RESUMO
Migraine is one of the common neurological disease affecting around 23% of the Pakistani population. Prompt treatment is required to regain the functional ability of patients. The present study was designed to develop sumatriptan succinate orodispersible tablets that would quickly overcome acute migraine episodes using 22 full-factorial design. The chitosan and sodium starch glycolate were taken as independent variables; friability, disintegration, dispersion time and water absorption ratio as response variables. Eight trial formulations were generated by Design Expert® software. The main effect plots were used to check the interaction of formulations with response variables. All trial formulations showed good micromeritic properties in terms of angle of repose (19.59o-24.57°), Carr's index (17.08-24.90%) and Hausner's ratio (1.20-1.33). The tablets wetted quickly (17.1- 39 sec) in dispersion medium, showed higher water absorption ratio (188-341 sec) and disintegrated quickly (13-20 sec) with an excellent dissolution rate (94-99%). The main effect plots show interactions between the independent variables against most of the study responses. A 22 full-factorial model was found to be effective in studying the influence of formulation variables on response parameters. Both chitosan and sodium starch glycolate can be used in combination to fabricate an effective orodispersible formulation of sumatriptan succinate.
Assuntos
Quitosana , Transtornos de Enxaqueca , Amido , Sumatriptana , Comprimidos , Sumatriptana/administração & dosagem , Sumatriptana/química , Transtornos de Enxaqueca/tratamento farmacológico , Amido/química , Amido/análogos & derivados , Amido/administração & dosagem , Quitosana/química , Humanos , Administração Oral , Solubilidade , Composição de Medicamentos , Química Farmacêutica , Excipientes/químicaRESUMO
The study aimed at simultaneous quantification of sumatriptan succinate (SUM) and prochlorperazine maleate (PCP) in an orodispersible film using two validated spectroscopic methods viz. simultaneous equation (Method I) and the Q-absorption ratio (Method II). The Method I involved measurement of absorbances at λmax of both drugs while in Method II, absorbances were measured at isosbestic wavelength and λmax of one of the two components. Method validation were accomplished as per the ICH guidelines. A 1:1 mixture of the drugs and an orodispersible film (ODF) containing these drugs were assayed by both methods. The absorbance data of SUM and PCP in both methods were linear at respective wavelengths with correlation coefficient values >0.995. Both methods were precise as % RSD in repeatability, interday and intraday precision was less than 2. The estimation of SUM and PCP from the film dosage form by method I was104.74% and 98.34% and by method II was 103.45% and 98.85%, respectively, with a standard deviation <2. The study concluded that both the methods were simple, reliable and robust and can be applied successfully for the simultaneous quantification of SUM and PCP in mixture and orodispersible film dosage form.
Assuntos
Antieméticos/química , Proclorperazina/química , Espectrofotometria Ultravioleta , Sumatriptana/química , Vasoconstritores/química , Administração Oral , Antieméticos/administração & dosagem , Membranas Artificiais , Proclorperazina/administração & dosagem , Sumatriptana/administração & dosagem , Propriedades de Superfície , Vasoconstritores/administração & dosagemRESUMO
PURPOSE: The purpose of this report was to describe a case with paracentral acute middle maculopathy after oral intake of sumatriptan. METHODS: Case presentation. RESULTS: One patient showed typical findings on fundoscopic examination and optical coherence tomography consistent with paracentral acute middle maculopathy following oral intake of sumatriptan. CONCLUSION: Sumatriptan may be a trigger for paracentral acute middle maculopathy.
Assuntos
Degeneração Macular , Doenças Retinianas , Sumatriptana , Doença Aguda , Administração Oral , Humanos , Degeneração Macular/induzido quimicamente , Degeneração Macular/diagnóstico por imagem , Doenças Retinianas/induzido quimicamente , Doenças Retinianas/diagnóstico por imagem , Sumatriptana/administração & dosagem , Sumatriptana/efeitos adversos , Tomografia de Coerência ÓpticaRESUMO
Objective: This study aimed at estimating the treated cluster headache (CH) prevalence and describing prescription patterns and direct costs paid by the Italian National-Health-System.Methods: Through the ReS database (healthcare administrative data collection of a large sample of the Italian population), adults in treatment for CH (acute therapy with sumatriptan/subcutaneous or oxygen, associated with preventive therapy with verapamil or lithium) were selected. A cross-sectional analysis described the prevalence of CH-treated subjects repeated annually in 2013-2017. A longitudinal analysis of patients selected in 2013-2015 and followed for 2 years provided the prescription patterns.Results: The annual prevalence of CH-treated patients increased from 6.4×100,000 adults in 2013 to 6.7 in 2017. In 2013-2015, 570 patients (80.7% M; mean age 46) treated for CH were found. In 50.4%, the identifying CH treatment was sumatriptan/subcutaneous+verapamil. During follow-up, >1/3 changed the preventive drug and interruption was the most frequent modification, although acute treatments were still prescribed. The mean annual cost/patient ranged from 2,956 to 2,267; pharmaceuticals expenditure represented the 56.4% and 57.3%, respectively.Conclusions: This study showed an important unmet need among CH patients, carrying a high economic burden that should be considered in the evaluation of the impact of incoming therapies (e.g. Calcitonin-Gene-Related-Peptide antibodies).
