The 5-HT1B and 5-HT1D agonists in acute migraine therapy: Ergotamine, dihydroergotamine, and the triptans.

The advent of the triptans revolutionized acute migraine treatment. The older migraine-specific drugs, the ergot alkaloids (ergotamine and dihydroergotamine), also relieve migraine attacks through agonism at the 5-HT1B and 5-HT1D receptors, but the triptans have much greater specificity for these receptors. Unlike the ergot alkaloids, the triptans do not activate many other receptor types, and therefore are much better tolerated. This reduction in side effects greatly enhanced their clinical utility as it allowed a far greater proportion of patients to take a full therapeutic dose. As a result, the clinical use of ergotamine is minimal today, although dihydroergotamine still has a significant clinical role. There is extensive evidence that the seven triptans available today, sumatriptan, zolmitriptan, rizatriptan, eletriptan, naratriptan, almotriptan, and frovatriptan, are effective in the acute treatment of migraine. Available formulations include oral tablets, orally dissolving tablets, subcutaneous injections, nasal sprays, and in some countries, rectal suppositories. For optimal benefit, therapy needs to be individualized for a given patient both regarding the triptan chosen and the formulation. This chapter discusses the ergot alkaloids and the triptans, including mechanism of action, evidence for efficacy, clinical use, and adverse effects.

Interdigitation of lipids for vesosomal formulation of ergotamine tartrate with caffeine: a futuristic trend of intranasal route.

OBJECTIVE: This research work aimed to form vesosomes using combination of two drugs ergotamine (ERG) and caffeine for synergistic activity when given intranasally resulting in faster absorption, steric stability, and controlled release. SIGNIFICANCE: The multicompartment vesicles viz., vesosomes of ERG tartrate proved to increase absorption of drugs post-intranasal administration, bypassing the blood-brain barrier via the olfactory pathway. METHODS: The phospholipids like soya lecithin, cholesterol, and dipalmitoyl phosphatidylcholine (DPPC) were used to form a multicompartment structure called vesosomes using ethanol-induced interdigitation of lipids as the preparation method. RESULTS: The formulation showed low particle size (PS) of 315.48 ± 14.27 nm with zeta potential (ZP) of -21.78 ± 4.72 mV, higher % EE of 91.13 ± 1.29%, and controlled release kinetics, when assessed for in-vitro and ex-vivo studies as 97.64 ± 5.13% and 82.25 ± 3.27% release, respectively. Vesosomes displayed several advantages over liposomes like improved stability against phospholipase-induced enzymatic degradation and higher brain uptake 3.41-fold increase of ERG via the olfactory pathway. CONCLUSIONS: The stable vesosomes prepared using interdigitation of saturated phospholipids proved to be a viable option for ERG when administered intranasally for better absorption and bioavailability coupled with ease of administration gaining wider patient acceptance.

Vesosomes as multicompartment vesicles formulated of ergotamine (ERG) and caffeine for synergistic action in migraine treatment.Ethanol induced for interdigitation of lipids in vesosomes preparation exhibited nano-size, good colloidal stability, better encapsulation efficiency, and controlled release profile.ERG vesosomes demonstrated stability against phospholipase-induced enzymatic degradation.

Association Between Migraine and Ischemic Cardio-Cerebrovascular Disease (CCVD) and Effects of Triptans and Ergotamine on the Risk of Ischemic CCVD in Patients with Migraine in the Korean NHIS-HEALS Cohort.

