- Sumatriptan Does Not Antagonize CGRP-Induced Symptoms in Healthy Volunteers. [Journal Article]Headache 2020H
- CONCLUSIONS: Sumatriptan does not influence headache score, accompanying symptoms or other symptoms induced by CGRP. Furthermore, a 2-hour CGRP infusion causes a wide range of side effects and does not induce more headache than the usual 20-minute infusion. Thus, the prolonged infusion of CGRP in healthy volunteers is not a valid and pragmatic model for testing new anti-migraine drugs.
- Development and Evaluation of in-situ Nasal Gel Formulations of Nanosized Transferosomal Sumatriptan: Design, Optimization, in vitro and in vivo Evaluation. [Journal Article]Drug Des Devel Ther 2019; 13:4413-4430DD
- CONCLUSIONS: Based on enhancing the bioavailability and sustaining the drug release, it can be concluded that the in-situ gel of SUT-loaded nano-transferosomes were developed as a promising non-invasive drug delivery system for treating migraine.
- Subcutaneous sumatriptan: association with decreases in postoperative pain and opioid use after elective cranial surgery. [Journal Article]J Neurosurg 2020; :1-9JN
- CONCLUSIONS: The authors identified subcutaneous sumatriptan as a safe and efficacious tool for postoperative pain management after craniotomy. Large multicenter randomized controlled studies are needed to further evaluate the specific role of sumatriptan in postoperative pain management after craniotomy.
- The Headache Pipeline: Excitement and Uncertainty. [Journal Article]Headache 2020; 60(1):190-199H
- There are many new treatment options available for migraine and more are coming. Three calcitonin gene-related peptide (CGRP) antagonist monoclonal antibodies have been approved and a 4th is due in early 2020. Small molecule CGRP receptor-blocking oral compounds, both for acute care and prevention, are also coming. Four neurostimulators are available, with others on the way. New acute treatments …
There are many new treatment options available for migraine and more are coming. Three calcitonin gene-related peptide (CGRP) antagonist monoclonal antibodies have been approved and a 4th is due in early 2020. Small molecule CGRP receptor-blocking oral compounds, both for acute care and prevention, are also coming. Four neurostimulators are available, with others on the way. New acute treatments coming soon include the 5HT1F agonist lasmiditan, a zolmitriptan intradermal micro-needle patch, and a nasal mist sumatriptan with a permeability enhancer. Farther out, three novel dihydroergotamine delivery systems, and a liquid-filled capsule of celecoxib show early promise. A new, safer form of methysergide is in the works, as is a longer-duration onabotulinumtoxinA. As always with new products, questions regarding safety, tolerability, cost, and insurance coverage will need to be addressed. Despite these concerns and uncertainties, a robust headache treatment pipeline is good for patients who are not satisfied with the results of their treatment and/or cannot tolerate existing treatments.
- Contribution of intraganglionic CGRP to migraine-like responses in male and female rats. [Journal Article]Cephalalgia 2019; :333102419896539C
- CONCLUSIONS: Intraganglionar calcitonin gene-related peptide may play a major role in migraine-like responses, including periorbital mechanical allodynia, light sensitivity and anxiety like-behavior. Female rats are likely to be more susceptible to calcitonin gene-related peptide effects and a better understanding of the sexual dimorphism in calcitonin gene-related peptide signaling may help to improve migraine therapy.
- Ultra-rapid brain uptake of subcutaneous sumatriptan in the rat: Implication for cluster headache treatment. [Journal Article]Cephalalgia 2019; :333102419896370C
- CONCLUSIONS: Our findings indicate that sumatriptan distributes within the CNS soon after injection, and are in line with prompt pain relief by parenteral sumatriptan in CH patients.