Assuntos
Cefaleia Histamínica/tratamento farmacológico , Custos de Cuidados de Saúde/estatística & dados numéricos , Padrões de Prática Médica/estatística & dados numéricos , Adolescente , Adulto , Idoso , Cefaleia Histamínica/economia , Estudos Transversais , Bases de Dados Factuais , Custos de Medicamentos , Feminino , Humanos , Itália , Carbonato de Lítio/administração & dosagem , Carbonato de Lítio/economia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Oxigênio/administração & dosagem , Oxigênio/economia , Prevalência , Sumatriptana/administração & dosagem , Sumatriptana/economia , Verapamil/administração & dosagem , Verapamil/economia , Adulto JovemRESUMO
Hepatic clearance may be uptake rate limited by organic anion transporting polypeptides (OATPs) and organic cation transporter 1 (OCT1). While comparison of OATP activity has been investigated across species, little has been reported for OCT1. Additionally, while data on interspecies transporter expression in the liver exist, quantitative comparison of these transporters in multiple tissues is lacking. In the current research, the pharmacokinetics of OCT1 substrates (sumatriptan and metformin) were assessed in Oct knockout rats for comparison with previous Oct1/2-/- mice data and OCT1 pharmacogenetics in humans. Effect of OCT1 inhibitors verapamil and erlotinib on OCT1 substrate liver partitioning was also evaluated in rats. Expression of 18 transporters, including Oatps and Octs, in 9 tissues from mice and rats was quantitated using nanoLC/MS-MS, along with uptake transporters in hepatocytes from 5 species. Interspecies differences in OCT1 activity were further evaluated via uptake of OCT1 substrates in hepatocytes with corresponding in vivo liver partitioning in rodents and monkey. In Oct1-/- rats, sumatriptan hepatic clearance and liver partitioning decreased; however, metformin pharmacokinetics were unaffected. OCT1 inhibitor coadministration decreased sumatriptan liver partitioning. In rodents, Oatp expression was highest in the liver, although comparable expression of Oatps in other tissues was determined. Expression of Octs was highest in the kidney, with liver Oct1 expression comparably lower than Oatps. Liver partitioning of OCT1 substrates was lower in rodents than in monkey, in agreement with the highest OCT1 expression and uptake of OCT1 substrates in monkey hepatocytes. Species-dependent OCT1 activity requires consideration when translating preclinical data to the clinic.
Assuntos
Eliminação Hepatobiliar/fisiologia , Transportador 1 de Cátions Orgânicos/metabolismo , Animais , Cães , Cloridrato de Erlotinib/farmacologia , Feminino , Células HEK293 , Haplorrinos , Eliminação Hepatobiliar/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Rim/metabolismo , Fígado/metabolismo , Masculino , Metformina/administração & dosagem , Metformina/farmacocinética , Camundongos , Camundongos Knockout , Transportador 1 de Cátions Orgânicos/antagonistas & inibidores , Transportador 1 de Cátions Orgânicos/genética , Ratos , Ratos Transgênicos , Especificidade da Espécie , Sumatriptana/administração & dosagem , Sumatriptana/farmacocinética , Verapamil/farmacologiaRESUMO
The current study was conducted to fabricate Metoclopramide HCL (MCH) and Sumatriptan succinate (SS) instant release buccal films (IRBF) without using any super disintegrant. The solvent casting method was used for the preparation of IRBFs and prepared IRBFs were physicochemically evaluated. Spectrophotometric analysis was done to determine the lambda max followed by the linearity determination of both drugs. Different concentrations such as 100, 125, and 150mg of hydrophilic polymer (HPMC E5) were employed but the concentration of glycerol was variable. Comparatively better results were observed for the formulation with 150mg of HPMC E5 and 30% glycerol. Formulated IRBFs showed good tensile strength with a mean disintegration time of 12.4-28.4 seconds and rapid dissolution with more than 50% drug release within 2 minutes. It was concluded that the chosen combination of polymers was appropriate for the fabrication of MCH and SS buccal strips.