BACKGROUND AND OBJECTIVES: Triptans and ergotamine are commonly used to treat migraine, a risk factor for ischemic stroke. This study aimed to investigate the association between migraine and ischemic cardio-cerebrovascular disease (CCVD). Further analyses were performed to examine whether symptom-relieving treatment of migraine with triptans and ergotamine reduces ischemic CCVD in migraineurs. METHODS: Participants from the Korean NHIS-HEALS cohort database were divided into patients reporting headache without migraine (HA), migraineurs who received at least one prescription for triptans or ergotamine (TE), and migraineurs who were prescribed neither triptans nor ergotamine (NTNE). Ischemic CCVDs comprised ischemic cerebrovascular diseases and cardiovascular diseases. Using cox proportional hazards regression models, primary and secondary analysis for risk of ischemic CCVDs was compared. RESULTS: Among 62,272 patients diagnosed with migraine or HA, men with migraine or HA numbered 14,747 and 8935, respectively, while the numbers of women were 27,836 and 10,754, respectively. The median follow-up was 6.65 years. The overall incidence rate of CCVDs was 4728/38,590 (12.25%) in females and 3158/23,682 (13.33%) in males. Compared with the HA group, the hazard ratios (HRs) (95% CIs) of the TE and NTNE groups for ischemic CCVDs were 1.18 (1.01-1.39) and 1.39 (1.28-1.50), respectively, in males, and 1.22 (1.09-1.37) and 1.53 (1.42-1.65), respectively, in females, after full adjustment for confounding variables. Compared with the NTNE group, the HRs (95% CIs) of the TE group for ischemic CCVDs were 0.86 (0.73-0.999) in males and 0.80 (0.72-0.88) in females. CONCLUSIONS: Migraine increased the risk of ischemic CCVDs in both sexes, and migraineurs treated with triptans and ergotamine were at lower risk of ischemic CCVDs than migraineurs who did not take those medications, especially in women.

Ergotamine Stimulates Human 5-HT4-Serotonin Receptors and Human H2-Histamine Receptors in the Heart.

Ergotamine (2'-methyl-5'α-benzyl-12'-hydroxy-3',6',18-trioxoergotaman) is a tryptamine-related alkaloid from the fungus Claviceps purpurea. Ergotamine is used to treat migraine. Ergotamine can bind to and activate several types of 5-HT1-serotonin receptors. Based on the structural formula of ergotamine, we hypothesized that ergotamine might stimulate 5-HT4-serotonin receptors or H2-histamine receptors in the human heart. We observed that ergotamine exerted concentration- and time-dependent positive inotropic effects in isolated left atrial preparations in H2-TG (mouse which exhibits cardiac-specific overexpression of the human H2-histamine receptor). Similarly, ergotamine increased force of contraction in left atrial preparations from 5-HT4-TG (mouse which exhibits cardiac-specific overexpression of the human 5-HT4-serotonin receptor). An amount of 10 µM ergotamine increased the left ventricular force of contraction in isolated retrogradely perfused spontaneously beating heart preparations of both 5-HT4-TG and H2-TG. In the presence of the phosphodiesterase inhibitor cilostamide (1 µM), ergotamine 10 µM exerted positive inotropic effects in isolated electrically stimulated human right atrial preparations, obtained during cardiac surgery, that were attenuated by 10 µM of the H2-histamine receptor antagonist cimetidine, but not by 10 µM of the 5-HT4-serotonin receptor antagonist tropisetron. These data suggest that ergotamine is in principle an agonist at human 5-HT4-serotonin receptors as well at human H2-histamine receptors. Ergotamine acts as an agonist on H2-histamine receptors in the human atrium.

Validated HPLC-DAD and Spectrophotometric Methods for Simultaneous Determination of Ternary Mixture of Analgin, Caffeine, and Ergotamine.

