Recent Development of Zolmitriptan Formulation in Migraine Therapy: Production, Metabolism and Pharmaceutical Aspects.

The triptans class of pharmaceuticals, which was created to treat acute migraine, is made up of indole-containing drugs that bind to a subset (1B/1D) of 5-hydroxytryptamine receptors and are agonists of serotonin receptors. At the moment, naratriptan, eletriptan, zolmitriptan, rizatriptan, almotriptan, and frovatriptan are the seven types of triptans available on the market. Among these are the FDA-approved triptans, Zolmitriptan and Sumatriptan, which are selective serotonin (5-hydroxytryptamine) agonists. Zolmitriptan, a synthetic tryptamine derivative and a well-known member of the triptan family, is available as an orally disintegrating tablet, nasal spray, and tablet. There are melt formulations of rizatriptan and zolmitriptan available on the market that are easier to use and absorb, comparable to regular pills. Recently, the FDA approved zolmitriptan, a medication with tolerability comparable to sumatriptan. Whereas zolmitriptan is only available as an oral melt or tablet, sumatriptan is available as a nasal spray, oral preparation, or self-injectable kit. The only known antimigraine drugs that were widely utilized before the triptan period were ergotamine and dihydroergotamine. However, zolmitriptan binds to plasma proteins only 25% of the time because of significant first-pass degradation. Researchers have looked into fresh ideas for solving this issue and innovations to overcome its pharmacokinetic difficulties. This article emphasizes the role of zolmitriptan in the treatment of migraines, highlighting its pharmacological properties, production, metabolism, and structural features.

A Drug Repositioning Approach Reveals Ergotamine May Be a Potential Drug for the Treatment of Alzheimer's Disease.

Background: Alzheimer's disease (AD) is a neurodegenerative disorder that is the most common form of dementia in the elderly. The drugs currently used to treat AD only have limited effects and are not able to cure the disease. Drug repositioning has increasingly become a promising approach to find potential drugs for diseases like AD. Objective: To screen potential drug candidates for AD based on the relationship between risk genes of AD and drugs. Methods: We collected the risk genes of AD and retrieved the information of known drugs from DrugBank. Then, the AD-related genes and the targets of each drug were mapped to the human protein-protein interaction network (PPIN) to represent AD and the drugs on the network. The network distances between each drug and AD were calculated to screen the drugs proximal to AD-related genes on PPIN, and the screened drug candidates were further analyzed by molecular docking and molecular dynamics simulations. Results: We compiled a list of 714 genes associated with AD. From 5,833 drugs used for human diseases, we identified 1,044 drugs that could be potentially used to treat AD. Then, amyloid-ß (Aß) protein, the key molecule involved in the pathogenesis of AD was selected as the target to further screen drugs that may inhibit Aß aggregation by molecular docking. We found that ergotamine and RAF-265 could bind stably with Aß. In further analysis by molecular dynamics simulations, both drugs exhibited reasonable stability. Conclusions: Our work indicated that ergotamine and RAF-265 may be potential candidates for treating AD.

Identifying potential drug targets in the kinomes of two monogenean species.

Protein kinases are enzymes involved in essential biological processes such as signal transduction, transcription, metabolism, and the cell cycle. Human kinases are targets for several drugs approved by the US Food and Drug Administration. Therefore, the identification and classification of kinases in other organisms, including pathogenic parasites, is an interesting subject of study. Monogeneans are platyhelminths, mainly ectoparasites, capable of causing health problems in farmed fish. Although some genomes and transcriptomes are available for monogenean species, their full repertoire of kinases is unknown. The aim of this study was to identify and classify the putative kinases in the transcriptomes of two monogeneans, Rhabdosynochus viridisi and Scutogyrus longicornis, and then to predict potential monogenean drug targets (MDTs) and selective inhibitor drugs using computational approaches. Monogenean kinases having orthologs in the lethal phenotype of C. elegans but not in fish or humans were considered MDTs. A total of 160 and 193 kinases were identified in R. viridisi and S. longicornis, respectively. Of these, 22 kinases, belonging mainly to the major groups CAMK, AGC, and TK, were classified as MDTs, five of which were evaluated further. Molecular docking analysis indicated that dihydroergotamine, ergotamine, and lomitapide have the highest affinity for the kinases BRSK and MEKK1. These well-known drugs could be evaluated in future studies for potential repurposing as anti-monogenean agents. The present study contributes valuable data for the development of new antiparasitic candidates for finfish aquaculture.