Assuntos
Antagonistas dos Receptores de Dopamina D2/química , Glicerol/química , Derivados da Hipromelose/química , Metoclopramida/química , Agonistas do Receptor 5-HT1 de Serotonina/química , Sumatriptana/química , Administração Bucal , Antagonistas dos Receptores de Dopamina D2/administração & dosagem , Formas de Dosagem , Composição de Medicamentos , Liberação Controlada de Fármacos , Cinética , Metoclopramida/administração & dosagem , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Solubilidade , Espectrofotometria Ultravioleta , Sumatriptana/administração & dosagem , Resistência à TraçãoRESUMO
OBJECTIVES: Migraine is a neurological disorder with unilateral pulsatile headache which can affect the functions of sufferers. Migraineurs experience some undesirable symptoms such as pain, nausea, vomiting and in some cases auras which make the oral delivery non-selective. The lipid nanoparticles are considered as good carriers for nose-to-brain drug delivery. The present study aimed to formulate and evaluate a sumatriptan-loaded nanostructured lipid carrier (NLC). METHODS: A drug-loaded NLC was optimized using D-optimal design of experiment and then the characterization of the formulated NLC including particle size, zeta potential, electron microscopy, thermal analysis, drug loading efficiency and release kinetics were carried out. Pharmacokinetic evaluations were also performed during an in-vivo study on Sprague-Dawley rats and neuropharmacokinetic parameters such as drug targeting efficiency (DTE) and direct transport percentage (DTP) were calculated. KEY FINDINGS: The optimization of experiments led to nanoparticles with 101 nm mean diameter and polydispersity index (PDI) of 0.27. The drug entrapment efficiency (EE) for optimized nanoparticle was found to be 91.00%. DTE and DTP of intranasal-administered NLC were calculated 258.02% and 61.23%, respectively. CONCLUSIONS: Neuropharmacokinetic evaluation of intranasal NLC dispersion represents a suitable brain delivery system. The DTP of NLC formulation suggests the desirable entrance of sumatriptan into the brain.
Assuntos
Encéfalo/metabolismo , Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Nanoestruturas , Mucosa Nasal/metabolismo , Sumatriptana/farmacocinética , Administração Intranasal , Animais , Encéfalo/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão/métodos , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/síntese química , Lipídeos , Masculino , Nanoestruturas/administração & dosagem , Nanoestruturas/química , Mucosa Nasal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Sumatriptana/administração & dosagem , Sumatriptana/síntese químicaRESUMO
OBJECTIVE: To evaluate the potential for pharmacokinetic interaction and the safety and tolerability when ubrogepant and sumatriptan are coadministered in a Phase 1 study in healthy participants, and to inform the safety and tolerability of ubrogepant alone and in combination with triptans in Phase 3 trials in participants with migraine. BACKGROUND: Calcitonin gene-related peptide is a potent vasodilatory neurotransmitter believed to play a key role in the pathophysiology of migraine. Ubrogepant (UBRELVY™) is a potent and selective antagonist of the human calcitonin gene-related peptide receptor approved for the acute treatment of migraine. Sumatriptan is a serotonin receptor agonist and the most commonly used triptan for the acute treatment of migraine. Ubrogepant could be prescribed with triptans. DESIGN: The Phase 1 study was a single-center, open-label, randomized, 3-way crossover, single-dose, pharmacokinetic interaction study, where participants received each of 3 oral treatments with a 7-day washout period between treatments: single dose of ubrogepant 100 mg, single dose of sumatriptan 100 mg, and ubrogepant 100 mg plus sumatriptan 100 mg. Pharmacokinetic parameters were calculated using a model-independent approach. The ACHIEVE I and II trials were 2 multicenter, single-attack, randomized, Phase 3 trials in adults with a history of migraine with or without aura. Participants had the option to take a second dose of study medication or rescue medication to treat a nonresponding migraine or a migraine recurrence from 2 to 48 hours after the initial dose of study medication. Rescue medication options included acetaminophen, nonsteroidal anti-inflammatory drugs, opioids, anti-emetics, or triptans. Treatment-emergent adverse events were evaluated up to 30 days after the last dose in the Phase 1 and Phase 3 studies. RESULTS: Ubrogepant median time to maximum plasma concentration was delayed (3 hours [range: 1-5 hours] vs 1.5 hours [range: 1-4 hours]), mean maximum plasma concentration was reduced by 24% (coefficient of variation: 37.4%) when ubrogepant was coadministered with sumatriptan (n = 29) compared with ubrogepant administered alone (N = 30). No significant effect was observed on the area under the plasma concentration-time curve of ubrogepant. Sumatriptan area under the curve and maximum plasma concentration showed no significant change when sumatriptan was coadministered with ubrogepant (n = 29), but the sumatriptan time to maximum plasma concentration was delayed (1 hour [range: 0.5-5 hours] vs 3 hours [range: 0.5-6 hours]. No treatment-emergent adverse events were reported with the coadministration of ubrogepant 100 mg and sumatriptan 100 mg in the Phase 1 study. The pooled safety data from ACHIEVE trials (N = 1938) showed similar rates of treatment-related treatment-emergent adverse events between participants who took ubrogepant alone and participants who took ubrogepant and a triptan as a rescue medication (14.9% [53/355] vs 12.8% [5/39] in the ubrogepant 100 mg treatment group, respectively). CONCLUSIONS: Although there were slight alterations in ubrogepant pharmacokinetic parameters when coadministered with sumatriptan, such changes are expected to have minimal clinical relevance, especially because no changes were seen in sumatriptan area under the curve and maximum plasma concentration when coadministered with ubrogepant. Coadministration of ubrogepant with sumatriptan was well tolerated in healthy participants in the Phase 1 study, and coadministration of ubrogepant with triptans was well tolerated in participants with migraine in the Phase 3 trials. No new safety concerns for ubrogepant were identified across all trials.
Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Transtornos de Enxaqueca/tratamento farmacológico , Piridinas , Pirróis , Sumatriptana , Triptaminas , Adulto , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/administração & dosagem , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/efeitos adversos , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/farmacocinética , Estudos Cross-Over , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Humanos , Masculino , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridinas/farmacocinética , Pirróis/administração & dosagem , Pirróis/efeitos adversos , Pirróis/farmacocinética , Sumatriptana/administração & dosagem , Sumatriptana/efeitos adversos , Sumatriptana/farmacocinética , Triptaminas/administração & dosagem , Triptaminas/efeitos adversos , Triptaminas/farmacocinéticaRESUMO
OBJECTIVE: The monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor are new antimigraine drugs from which many patients already benefit. Very few side effects have been reported from the antibody trials, including very few gastrointestinal (GI) side effects. The current data derive from a double-blind cross-over study of CGRP infusion for 2 hours. We present the GI side effects of the infusion and raise the question if underreporting of GI symptoms in CGRP antibody trials has occurred. We also discuss why constipation may be more likely with CGRP receptor blockade than with CGRP neutralizing antibodies. METHODS: Thirty healthy volunteers were recruited to receive a 2-hour infusion of CGRP 1.5 µg/minutes on 2 different days. The participants were pretreated with sumatriptan tablets (2 × 50 mg) 1 day and with placebo the other day. During the infusion, the participants were asked about side effects including a detailed description about their GI symptoms. Clinical observations like flatulence, rumbling, and use of bedpan were also noted. After the infusion, the participants filled out a questionnaire about side effects at home until 12-hour after the infusion start. The study was conducted at the Danish Headache Center at Rigshospitalet Glostrup in the period February 2018 to July 2018. RESULTS: On both study days 93% (27/29 participants) experienced symptoms from the GI system during the infusion. Rumbling, stomach pain, nausea, diarrhea, and an urge to defecate were the most commonly experienced GI side effects. There was no difference in symptoms between placebo and sumatriptan pretreatment. CONCLUSION: We conclude that a 2-hour infusion of CGRP causes frequent and sometimes severe symptoms from the GI system. The symptoms are not antagonized by sumatriptan. More attention should be paid to constipation as a possible side effect of CGRP receptor antagonists.
Assuntos
Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Diarreia/induzido quimicamente , Motilidade Gastrointestinal/efeitos dos fármacos , Náusea/induzido quimicamente , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Sumatriptana/farmacologia , Adulto , Peptídeo Relacionado com Gene de Calcitonina/administração & dosagem , Constipação Intestinal/induzido quimicamente , Estudos Cross-Over , Diarreia/prevenção & controle , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/prevenção & controle , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Sumatriptana/administração & dosagem , Adulto JovemRESUMO
OBJECTIVES: The authors have previously tried to develop a model for the testing of novel drug candidates for migraine, using the headache and migraine provoking agent cilostazol. Previous studies have used sumatriptan tablets as the validating drug, but they were not sufficiently effective. In this study we test the effect of subcutaneous sumatriptan on cilostazol induced headache in patients with migraine without aura. METHOD: Thirty patients with migraine without aura received 200 mg cilostazol on two different study days. The induced headache was treated with subcutaneous sumatriptan in a randomized, double-blind cross-over design. The patients filled out a self-reported headache questionnaire until 12 h after cilostazol. RESULTS: All 30 patients experienced headache (range 3-10) on both study days and the headache fulfilled the criteria for a migraine-like attack in 73% on the sumatriptan day and in 77% on the placebo day. Sumatriptan injection reduced the headache score 2 h after treatment (p = 0.003). The difference between headache intensity on the sumatriptan day and the placebo day was significant at both 2 h (p = 0.01) and 4 h (p = 0.0007) after treatment. CONCLUSION: Subcutaneous sumatriptan reduces cilostazol induced headache in migraine patients. The cilostazol model may be useful as a tool to test the potential of new anti-migraine drugs.Trial registration: The study is registered on clinicaltrials.gov (NCT03422796).