BACKGROUND: Amigrain®, the market formulation of the ternary mixture of analgin, caffeine, and ergotamine, is used for the symptomatic treatment of migraine. OBJECTIVE: The aim of the work is to develop and validate an high-performance liquid chromatography-diode array-fluorescence (HPLC-DAD) method and a novel spectrophotometric method for simultaneous determination of analgin, caffeine, and ergotamine in their pharmaceutical formulation. METHOD: The HPLC separation of the ternary mixture was carried out using an Inertsil-C8 column and a gradient elution of mobile phase composed of acetonitrile and ammonium format buffer (pH 4.2), the ultraviolet detection for analgin and caffeine was carried out at λ = 280, 254 nm, and fluorometric detection for ergotamine was carried out at λ exc =310 nm, λ emm =360 nm. The two spectrophotometric methods were double divisor ratio spectra derivative (DDRD) and ratio dual wavelength (RDW) methods. The first method was used for determination of ergotamine at 355 nm and caffeine at 268 nm by the third and first derivative. The second one was based on using amplitude difference for the determination of caffeine and analgin. RESULTS: HPLC and spectrophotometric methods were applied over the concentration ranges of 50-400, 25-200, and 0.5-10 µg/mL and 10-35, 2-30, and 10-70 µg/mL for analgin, caffeine, and ergotamine for the two methods. CONCLUSIONS: The proposed methods were successfully applied for the determination of the cited drugs in their pharmaceutical formulation, and the obtained results were statistically compared with those of the reported methods without any significant difference. HIGHLIGHTS: The developed HPLC-DAD method has a high sensitivity for ergotamine. The spectrophotometric methods offer novelty, green solvent usage, and economic cost.

Effects of Heating, Pelleting, and Feed Matrix on Apparent Concentrations of Cereal Ergot Alkaloids in Relation to Growth Performance and Welfare Parameters of Backgrounding Beef Steers.

As the contamination of cereal grains with ergot has been increasing in Western Canada, studies were undertaken to evaluate the impacts of heating (60, 80, 120, or 190 °C) alone or in combination with pelleting on concentrations of ergot alkaloids. Fifteen samples of ergot-contaminated grain from Alberta and Saskatchewan were assayed for R and S epimers of six alkaloids (ergocryptine, ergocristine, ergocornine, ergometrine, ergosine, and ergotamine) using HPLC MS/MS. Five samples with distinct alkaloid profiles were then selected for heating and pelleting studies. Heating resulted in a linear increase (p < 0.05) of total R and total S epimers with increasing temperature, although some individual R epimers were stable (ergometrine, ergosine, ergotamine). Pelleting also increased (p < 0.05) concentrations of total R and total S epimers detected, although ergometrine concentration decreased (p < 0.05) after pelleting. A feeding study arranged in a 2 × 2 factorial structure used 48 backgrounding Angus-cross steers fed four different diets: (1) Control Mash (CM, no added ergot), (2) Control Pellet (CP), (3) Ergot Mash (EM), or (4) Ergot Pellet (EP). Pelleting heated the ergot to 90−100 °C under 4 bars pressure, but the ergot used in the feeding study was not otherwise heated. Alkaloid concentrations of EM and EP varied by up to 1.1 mg/kg depending on the feed matrix assayed. No differences among treatments were noted for growth performance, feed intake, feed conversion, concentrations of serum prolactin and haptoglobin, hair cortisol, or in temperatures of extremities measured by infrared thermography. The only negative impacts of ergot alkaloids were on blood parameters indicative of reduced immune function or chronic inflammation. Pelleting did not heighten the negative clinical outcomes of ergot, although alkaloid concentrations of pelleted feed increased depending on the matrix assayed. It was hypothesized that the heat and pressure associated with pelleting may enhance the recovery of alkaloids from pelleted feed.

Information on migraine drugs in commonly available Indian drug information sources - Whether we satisfied the community needs?

Drug information can be obtained from various drug information sources that were available as government (National Formulary of India [NFI]; Central Drugs Standard Control Organization [CDSCO]), as well as commercial documents (Current Index of Medical Specialties [CIMS] and Monthly Index of Medical Specialties [MIMS]). Irrational drug usage may happen due to wide variation in the information available in these sources. In this study, we tried to assess these variations in a sample of drugs for the acute-specific management of migraine with ergot and Triptans antimigraine drugs in drug information sources such as NFI, CIMS, MIMS, and CDSCO. Scoring was done for various drug information based on the completeness of information about drugs used in acute-specific management of migraine. The scores for the completeness of drug information about the selected antimigraine drugs are 18.37% for CIMS (Ergotamine, Sumatriptan, Rizatriptan, and Zolmitriptan), 21.1% for NFI (Dihydroergotamine, Sumatriptan), 72.79% for MIMS (Ergotamine tartrate, Sumatriptan, Rizatriptan, Naratriptan, zolmitriptan, Almotriptan) and 21.77% for CDSCO (Ergotamine tartrate, Sumatriptan, Rizatriptan, Naratriptan, Zolmitriptan, eletriptan and almotriptan). The information for the antimigraine drugs available from various sources found to so much deficient. Necessary steps need to be taken in case of government public or hard documents to streamline drug information available with them as well the commercial documents as to provide reliable drug information uniformly for promoting rational use of the drug.