Post-partum maternal bradycardia: A case series and literature review.

Background: Unlike tachyarrhythmias, which are common in pregnancy, there is a paucity of data regarding maternal bradycardias. Our objective was to describe the characteristics, associated conditions, and prognosis of women who develop bradycardia post-partum. Method: We conducted a retrospective chart review of patients referred to the Obstetrical Medicine service at British Columbia Women's Hospital from January 2012 to May 2020 for post-partum maternal bradycardia. Results: Twenty-four patients with post-partum bradycardia were included (age 34.2 ± 4.8 years; heart rate 40.4 ± 8.1 beats per minute; blood pressure 131/72 mm Hg). Sinus bradycardia (79.2%) was the most common rhythm. Dyspnea (29.4%) and chest pain (23.5%) were common symptoms. Mean time to resolution of bradycardia was 3.6 ± 3.8 days. Associated conditions potentially explaining the bradycardia were preeclampsia (54.1%), underlying (16.7%), medications (8.3%), and neuraxial anesthesia (8.3%). Conclusions: Maternal bradycardia is an uncommon condition complicating the post-partum period, that is generally self-limiting, with the majority only require clinical observation.

Dihydroergotamine mesylate nasal spray: an acute treatment option for migraine in adults.

INTRODUCTION: Although the landscape of migraine symptomatic treatment has been enriched by novel effective drugs, it is mandatory to critically reappraise older molecules to ascertain whether they could still represent reliable alternatives in specific endophenotypes of patients or migraine attacks. Among these, dihydroergotamine (DHE) nasal spray has been shown to be effective and is characterized by greater tolerability and manageability than the parenteral DHE formulation. AREAS COVERED: In this narrative review, the authors describe the pharmacodynamic and pharmacokinetic properties of DHE nasal spray and explore the results of the trials which explored its efficacy, safety and tolerability as migraine symptomatic treatment. They also discuss the limitations of the classically used device and the attempts that several companies are carrying out to generate devices warranting a more reproducible drug absorption. EXPERT OPINION: DHE nasal spray could be considered as rescue treatment in patients who have failed other symptomatic therapeutic strategies. Nevertheless, in the perspective of tailored therapy, the intranasal route of administration and the consequent rapid onset of action may represent benefits putatively making DHE a treatment of choice for challenging migraine attacks such as those with nocturnal onset or quickly reaching the climax of both headache and neurovegetative associated symptoms.

Effects of hallucinogenic drugs on the human heart.

Hallucinogenic drugs are used because they have effects on the central nervous system. Their hallucinogenic effects probably occur via stimulation of serotonin receptors, namely, 5-HT2A-serotonin receptors in the brain. However, a close study reveals that they also act on the heart, possibly increasing the force of contraction and beating rate and may lead to arrhythmias. Here, we will review the inotropic and chronotropic actions of bufotenin, psilocin, psilocybin, lysergic acid diethylamide (LSD), ergotamine, ergometrine, N,N-dimethyltryptamine, and 5-methoxy-N,N-dimethyltryptamine in the human heart.

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.

A Rapid and Sensitive Stability-Indicating Eco-Friendly HPTLC Assay for Fluorescence Detection of Ergotamine.

Eco-friendly liquid chromatographic methods for measuring ergotamine (EGT) are scant in the published database. Accordingly, the goal of the current study was to develop a high-performance thin-layer chromatography (HPTLC) method for fluorescence detection of EGT in commercially available tablets. This approach was based on the application of ethyl alcohol-water (80:20 v/v) as the eco-friendly eluent mixture. The fluorescence detection of EGT was carried out at 322 nm. The greenness score of the present approach was evaluated by "Analytical GREENness (AGREE)" technology. The present approach for measuring EGT in the 25-1000 ng band-1 range was linear. The present assay for fluorescence detection of EGT was validated successfully by ICH guidelines for various parameters. The method was found to be rapid, sensitive, eco-friendly, and stability-indicating. The computed AGREE index for the current strategy was 0.84, displaying outstanding greenness features. The present methodology successfully separated the EGT degradation products under forced-degradation circumstances, exhibiting its stability-indicating qualities and selectivity. An amount of 99.33% of EGT was found in commercial formulations, indicating the validity of the current method for pharmaceutical analysis of EGT in commercial products. The results showed that EGT in commercial products might be regularly measured by the existing method.