Assuntos
Cilostazol/efeitos adversos , Transtornos de Enxaqueca/tratamento farmacológico , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Sumatriptana/administração & dosagem , Vasodilatadores/efeitos adversos , Adulto , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/induzido quimicamente , Adulto JovemRESUMO
BACKGROUND: Pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) induces headache in healthy volunteers but the precise mechanisms by which PACAP38 leads to headache are unclear. We investigated the headache preventive effect of sumatriptan and ketorolac on PACAP38-induced headache in healthy volunteers. In addition, we explored contribution of vascular mechanisms to PACAP38-induced headache using high resolution magnetic resonance angiography. METHODS: Thirty-four healthy volunteers were divided in two groups (A and B) and received infusion of PACAP38 (10 picomol/kg/min) over 20 min. Group A was pretreated with intravenous sumatriptan (4 mg) or ketorolac (30 mg) 20 min before infusion of PACAP38. Group B received infusion of sumatriptan or ketorolac as post-treatment 90 min after infusion of PACAP38. In both experiments, we used a randomized, double-blind, cross-over design. We recorded headache characteristics and circumference of extra-intracerebral arteries. RESULTS: We found no difference in AUC (0-6 h) of PACAP38-induced headache in group A, pretreated with sumatriptan or ketorolac (p = 0.297). There was no difference between sumatriptan and ketorolac in PACAP38-induced circumference change (AUCBaseline-110 min) of MMA (p = 0.227), STA (p = 0.795) and MCA (p = 0.356). In group B, post-treatment with ketorolac reduced PACAP38-headache compared to sumatriptan (p < 0.001). Post-treatment with sumatriptan significantly reduced the circumference of STA (p = 0.039) and MMA (p = 0.015) but not of MCA (p = 0.981) compared to ketorolac. In an explorative analysis, we found that pre-treatment with sumatriptan reduced PACAP38-induced headache compared to no treatment (AUC0-90min). CONCLUSIONS: Post-treatment with ketorolac was more effective in attenuating PACAP38-induced headache compared to sumatriptan. Ketorolac exerted its effect without affecting PACAP38-induced arterial dilation, whereas sumatriptan post-treatment attenuated PACAP38-induced dilation of MMA and STA. Pre-treatment with sumatriptan attenuated PACAP38-induced headache without affecting PACAP38-induced arterial dilation. Our findings suggest that ketorolac and sumatriptan attenuated PACAP38-induced headache in healthy volunteers without vascular effects. TRIAL REGISTRATION: Clinicaltrials.gov (NCT03585894). Registered 13 July 2018.
Assuntos
Cefaleia/induzido quimicamente , Cefaleia/tratamento farmacológico , Cetorolaco/administração & dosagem , Medição da Dor/efeitos dos fármacos , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/efeitos adversos , Sumatriptana/administração & dosagem , Adulto , Anti-Inflamatórios não Esteroides/administração & dosagem , Estudos Cross-Over , Método Duplo-Cego , Feminino , Cefaleia/diagnóstico , Humanos , Infusões Intravenosas , Angiografia por Ressonância Magnética , Masculino , Modelos Teóricos , Medição da Dor/métodos , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/administração & dosagem , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Vasodilatadores/administração & dosagem , Vasodilatadores/efeitos adversosRESUMO
OBJECTIVE: Previous attempts to develop a pragmatic human model for testing new anti-migraine drugs, have failed. Calcitonin gene-related peptide (CGRP) induces a mild headache in healthy volunteers and migraine-like headache in migraine patients. The induced headache must respond to already established migraine treatment for validation. Thus, the objective of the study was to test the effect of sumatriptan against CGRP-induced symptoms in an attempt to validate CGRP-induced headache as a model for drug testing. METHODS: Thirty healthy volunteers were recruited to receive a 2-hour infusion of CGRP on 2 separate days. The participants were pretreated with sumatriptan 1 day and with placebo the other day in a randomized double-blind cross-over fashion. During the infusion, a questionnaire about headache and side effects was administered. Electrocardiography, heart rate, blood pressure, dermal blood flow, and diameter of peripheral arteries were monitored during the infusion. Participants were carefully instructed to fill out a headache questionnaire at home until 12 hours after the infusion start. Primary endpoints are difference between the sumatriptan day and the placebo day in area under the headache score curve (AUC) 0-2 hours after infusion start and in headache intensity 2 hours after infusion start. The study was conducted at the Danish Headache Center in Glostrup, Denmark. RESULTS: CGRP-induced headache in 86% (25/29) of the participants on the sumatriptan day and in 96% (28/29) of the participants on the placebo day. There was no difference in AUCheadache, 0-2 hours between the days (P = .794). There was a statistically significant decrease in mean atrial pressure (MAP) over time on both days with a16.2% reduction on the sumatriptan day and a 14.8% reduction on the placebo day (P < .001) and a statistically significant increase in heart rate (HR) over time on both days (from mean 57.5 at baseline to mean 105.4 at 120 minutes on the sumatriptan day and from mean 60.2 at baseline to 105.8 at 120 minutes on the placebo day, P < .001). The diameter of peripheral arteries increased statistically significant on both days (P < .001). CONCLUSION: 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.