Simultaneous determination of ergotamine, caffeine and dipyrone in their ternary mixture by applying double divisor and first derivative ratio spectra methods.

Two validated methods namely, double divisor ratio spectra derivative spectroscopy and derivative ratio spectroscopy with zero crossing point were applied to assay a ternary mixture of ergotamine tartrate (EGT), caffeine (CAF) and dipyrone sodium (DIP) without any additional separation steps. The linearity ranges using both methods were (1.0µg/mL-70.0µg/mL), (60.0µg/mL-100.0µg/mL) and (100.0µg/mL-300.0µg/mL) for EGT, CAF and DIP respectively. Double divisor ratio spectroscopy (method A) depends on dividing the different peak responses of EGT on (summation of peaks responses of CAF and DIP each of 10.0µg/mL concentration) at λ max=342nm, 310nm and 315nm for EGT, CAF and DIP respectively. Derivative ratio spectroscopy with zero crossing point (method B) depends on dividing the peak responses of two drugs (EGT and CAF) on (10.0µg/mL of DIP) and dividing the peak response of DIP on peak response of (10.0µg/mL of EGT). The detection limits of the studied drugs applying method A were (3.54, 12.96 and 8.748µg/mL), with quantitation limits of (10.73, 39.28 and 26.51µg/mL) for EGT, CAF and DIP respectively. Regarding method B, the limits of detection and quantitation for EGT were 0.604µg/mL and 1.829µg/mL respectively: with corresponding values of 19.44µg/mL and 58.92µg/mL for CAF and 20.44µg/mL and 61.9µg/mL for DIP. The obtained results were compared to those obtained by published methods and were found to be in accordance.

Acute Ischemia of Lower Extremities Caused by Ergotamine Toxicity due to Pharmacologic Interaction With Cobicistat in an HIV-Positive Patient.

Ergotism is an uncommon condition that affects patients with exposure to ergot alkaloids causing ischemia of extremities. We report the case of lower extremities ischemia caused by ergot toxicity in a human immunodeficiency virus (HIV) positive individual due to the interaction between ergot alkaloid and Cobicistat. In addition, we present a brief review of medical, and pharmacological aspects of this condition. To our knowledge, this is the second reported case describing this interaction.

Effects of ergotamine on the central nervous system using untargeted metabolomics analysis in a mouse model.

The ergot alkaloid ergotamine is produced by Claviceps purpurea, a parasitic fungus that commonly infects crops and pastures of high agricultural and economic importance. In humans and livestock, symptoms of ergotism include necrosis and gangrene, high blood pressure, heart rate, thermoregulatory dysfunction and hallucinations. However, ergotamine is also used in pharmaceutical applications to treat migraines and stop post-partum hemorrhage. To define its effects, metabolomic profiling of the brain was undertaken to determine pathways perturbed by ergotamine treatment. Metabolomic profiling identified the brainstem and cerebral cortex as regions with greatest variation. In the brainstem, dysregulation of the neurotransmitter epinephrine, and the psychoactive compound 2-arachidonylglycerol was identified. In the cerebral cortex, energy related metabolites isobutyryl-L-carnitine and S-3-oxodecanoyl cysteamine were affected and concentrations of adenylosuccinate, a metabolite associated with mental retardation, were higher. This study demonstrates, for the first time, key metabolomic pathways involved in the behavioural and physiological dysfunction of ergot alkaloid intoxicated animals.

Induction of Ticlike Involuntary Movements in Rats by Striatotomy and Subsequent Neurochemical Sensitization.