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.

Use of 3D applicator for intranasal microneedle arrays for combinational therapy in migraine.

The objective of current research work was to fabricate dissolving microneedles combining ergotamine and caffeine for synergistic action using controlled release kinetics with better permeability. The method of preparation for microneedles utilized multiple emulsion (w/o/w) approach by solvent-diffusion-evaporation process wherein the nano-emulsion of ergotamine and caffeine prepared using PLGA polymer and PVA as a stabilizer. The PLGA nanospheres were further loaded in polymer matrix of PVA and PVP K-90 and the final mixture poured in sterile silicon molds of microneedles. The PLGA nanospheres exhibited particle size in narrow range of 280.34 ± 6.61 to 416.0 ± 9.67 nm and good colloidal stability with negative zeta potential ranging between -19.08 ± 8.77 to -22.49 ± 8.09 mV. Higher entrapment efficiency (86.21 ± 4.52 %) for ergotamine and controlled release pattern (49.79 ± 4.16 % at 48 h) displayed by PLGA nanospheres. Similarly, the dissolving microneedles loaded with PLGA nanospheres showed controlled release pattern for in-vitro and ex-vivo drug release studies with 52.01 ± 5.71 % for ERM and 87.04 ± 2.44 % for CFE at 48 h whereas ex-vivo release studies illustrated similar results of 51.08 ± 3.56 % for ERM and 69.2 ± 2.16 % for CFE. The anti-hyperalgesic capability of microneedles was verified by the acetic acid writhing test, and the non-toxicity of synthetic microneedles was confirmed by histopathology and serotonin toxicity studies. The novel 3D applicator effectively delivered the microneedle array into the nasal cavity for systemic action. Therefore, the fabricated rapid dissolving microneedles combining two drugs ergotamine and caffeine with use of 3D applicator proved to be a coherent technique for intranasal delivery of ergotamine in the treatment of migraine.

Self-Assembled Lipid Polymer Hybrid Nanoparticles Using Combinational Drugs for Migraine Via Intranasal Route.

The objective of the current research study was to formulate the PEGylated lipid polymer hybrid nanoparticles of ergotamine and caffeine for intranasal administration with higher entrapment efficiency, better permeability, desirable controlled release pattern, and significant brain uptake in animal studies. A single-step nanoprecipitation method was employed in the processing of self-assembled hybrid nanoparticles constituting polymer PLGA, lipids soya lecithin, and DPPC with PEGylation using polyethylene glycol (PEG-2000). The optimal lipid/polymer weight ratio of 15% w/w showed lower particle size of 239.46 ± 2.31 nm with good colloidal stability depicted by zeta potential (- 18.36 ± 6.59 mV), higher entrapment efficiency of 86.88 ± 1.67%, and controlled release profile when evaluated for in vitro and ex vivo studies as 97.12 ± 2.79% and 75.13 ± 5.62% release, respectively, for 48 h. The formulation showed long-term serum stability when incubated in bovine serum albumin and displayed high brain uptake (4.35-fold) offering significant permeability in the brain post-intranasal administration via olfactory route. Histopathological investigations and serotonin toxicity studies in animals confirmed the safe and non-toxic nature of the formulation while the acetic acid writhing test proved the anti-hyperalgesic activity. The PEGylated lipid polymer hybrid nanoparticles of ergotamine and caffeine showed synergistic activity with efficacious higher anti-migraine potential.

The Application of the Neuroprotective and Potential Antioxidant Effect of Ergotamine Mediated by Targeting N-Methyl-D-Aspartate Receptors.