Assuntos
Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Transtornos de Enxaqueca/induzido quimicamente , Transtornos de Enxaqueca/tratamento farmacológico , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Sumatriptana/farmacologia , Vasodilatadores/farmacologia , Adulto , Peptídeo Relacionado com Gene de Calcitonina/administração & dosagem , Estudos Cross-Over , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Sumatriptana/administração & dosagem , Resultado do Tratamento , Vasodilatadores/administração & dosagem , Adulto JovemRESUMO
BACKGROUND: In spite of the substantial therapeutic efficacy of triptans, their site of action is still debated. Subcutaneous sumatriptan is the most efficacious symptomatic treatment for cluster headache (CH) patients, showing therapeutic onset within a few minutes after injection even in migraine patients. However, whether subcutaneous sumatriptan is able to reach the CNS within this short time frame is currently unknown. METHODS: Here, by means of liquid chromatography/mass spectrometry, we investigated peripheral and brain distribution of subcutaneous sumatriptan soon after injection in rats at a dose equivalent to that used in patients. Tissue sumatriptan contents were compared to those of oxazepam, a prototypical lipophilic, neuroactive drug. RESULTS: We report that sumatriptan accumulated within brain regions of relevance to migraine and CH pathogenesis such as the hypothalamus and the brainstem as soon as 1 and 5 minutes after injection. Notably, sumatriptan brain distribution was faster than that of oxazepam, reaching concentrations exceeding its reported binding affinity for 5HT1B/D receptors, and in the range of those able to inhibit neurotransmitter release in vivo. CONCLUSION: 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.
Assuntos
Encéfalo/metabolismo , Cefaleia Histamínica/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/metabolismo , Sumatriptana/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Cromatografia Líquida/métodos , Cefaleia Histamínica/tratamento farmacológico , Injeções Subcutâneas , Masculino , Espectrometria de Massas/métodos , Ratos , Ratos Wistar , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Sumatriptana/administração & dosagem , Fatores de TempoRESUMO
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.
Assuntos
Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Modelos Biológicos , Povidona/química , Sumatriptana/farmacocinética , Administração Cutânea , Animais , Liberação Controlada de Fármacos , Agulhas , Pele/metabolismo , Absorção Cutânea , Sumatriptana/administração & dosagem , Suínos , Porco MiniaturaRESUMO
BACKGROUND AND OBJECTIVES: Cluster headache (CR) is the most severe human headache and is chronic in 10%-20% of patients, and 10% can become refractory to all effective drugs. In this scenario, surgical procedures are indicated: radiofrequencies of the sphenopalatine ganglion ipsilateral to pain (RF-SPG), bilateral stimulation of the occipital nerves (NOM-S) and deep brain stimulation (DBS) of the ipsilateral posterior hypothalamus. The efficacy and safety of each of these procedures has been specifically analyzed, but the progress of a series of patients following this surgical route in order of aggressiveness has not been described. PATIENTS: Patients with chronic and refractory CR according to the criteria of the European Headache Federation. The patients underwent RF-SPG, NOM-S sequentially if the previous procedure had been ineffective, and DBS if the previous procedure had been ineffective. RESULTS: We prospectively included 44 patients between November 2003 and June 2018 with an average age of 38.3 years; 70% were men. The mean follow-up was 87.4 months. Nineteen patients responded to 74 procedures of RF-SPG (33.3%). Of the remaining 25 patients, a NOM-S device was implanted in 22, showing an efficacy of 50%. Finally, 9 patients underwent ECP of the ipsilateral lower-posterior hypothalamus with an efficacy of 88.8%. No serious complications were found following any of these 3 procedures. CONCLUSIONS: The sequential application of these three surgical procedures succeeded in reversing the serious situation of chronic CR refractory to an episodic CR in 93% of patients with acceptable surgical morbidity.