- A Brief Look at Urgent Care Visits for Migraine: The Care Received and Ideas to Guide Migraine Care in this Proliferating Medical Setting. [Journal Article]Headache 2019H
- CONCLUSIONS: The majority of patients in our study who sought medical treatment for migraine in these 2 urgent care centers were not established patients within the urgent care centers' healthcare system. While 93.6% (73/78) of patients were experiencing current pain upon presentation to the urgent care centers, only 12.3% (9/73) received administration of the medications with the highest level of evidence by the American Headache Society (Level B) for acute migraine treatment in an ED. In addition, the majority of patients with a migraine history presenting to the urgent care setting were not given triptans or anti-emetic prescriptions upon discharge from their urgent care visit. Having these migraine-specific prescriptions may improve self-treatment at home should a migraine attack recur.
- Experimental and mathematical study of the transdermal delivery of sumatriptan succinate from polyvinylpyrrolidone-based microneedles. [Journal Article]Eur J Pharm Biopharm 2020; 146:32-40EJ
- A mechanistic model was developed and tested to predict the release of sumatriptan succinate from dissolving microneedles and its permeation across the epidermal skin layers. Material balance equations were written to describe molecular transport followed by absorption into the systemic circulation. The solid drug particles were encapsulated in pyramid-shaped, polyvinylpyrrolidone-based water-sol…
A mechanistic model was developed and tested to predict the release of sumatriptan succinate from dissolving microneedles and its permeation across the epidermal skin layers. Material balance equations were written to describe molecular transport followed by absorption into the systemic circulation. The solid drug particles were encapsulated in pyramid-shaped, polyvinylpyrrolidone-based water-soluble microneedles. Plots, generated from literature values and designed to simulate concentration distributions in the epidermal layers, agreed with optical coherence tomography (OCT)images captured at early stages of the experiments. Simulations showed that an increase in the pitch width led to a faster release of the medication. By modifying the governing equations to include a microneedle baseplate, the model was able to estimate short- and long-term release behaviors from in vitro Franz cellexperiments. These studies were performed using three distinct dissolving microneedle formulations and minipig skin as the biological membrane. The calculated diffusion coefficients were one order of magnitude greater than the value estimated when the drug was directly applied to the skin surface. The dissolution rate constant was affected by the concentration of the polymer matrix.
- Pharmacokinetics of Organic Cation Transporter 1 (OCT1) Substrates in Oct1/2 Knockout Mice and Species Difference in Hepatic OCT1-Mediated Uptake. [Journal Article]Drug Metab Dispos 2020; 48(2):93-105DM
- Organic cation transporter 1 (OCT1) plays a role in hepatic uptake of drugs, affecting in vivo exposure, distinguished primarily through pharmacogenetics of the SLC22A1 gene. The role of OCT1 in vivo has not been confirmed, however, via drug-drug interactions that similarly affect exposure. In the current research, we used Oct1/2 knockout mice to assess the role of Oct1 in hepatic clearance and l…
Organic cation transporter 1 (OCT1) plays a role in hepatic uptake of drugs, affecting in vivo exposure, distinguished primarily through pharmacogenetics of the SLC22A1 gene. The role of OCT1 in vivo has not been confirmed, however, via drug-drug interactions that similarly affect exposure. In the current research, we used Oct1/2 knockout mice to assess the role of Oct1 in hepatic clearance and liver partitioning of clinical substrates and assess the model for predicting an effect of OCT1 function on pharmacokinetics in humans. Four OCT1 substrates (sumatriptan, fenoterol, ondansetron, and tropisetron) were administered to wild-type and knockout mice, and plasma, tissue, and urine were collected. Tissue transporter expression was evaluated using liquid chromatography-mass spectrometry. In vitro, uptake of all compounds in human and mouse hepatocytes and human OCT1- and OCT2-expressing cells was evaluated. The largest effect of knockout was on hepatic clearance and liver partitioning of sumatriptan (2- to 5-fold change), followed by fenoterol, whereas minimal changes in the pharmacokinetics of ondansetron and tropisetron were observed. This aligned with uptake in mouse hepatocytes, in which inhibition of uptake of sumatriptan and fenoterol into mouse hepatocytes by an OCT1 inhibitor was much greater compared with ondansetron and tropisetron. Conversely, inhibition of all four substrates was evident in human hepatocytes, in line with reported clinical pharmacogenetic data. These data confirm the role of Oct1 in the hepatic uptake of the four OCT1 substrates and elucidate species differences in OCT1-mediated hepatocyte uptake that should be considered when utilizing the model to predict effects in humans. SIGNIFICANCE STATEMENT: Studies in carriers of SLC22A1 null variants indicate a role of organic cation transporter 1 (OCT1) in the hepatic uptake of therapeutic agents, although OCT1-mediated drug-drug interactions have not been reported. This work used Oct1/2 knockout mice to confirm the role of Oct1 in the hepatic clearance and liver partitioning in mice for OCT1 substrates with reported pharmacogenetic effects. Species differences observed in mouse and human hepatocyte uptake clarify limitations of the knockout model for predicting exposure changes in humans for some OCT1 substrates.
