan in 100% (2/2) of studies. For drugs with low or moderate pharmacokinetic variability, treatment can start without initial titration of doses, whereas titration is used to possibly enhance tolerability of topiramate and amitriptyline. The very high pharmacokinetic variability of metoprolol and propranolol can result in very high plasma concentrations in a small minority of patients, and those drugs should therefore be titrated up from a low initial dose, depending mainly on the occurrence of adverse events.