Assuntos
Cefaleia Histamínica/terapia , Estimulação Encefálica Profunda/métodos , Denervação/métodos , Neuroestimuladores Implantáveis , Terapia por Radiofrequência/métodos , Adulto , Cefaleia Histamínica/cirurgia , Terapia por Estimulação Elétrica/métodos , Feminino , Gânglios Autônomos , Humanos , Hipotálamo Posterior , Masculino , Estudos Prospectivos , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Sumatriptana/administração & dosagem , Resultado do Tratamento , Nervo TrigêmeoRESUMO
This study focuses on the in vitro transdermal transport of sumatriptan succinate using combined iontophoresis and dissolving polymeric microneedle arrays. Permeation experiments were performed to evaluate the effects of formulation parameters on drug release from polyvinylpyrrolidone systems under mild electrical current (≤500 µA/cm2). The preparations consisted of hydrophilic, positively charged molecules encapsulated in a water-soluble and biocompatible polymeric material. Current densities of 100, 300, and 500 µA/cm2 were applied during a 6-h period using silver/silver chloride electrodes. The circular array consisted of 600 needles and occupied a 0.785 cm2 area. Tests, carried out with Franz diffusion cells and skin of Göttingen minipigs, showed that small decreases in the polymer concentration led to negligible lag times and marked increases in the cumulative amount of drug permeated in 6 h (Q6h) and in the flux (Jss). At 500 µA/cm2, Q6h and Jss nearly doubled for a microneedle loaded with 5% (w/w) sumatriptan and 20% (w/w) PVP (lag time = 0 min; Q6h = 2888 µg/cm2; Jss = 490 µg/cm2/h) relative to a system loaded with 5% (w/w) drug and 30% (w/w) PVP (lag time = 36 min; Q6h = 1437 µg/cm2; Jss = 266 µg/cm2/h).
Assuntos
Pele/metabolismo , Sumatriptana/administração & dosagem , Sumatriptana/metabolismo , Administração Cutânea , Animais , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Feminino , Iontoforese/métodos , Microinjeções/métodos , Agulhas , Povidona/química , Absorção Cutânea/efeitos dos fármacos , Solubilidade/efeitos dos fármacos , Suínos , Porco MiniaturaRESUMO
OBJECTIVE: To provide evidence-based recommendations for the acute symptomatic treatment of children and adolescents with migraine. METHODS: We performed a systematic review of the literature and rated risk of bias of included studies according to the American Academy of Neurology classification of evidence criteria. A multidisciplinary panel developed practice recommendations, integrating findings from the systematic review and following an Institute of Medicine-compliant process to ensure transparency and patient engagement. Recommendations were supported by structured rationales, integrating evidence from the systematic review, related evidence, principles of care, and inferences from evidence. RESULTS: There is evidence to support the efficacy of the use of ibuprofen, acetaminophen (in children and adolescents), and triptans (mainly in adolescents) for the relief of migraine pain, although confidence in the evidence varies between agents. There is high confidence that adolescents receiving oral sumatriptan/naproxen and zolmitriptan nasal spray are more likely to be headache-free at 2 hours than those receiving placebo. No acute treatments were effective for migraine-related nausea or vomiting; some triptans were effective for migraine-related phonophobia and photophobia. RECOMMENDATIONS: Recommendations for the treatment of acute migraine in children and adolescents focus on the importance of early treatment, choosing the route of administration best suited to the characteristics of the individual migraine attack, and providing counseling on lifestyle factors that can exacerbate migraine, including trigger avoidance and medication overuse.