OBJECTIVE: It has been proposed that Tourette syndrome is associated with dysfunction in widespread cortical areas and globus pallidus externus hyperactivity secondary to dopaminergic hyperactivity and serotonergic/dynorphinergic hypoactivity. The main objective of this study was to test this hypothesis by developing an animal model of Tourette syndrome via striatotomy, followed by administration of drugs that mimic the neurotransmitter environment, so as to induce globus pallidus externus hyperactivity. METHODS: Rats were assigned to 3 groups: stereotactic striatotomy (STT) and striatal sham -lesion (SHAM) groups, treated with anterior and posterior striatum procedures in both hemispheres, and a group of nonoperated animals (NAIVE). Postoperatively, all rodents were blindly administered 3 drug protocols: levodopa/benserazide; levodopa/benserazide/ergotamine/naloxone (MIX); and saline. The animals were filmed at the peak action of these drugs. The videos were evaluated by a single blinded researcher. RESULTS: Six types of involuntary movements (IMs) were observed: cephalic, trunk jerks, oromandibular, forepaw jerks, dystonic, and locomotive. The number of animals with IM and the mean number of IM after both levodopa/benserazide and MIX was significantly higher in the STT compared with the SHAM and NAIVE groups. In the SHAM and NAIVE, MIX was superior to levodopa/benserazide in the induction of IM. In the STT, MIX was superior to levodopa/benserazide in the induction of trunk jerks. Appendicular IM were more common after posterior than after anterior striatotomy. CONCLUSIONS: These results show that striatotomy, followed by administration of levodopa/benserazide alone or associated with ergotamine and naloxone, is efficacious in inducing IM, supporting the hypothesis that led to this study.

The Usage of Ergot (Claviceps purpurea (fr.) Tul.) in Obstetrics and Gynecology: A Historical Perspective.

In the past centuries consumption of bread made of ergot-infected flour resulted in mass poisonings and miscarriages. The reason was the sclerotia of Claviceps purpurea (Fr.) Tul.-a source of noxious ergot alkaloids (ergotamine and ergovaline). The authors have searched the 19th century medical literature in order to find information on the following topics: dosage forms of drugs based on ergot and their application in official gynecology and obstetrics. The authors also briefly address the relevant data from the previous periods as well as the 20th century research on ergot. The research resulted in a conclusion that applications of ergot in gynecology and obstetrics in the 19th century were limited to controlling excessive uterine bleeding and irregular spasms, treatment of fibrous tumors of the uterus, and prevention of miscarriage, abortion, and amenorrhoea. The most common dosage forms mentioned in the works included in our review were the following: tinctures, water extracts (Wernich's and Squibb's watery extract of ergot), pills, and powders. The information documented in this paper will be helpful for further research and helpful in broadening the understanding of the historical application of the described controversial crude drugs. Ergot alkaloids were widely used in obstetrics, but in modern times they are not used in developed countries anymore. They may, however, play a significant role in developing countries where, in some cases, they can be used as an anti-hemorrhage agent during labor.

Occurrence of Ergot Alkaloids in Barley and Wheat from Algeria.

The natural occurrence of six major ergot alkaloids, ergometrine, ergosine, ergotamine, ergocornine, ergokryptine and ergocristine, as well as their corresponding epimers, were investigated in 60 cereal samples (barley and wheat) from Algeria. Ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) and a QuEChERS extraction method were used for sample analysis. The results revealed that 12 out of 60 samples (20%) were contaminated with ergot alkaloids. Wheat was the most contaminated matrix, with an incidence of 26.7% (8 out of 30 samples). The concentration of total ergot alkaloids ranged from 17.8 to 53.9 µg/kg for barley and from 3.66 to 76.0 µg/kg for wheat samples. Ergosine, ergokryptine and ergocristine showed the highest incidences in wheat, while ergometrine was the most common ergot in barley.

The discovery of a new antibody for BRIL-fused GPCR structure determination.