(1) Background: The N-methyl-D-aspartate receptors (NMDARs) mediate fast excitatory currents leading to depolarization. Postsynaptic NMDARs are ionotropic glutamate receptors that mediate excitatory glutamate or glycine signaling in the CNS and play a primary role in long-term potentiation, which is a major form of use-dependent synaptic plasticity. The overstimulation of NMDARs mediates excessive Ca2+ influx to postsynaptic neurons and facilitates more production of ROS, which induces neuronal apoptosis. (2) Methods: To confirm the induced inward currents by the coapplication of glutamate and ergotamine on NMDARs, a two-electrode voltage clamp (TEVC) was conducted. The ergotamine-mediated inhibitory effects of NR1a/NR2A subunits were explored among four different kinds of recombinant NMDA subunits. In silico docking modeling was performed to confirm the main binding site of ergotamine. (3) Results: The ergotamine-mediated inhibitory effect on the NR1a/NR2A subunits has concentration-dependent, reversible, and voltage-independent properties. The major binding sites were V169 of the NR1a subunit and N466 of the NR2A subunit. (4) Conclusion: Ergotamine effectively inhibited NR1a/NR2A subunit among the subtypes of NMDAR. This inhibition effect can prevent excessive Ca2+ influx, which prevents neuronal death.

Tracing the influence of caffeine on the pharmacokinetic parameters of three headache relieving pharmaceuticals applying synchronous fluorescence spectroscopy.

A simple, sensitive, and selective first derivative synchronous fluorimetric method was developed and optimized to track the influence of caffeine content in beverages on the pharmacokinetic parameters of three pharmaceuticals used in relieving headache namely, aspirin (ASP), ibuprofen (IBU), and ergotamine tartrate (ERG). A full validation procedure was carried out to impart validity to the proposed method to apply it to biological fluids. The unique dissolving power of micellar solutions was utilized to avoid multiple extraction steps for both thein vitroandin vivoexperiments, aiming to obtain acceptable recoveries and to accomplish sustainability, where 0.1 M sodium dodecyl sulphate (SDS) was used for this purpose. Moreover, the developed bioanalytical method was subjected to full validation to avoid interferences emerging from biological matrices. The greenness of the proposed method was assessed according to the Analytical Eco-Scale and proved to be excellent green carrying a score of 98%.

Clinical characteristics of medication-overuse headache according to the class of acute medication: A cross-sectional multicenter study.

OBJECTIVE: To characterize the clinical features of patients with medication-overuse headache (MOH) according to the class of acute medications being overused. BACKGROUND: MOH is a common global health problem, severely disabling the majority of the patients affected. Although various medications can cause MOH, whether clinical features differ according to the overused medication type remains unclear. METHODS: We analyzed data from a multicenter cross-sectional study in neurology clinics in Korea from April 2020 to June 2021. RESULTS: Among 229 eligible patients, MOH was documented in patients who overused multiple drug classes (69/229, 30.1%; most frequent occurrence), triptans (50/229, 21.8%), non-opioid analgesics (48/229, 21.0%), and combination-analgesics (40/229, 17.4%). Patients who overused multiple drug classes reported more frequent use of acute medications (median [25th-75th percentiles]: 25.0 [15.0-30.0] vs. 17.5 [10.0-25.5] days/month, p = 0.029) and fewer crystal-clear days (0.0 [0.0-9.5] vs. 9.0 [0.0-10.0] days/month, p = 0.048) than those who overused triptans. Patients who overused multiple drug classes also reported shorter intervals from chronic daily headache to the onset of MOH than patients who overused combination-analgesics (0.6 [0.2-1.9] vs. 2.4 [0.7-5.4] years, p = 0.001) or non-opioid analgesics (1.5 [0.6-4.3] years, p = 0.004). Patients who overused multiple drug classes reported more emergency room visits (1.0 [0.0-1.0] visits/year) than those who overused combination-analgesics (0.0 [0.0-1.0], p = 0.024) or non-opioid analgesics (0.0 [0.0-1.0], p = 0.030). Patients who overused triptans reported fewer headache days (21.0 [20.0-30.0] vs. 30.0 [20.5-30.0] days/month, p = 0.008) and fewer severe headache days (7.0 [4.0-10.0] vs. 10.0 [5.0-15.0] days/month, p = 0.017) than those who overused non-opioid analgesics. CONCLUSIONS: Some clinical characteristics of MOH significantly differed according to the class of overused medications. The findings from this study may contribute to the understanding of the clinical characteristics and pathophysiology of MOH.

Impact of the 2018 Japan Floods on prescriptions for migraine: A longitudinal analysis using the National Database of Health Insurance Claims.