Assuntos
Academias e Institutos/normas , Transtornos de Enxaqueca/tratamento farmacológico , Neurologia/normas , Guias de Prática Clínica como Assunto/normas , Sociedades Médicas/normas , Adolescente , Criança , Combinação de Medicamentos , Cefaleia/diagnóstico , Cefaleia/tratamento farmacológico , Cefaleia/epidemiologia , Humanos , Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/epidemiologia , Naproxeno/administração & dosagem , Relatório de Pesquisa/normas , Sumatriptana/administração & dosagem , Resultado do Tratamento , Estados Unidos/epidemiologiaRESUMO
INTRODUCTION: Postcraniotomy pain protocols use opioids, which are considered suboptimal analgesia following this procedure. Multimodal analgesia components are sparse. Our null hypothesis states that sumatriptan is not different to placebo in addition to usual intravenous opioids, for the treatment of acute postcraniotomy pain. METHODS AND ANALYSIS: This is a prospective single-centre randomised double-blinded placebo-controlled phase III clinical trial comparing subcutaneous sumatriptan injection in the recovery area with placebo for the treatment of postcraniotomy pain. Eligible adult patients (18 years and older) undergoing craniotomy will be identified preoperatively. Both patient groups will receive a subcutaneous injection at a point where recovery-nursing staff would initiate the usual intravenous opioid analgesia as per standardised pain management protocol. In both groups, further pain management will be followed by the usual intravenous opioid administration. Primary outcome will consist of the difference in pain experienced by the two groups of patients in recovery area 60 min after the study drug administration. Postcraniotomy pain will be measured at regular intervals using the Visual Analogue Scale (VAS) in recovery area. The minimal clinically important difference of 10 mm on the VAS between the two groups will be considered as statistically significant. We will include selected clinical and patient-reported outcomes as secondary endpoints. Univariate regression will be conducted on each one of the clinically plausible potential confounders. We will enrol a total 136 patients, with the study duration of 2 years. This trial will commence recruitment on the 1 July 2019. ETHICS AND DISSEMINATION: This trial protocol has achieved approval by the Austin Health Research Committee, HREC/17/Austin/596. This trial was prospectively registered with Australian New Zealand Clinical Trials Registry on the 10/05/2018 with a unique trial identifier U1111-1209-9072 and registration Number ACTRN12618000793213P. Findings of this study will be disseminated in peer-reviewed academic journals. TRIAL REGISTRATION NUMBER: U1111-1209-9072, ACTRN12618000793213P.
Assuntos
Analgésicos Opioides/administração & dosagem , Craniotomia/efeitos adversos , Manejo da Dor/métodos , Dor Pós-Operatória/tratamento farmacológico , Sumatriptana/administração & dosagem , Administração Intravenosa , Austrália , Ensaios Clínicos Fase III como Assunto , Método Duplo-Cego , Humanos , Injeções Subcutâneas , Medição da Dor , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Escala Visual AnalógicaRESUMO
This study was planned to evaluate the effects of sumatriptan, 5-HT1B/1D receptors agonist, on ischaemia/reperfusion injury in bilateral testes after unilateral testicular torsion/detorsion in rats. Male Wistar rats (n = 42) were allocated into a sham-operated group, a control group and treatment groups which were injected sumatriptan (0.1, 0.3 and 1 mg/kg), GR-127935 (0.01 mg/kg)-5-HT1B/1D receptors antagonist-and sumatriptan (0.1 mg/kg) + GR-127935 (0.01 mg/kg). Torsion was induced for 1 hr by rotating right testis 7200 in the clockwise direction, and after 7 days of detorsion, bilateral orchiectomy was conducted. While the level of TNF-α rose in testicular tissue after inducing torsion/detorsion, sumatriptan injection notably lowered TNF-α level in ipsilateral (torted) and contralateral (nontorted) testes (p < 0.001). Moreover, after inducing testicular torsion/detorsion, SOD activity was decreased, whereas administration of sumatriptan significantly increased SOD activity in bilateral testes (p < 0.001). After induction of torsion/detorsion, macroscopic and histological analyses also showed severe damages which were improved by sumatriptan injection. Interestingly, co-administration of sumatriptan with GR-127935 reversed the beneficial impacts of sumatriptan on macroscopic appearance, microscopic pattern and biochemical markers. It is concluded that sumatriptan presumably via stimulation of 5-HT1B/1D receptors decreased inflammation, oxidative stress and deteriorations induced by ischaemia/reperfusion injury following testicular torsion/detorsion.
Assuntos
Traumatismo por Reperfusão/tratamento farmacológico , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Torção do Cordão Espermático/complicações , Sumatriptana/administração & dosagem , Testículo/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Humanos , Masculino , Oxidiazóis/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Piperazinas/administração & dosagem , Ratos , Ratos Wistar , Receptor 5-HT1B de Serotonina/metabolismo , Receptor 5-HT1D de Serotonina/metabolismo , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/patologia , Antagonistas da Serotonina/administração & dosagem , Superóxido Dismutase/metabolismo , Testículo/patologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Nanoformulations in the past few decades have gained tremendous attention owing to their affirmative applications in increasing the bioavailability of poorly soluble drugs. Micelles in particular are favored due to their varied advantages which include thermodynamic stability, simple formulating steps, Newtonian flow, and enhanced biological barrier penetration. Owing to these advantages micellar nanosystems find extensive applications in oral, transdermal, and parenteral administration, and are now being explored for ocular and other noninvasive novel pathways of drug delivery such as nose to brain. In this chapter, we have discussed the protocol for the preparation of sumatriptan loaded micelles for the therapy of migraine. The inner core of these micelles comprises hydrophobic region of diblock polymer which holds the drug, while the hydrophilic region of the same provides conformational stability in the aqueous environment.