G-protein-coupled receptors (GPCRs)-the largest family of cell-surface membrane proteins-mediate the intracellular signal transduction of many external ligands. Thus, GPCRs have become important drug targets. X-ray crystal structures of GPCRs are very useful for structure-based drug design (SBDD). Herein, we produced a new antibody (SRP2070) targeting the thermostabilised apocytochrome b562 from Escherichia coli M7W/H102I/R106L (BRIL). We found that a fragment of this antibody (SRP2070Fab) facilitated the crystallisation of the BRIL-tagged, ligand bound GPCRs, 5HT1B and AT2R. Furthermore, the electron densities of the ligands were resolved, suggesting that SPR2070Fab is versatile and adaptable for GPCR SBDD. We anticipate that this new tool will significantly accelerate structure determination of other GPCRs and the design of small molecular drugs targeting them.

Ergot alkaloid mycotoxins: physiological effects, metabolism and distribution of the residual toxin in mice.

The complex ergot alkaloids, ergovaline and ergotamine, cause dysregulation of physiological functions, characterised by vasoconstriction as well as thermoregulatory and cardiovascular effects in grazing livestock. To assess the effect of the mycotoxins, blood pressure and heart rate of male mice were measured, and metabolite profiling undertaken to determine relative abundances of both ergotamine and its metabolic products in body and brain tissue. Ergotamine showed similar cardiovascular effects to ergovaline, causing elevations in blood pressure and reduced heart rate. Bradycardia was preserved at low-levels of ergovaline despite no changes in blood pressure. Ergotamine was identified in kidney, liver and brainstem but not in other regions of the brain, which indicates region-specific effects of the toxin. The structural configuration of two biotransformation products of ergotamine were determined and identified in the liver and kidney, but not the brain. Thus, the dysregulation in respiratory, thermoregulatory, cardiac and vasomotor function, evoked by ergot alkaloids in animals observed in various studies, could be partially explained by dysfunction in the autonomic nervous system, located in the brainstem.

Validated ecofriendly chromatographic method for quantitative determination of anti-migraine quaternary mixture.

A novel ecofriendly, cost and time saving high-performance thin-layer chromatographic method was developed and validated for simultaneous determination of metoclopramide, ergotamine, caffeine, and paracetamol in bulk and pharmaceutical formulation. The separation was carried out on silica gel plates, using ethyl acetate:ethanol:ammonia (9:1:0.1, v/v/v) as a developing system. Ultraviolet detection was carried out at 272 nm. The resulting retention times were 0.15, 0.36, 0.49, and 0.74 min for metoclopramide, ergotamine, caffeine, and paracetamol, respectively. The greenness profile assessment was achieved to the proposed method to evaluate its greenness characters to the environment with acceptable results. Validation parameters were checked according to International Conference of Harmonization guidelines to achieve the international requirements for quality control analysis of the proposed drugs.

Binding Interactions of Ergotamine and Dihydroergotamine to 5-Hydroxytryptamine Receptor 1B (5-HT1b) Using Molecular Dynamics Simulations and Dynamic Network Analysis.

Ergotamine (ERG) and dihydroergotamine (DHE), common migraine drugs, have small structural differences but lead to clinically important distinctions in their pharmacological profiles. For example, DHE is less potent than ERG by about 10-fold at the 5-hydroxytrptamine receptor 1B (5-HT1B). Although the high-resolution crystal structures of the 5-HT1B receptor with both ligands have been solved, the high similarity between these two complex structures does not sufficiently explain their activity differences and the activation mechanism of the receptor. Hence, an examination of the dynamic motion of both drugs with the receptor is required. In this study, we ran a total of 6.0 µs molecular dynamics simulations on each system. Our simulation data show the subtle variations between the two systems in terms of the ligand-receptor interactions and receptor secondary structures. More importantly, the ligand and protein root-mean-square fluctuations (RMSFs) for the two systems were distinct, with ERG having a trend of lower RMSF values, indicating it to be bound tighter to 5-HT1B with less fluctuations. The molecular mechanism-general born surface area (MM-GBSA) binding energies illustrate this further, proving ERG has an overall stronger MM-GBSA binding energy. Analysis of several different microswitches has shown that the 5-HT1B-ERG complex is in a more active conformation state than 5-HT1B-DHE, which is further supported by the dynamic network model, with reference to mutagenesis data with the critical nodes and the first three low-energy modes from the normal mode analysis. We also identify Trp3276.48 and Phe3316.52 as key residues involved in the active state 5-HT1B for both ligands. Using the detailed dynamic information from our analysis, we made predictions for possible modifications to DHE and ERG that yielded five derivatives that might have more favorable binding energies and reduced structural fluctuations.