OBJECTIVE: To determine the impact of the 2018 Japan Floods, one of the largest water disasters in Japan, on the number of prescriptions for triptans and ergotamine (acute treatment). BACKGROUND: Natural disasters frequently occur worldwide and may cause psychological stress-related diseases. Acute migraine attacks can be triggered by psychological stress. Disaster victims are likely to experience tremendous psychological stress; however, the relationship between natural disasters and migraine attacks is not well investigated. METHODS: A retrospective longitudinal cohort study was conducted using the National Database of Health Insurance Claims in the hardest-hit areas of the disaster 1 year before and after the disaster. We included people between the ages of 15 and 64 years. Those who had a victim code that was certificated by a local government were assigned to the victim group, and others to the nonvictim group. For those who were not prescribed acute treatment before the disaster (i.e., group without previous acute treatment), the cumulative incidence of new prescriptions for acute treatment at 12 months of follow-up was calculated and compared between victims and nonvictims with survival analysis. RESULTS: Of 3,475,515 people aged 15 to 64 years enrolled in the study, 16,103 (0.46%) were assigned to the victim group. In the group without previous acute treatment, 111 (0.70%) of 15,933 victims and 14,626 (0.43%) of 3,431,423 nonvictims were newly prescribed acute treatment after the disaster, and new prescriptions for acute treatment were significantly more likely to occur in victims than in nonvictims (adjusted hazard ratio, 1.68; 95% CI, 1.39-2.02). CONCLUSIONS: The 2018 Japan Floods increased the number of prescriptions for acute migraine medications among victims, suggesting that acute migraine attacks occurred more frequently after a natural disaster.

Network Pharmacology and Experimental Verification to Explore the Potential Mechanism of Yin-Huo-Tang for Lung Adenocarcinoma Recurrence.

PURPOSE: Yin-Huo-Tang (YHT) is a classic traditional Chinese prescription, used to prevent lung adenocarcinoma (LUAD) relapse by "nourishing yin and clearing heat". In this study, the mechanism of YHT in LUAD recurrence was investigated. METHODS: Firstly, the bioactive compounds and targets of YHT, as well as related targets of LUAD recurrence, were collected from public databases. The protein-protein interaction network, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to find the pivotal compounds, hub genes, functional annotation and main pathways. Subsequently, RNA sequencing of recurrent tumor tissues from Lewis lung carcinoma mice treated with YHT was used to explore the main pathways. At the same time, pathways screened by network pharmacology and RNA sequencing analysis were considered the most important pathways. Finally, liquid chromatography mass spectrometry was used to validate the pivotal active ingredients. Molecular docking technology was performed to validate the binding association between the hub genes and the pivotal active ingredients. PCR and WB analysis were used to validate the main pathways. RESULTS: There were 128 active compounds and 419 targets interacting with YHT and LUAD recurrence. Network analysis identified 4 pivotal compounds, 28 hub genes and 30 main pathways. Sphingolipid signaling pathway was the common main pathway in network pharmacology and RNA sequencing results. The hub gene related to the sphingolipid signaling pathway was S1PR5. Qualitative phytochemical analysis confirmed the presence of 3 pivotal compounds, namely stigmasterol, nootkatone and ergotamine. The molecular docking verified that the pivotal compounds could good affinity with S1PR5. The PCR and WB analysis verified YHT suppressed Lewis lung cancer cells proliferation and migration by inhibiting the sphingolipid signaling pathway. CONCLUSION: The potential mechanism and therapeutic effect of YHT against the recurrence of LUAD may be ascribed to inhibition of the sphingolipid signaling pathway.

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.

Ergotamine Induced Retroperitoneal Fibrosis.

Retroperitoneal fibrosis (RPF) is an uncommon disease characterised by the presence of fibroinflammatory reaction which starts around the infrarenal portion of the abdominal aorta in the retroperitoneum and frequently entrap the ureter causing obstructive uropathy. Approximately, two thirds of the cases are idiopathic, where aetiopathogenesis is not known. Ergotamine-induced RPF, although rare, is considered under secondary group. The fibrogenic process here is thought to be due to serotonergic activity. We report a case of RPF in a young female with obstructive uropathy who had history of long-term ergotamine intake for migraine. Histopathological evaluation revealed different evolving stages of necrotising vasculitis. In addition, the patient has responded to withdrawal of offending drug along with immunosuppressive therapy. We believe, apart from serotonergic activity, ergotamine can lead to RPF through a vasculitic process which has not been reported earlier.