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- LiverTox: Clinical and Research Information on Drug-Induced Liver Injury: Migraine Headache Agents [BOOK]National Institute of Diabetes and Digestive and Kidney Diseases: Bethesda (MD)BOOK
- Migraine headaches are marked by repeated, paroxysmal attacks of moderate-to-severe throbbing, one-sided headaches which (without treatment) last 4 to 72 hours and are usually associated with symptoms of nausea and vomiting. Migraine headaches are typically exacerbated by motion, bright lights and loud noises. Migraines may be associated with focal neurological symptoms referred to as “aura” whic…
Migraine headaches are marked by repeated, paroxysmal attacks of moderate-to-severe throbbing, one-sided headaches which (without treatment) last 4 to 72 hours and are usually associated with symptoms of nausea and vomiting. Migraine headaches are typically exacerbated by motion, bright lights and loud noises. Migraines may be associated with focal neurological symptoms referred to as “aura” which are typically visual, but may be sensory or motor. Migraine headaches are common, affecting at least 18% of women and 6.5% of men in the United States. The pattern of paroxysmal headaches typically arises in adolescence or young adulthood and may be life-long. The headaches often interfere with daily activities and can be incapacitating, result in major time loss from work and precipitate multiple physician and emergency room visits. Patients with migraine may also be at increased risk for other vascular complications such as stroke and eclampsia. The cause of migraine headaches is not fully understood, but appears to be related to arteriolar vasodilation and inflammation of the trigeminal nerve endings, perhaps caused by local release of vasoactive peptides. The most convincing candidate mediator of migraines is the calcitonin gene related protein (CGRP), a neuropeptide found throughout the central and peripheral nervous systems which has potent vasodilator and pain-signaling activities. Circulating levels of CGRP are elevated in pateints with migraines, and the efficacy of migraine therapies such as serotonin receptor agonists and ergot alkaloids is associated with lowering of circulating CGRP levels. Antagonists of CGRP have become a focus of migraine headache prevention and therapy. Therapy of migraine headache usually combines preventive treatments with early intervention for acute attacks. Early treatment approaches to migraine have included a number of different classes of medications including nonsteroidal antiinflammatory agents, opiate and nonopiate analgesics, barbiturates, antiemetics, ergot alkaloids, and serotonin receptor agonists. Medications used specifically to treat migraine headaches and discussed here are the ergot alkaloids and the more recently developed serotonin receptor agonists (triptans). The ergot alkaloids have been in use for many years, and currently available forms include ergotamine (Cafergot: year of approval, 1948) and dihydroergotamine (Migranal: 1946). The triptans include sumatriptan (Imitrex: 1997), zolmitriptan (Zomig: 1997), naratriptan (Amerge: 1998), rizatriptan (Maxalt: 1998), almotriptan (Almogran, Axert: 2001), frovatriptan (Frova: 2001), and eletriptan (Relpax: 2002).