Biased Ligands Differentially Shape the Conformation of the Extracellular Loop Region in 5-HT2B Receptors.

G protein-coupled receptors are linked to various intracellular transducers, each pathway associated with different physiological effects. Biased ligands, capable of activating one pathway over another, are gaining attention for their therapeutic potential, as they could selectively activate beneficial pathways whilst avoiding those responsible for adverse effects. We performed molecular dynamics simulations with known ß-arrestin-biased ligands like lysergic acid diethylamide and ergotamine in complex with the 5-HT2B receptor and discovered that the extent of ligand bias is directly connected with the degree of closure of the extracellular loop region. Given a loose allosteric coupling of extracellular and intracellular receptor regions, we delineate a concept for biased signaling at serotonin receptors, by which conformational interference with binding pocket closure restricts the signaling repertoire of the receptor. Molecular docking studies of biased ligands gathered from the BiasDB demonstrate that larger ligands only show plausible docking poses in the ergotamine-bound structure, highlighting the conformational constraints associated with bias. This emphasizes the importance of selecting the appropriate receptor conformation on which to base virtual screening workflows in structure-based drug design of biased ligands. As this mechanism of ligand bias has also been observed for muscarinic receptors, our studies provide a general mechanism of signaling bias transferable between aminergic receptors.

Triptan and ergotamine overdoses in the United States: Analysis of the National Poison Data System.

OBJECTIVE: To examine the clinical outcomes of intentional overdoses involving triptans and ergotamines with a retrospective review of the National Poison Data System (NPDS). METHODS: This was a 5-year retrospective cross-sectional study (2014-2018) using the NPDS. Demographics, exposure characteristics, and outcomes were described. Univariate logistic regression was used to estimate the odds ratio (OR) for major effect or death. A multivariable logistic regression model with inclusion criteria of p < 0.1 in univariate analysis was implemented with backwards selection. RESULTS: In this population (n = 1,489), multiple exposure was most common (n = 1,145). The mean age was 31.2 years and 1,197 (80.4%) participants were female. Major effects from a single exposure were seen in <1% with no recorded deaths. Triptan ingestion (n = 328) resulted in hypertension (14%), tachycardia (10.7%), drowsiness (11%), nausea (6.4%), vomiting (4.6%), vertigo (4%), chest pain (3.7%), and diaphoresis (2.4%). Ergotamine ingestion (n = 16) resulted in abdominal pain (16%), vomiting (12.5%), numbness (12.5%), nausea (6.3%), diarrhea (6.3%), and vertigo (6.3%). No clinical effect was seen in 90 (26.2%). No cases met Hunter criteria for serotonin syndrome. There is risk of major event or death due to age (OR 1.02; 95% confidence interval [CI] 1.01-1.04; p = 0.004), multiple product exposure (OR 9.50; 95% CI 2.29-39.48; p = 0.002), and concomitant overdose with benzodiazepines (OR 1.71; 95% CI 1.05-2.78; p = 0.032) or tricyclic antidepressants (OR 3.16; 95% CI 1.88-5.31; p < 0.001). CONCLUSION: The risk of major effect or death was low and predicted by age, multiple product exposure, and concomitant benzodiazepine or tricyclic antidepressant. The triptan toxidrome consists of hypertension, tachycardia, and drowsiness. The toxic effects of ergotamine are acute gastrointestinal syndrome with vertigo and numbness. No cases of serotonin syndrome were seen.