RESUMO
ABSTRACT: INTRODUCTION: Nurses have a central role in educating patients and families about treatment options and how to integrate them into action plans for neurologic conditions. In recent years, a growing number of intranasal formulations have become available as rescue therapy for neurologic conditions or symptoms including migraine, opioid overdose, and seizures. Rescue therapies do not replace maintenance medications or emergency care but are designed to enable rapid treatment of urgent or disabling conditions in community settings. Yet, discussion of rescue therapies for neurologic conditions remains limited in nursing literature. CONTENT: Intranasal formulations are specifically formulated for delivery and absorption in the nose and have several characteristics that are well suited as rescue therapies for neurologic conditions. Intranasal formulations include triptans for migraine, naloxone and nalmefene for opioid overdose, and benzodiazepines for seizure clusters in patients with epilepsy. Therapeutic attributes discussed here include ease of use in community settings by nonmedical professionals, relatively rapid onset of action, and favorable safety profile and patient experience. This information is critical for nurses to make informed decisions about rescue therapy options, incorporate these into plans of care, and educate patients, care partners, and other healthcare providers. CONCLUSION: Rescue therapies are increasingly important in the care of people with neurologic conditions. Various formulations are available and continue to evolve, offering easy and quick ways for nurses, patients, and nonmedical care partners to administer critical rescue medications. For nurses overseeing medication management, the attributes of intranasal rescue therapies should be considered in the context of providing patients with the right care at the right time.
Assuntos
Administração Intranasal , Doenças do Sistema Nervoso , Humanos , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/antagonistas & inibidores , Benzodiazepinas/administração & dosagem , Benzodiazepinas/uso terapêutico , Naloxona/administração & dosagem , Naloxona/uso terapêutico , Antagonistas de Entorpecentes/administração & dosagem , Antagonistas de Entorpecentes/uso terapêutico , Doenças do Sistema Nervoso/induzido quimicamente , Doenças do Sistema Nervoso/tratamento farmacológico , Triptaminas/uso terapêutico , Triptaminas/administração & dosagemRESUMO
Background: Psilocybin and related tryptamines have come into the spotlight in recent years as potential therapeutics for depression. Research on the mechanisms of these effects has historically focused on the direct effects of these drugs on neural processes. However, in addition to such neural effects, alterations in peripheral physiology may also contribute to their therapeutic effects. In particular, substantial support exists for a gut microbiome-mediated pathway for the antidepressant efficacy of other drug classes, but no prior studies have determined the effects of tryptamines on microbiota. Methods: To address this gap, in this preliminary study, male Long Evans rats were treated with varying dosages of oral psilocybin (0.2 or 2 mg/kg), norbaeocystin (0.25 or 2.52 mg/kg), or vehicle and their fecal samples were collected 1 week and 3 weeks after exposure for microbiome analysis using integrated 16S ribosomal DNA sequencing to determine gut microbiome composition. Results: We found that although treatment with neither psilocybin nor norbaeocystin significantly affected overall microbiome diversity, it did cause significant dose- and time-dependent changes in bacterial abundance at the phylum level, including increases in Verrucomicrobia and Actinobacteria, and decreases in Proteobacteria. Conclusion and Implications: These preliminary findings support the idea that psilocybin and other tryptamines may act on the gut microbiome in a dose- and time-dependent manner, potentially identifying a novel peripheral mechanism for their antidepressant activity. The results from this preliminary study also suggest that norbaeocystin may warrant further investigation as a potential antidepressant, given the similarity of its effects to psilocybin.
Assuntos
Fezes , Microbioma Gastrointestinal , Ratos Long-Evans , Triptaminas , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Masculino , Triptaminas/farmacologia , Triptaminas/administração & dosagem , Ratos , Fezes/microbiologia , Psilocibina/farmacologia , Psilocibina/administração & dosagem , Administração Oral , Antidepressivos/farmacologia , Antidepressivos/administração & dosagemRESUMO
AIM: Treatment for cluster headache is currently based on a trial-and-error approach. The available preventive treatment is unspecific and based on few and small studies not adhering to modern standards. Therefore, the authors collaborated to discuss acute and preventive treatment in cluster headache, addressing the unmet need of safe and tolerable preventive medication from the perspectives of people with cluster headache and society, headache specialist and cardiologist. FINDINGS: The impact of cluster headache on personal life is substantial. Mean annual direct and indirect costs of cluster headache are more than 11,000 Euros per patient. For acute treatment, the main problems are treatment response, availability, costs and, for triptans, contraindications and the maximum use allowed. Intermediate treatment with steroids and greater occipital nerve blocks are effective but cannot be used continuously. Preventive treatment is sparsely studied and overall limited by relatively low efficacy and side effects. Neurostimulation is a relevant option for treatment-refractory chronic patients. From a cardiologist's perspective use of verapamil and triptans may be worrisome and regular follow-up is essential when using verapamil and lithium. CONCLUSION: We find that there is a great and unmet need to pursue novel and targeted preventive modalities to suppress the horrific pain attacks for people with cluster headache.
Assuntos
Cefaleia Histamínica , Consenso , Medicina Preventiva , Humanos , Cefaleia Histamínica/tratamento farmacológico , Cefaleia Histamínica/prevenção & controle , Cefaleia Histamínica/terapia , Europa (Continente) , Compostos de Lítio/farmacologia , Compostos de Lítio/uso terapêutico , Dietilamida do Ácido Lisérgico/uso terapêutico , Oxigênio/uso terapêutico , Pacientes/psicologia , Médicos , Prednisona/uso terapêutico , Medicina Preventiva/métodos , Medicina Preventiva/tendências , Psilocibina/farmacologia , Psilocibina/uso terapêutico , Topiramato/farmacologia , Topiramato/uso terapêutico , Triptaminas/administração & dosagem , Triptaminas/uso terapêutico , Verapamil/farmacologia , Verapamil/uso terapêuticoRESUMO
PURPOSE: The present report describes findings from a Phase I clinical study that evaluated the single- and multiple-dose pharmacokinetics of frovatriptan succinate tablet in Chinese healthy subjects. METHODS: A total of 24 healthy subjects were enrolled. In single-dose study, 2.5, 5, and 10 mg oral doses of frovatriptan succinate tablet were administrated. A 2.5 mg frovatriptan succinate tablet was administrated 12 times in 7 days in the multiple-dose study. Blood samples were collected at scheduled time points. RESULTS: The results in single-dose study indicated that the blood levels were proportional to the administered dose, with the mean Cmax and AUClast ranging from approximately 6.27 ng/mL-17.35 ng/mL and 92.52 hâ ng/mL - 287.40 hâ ng/mL over the dose range. In the multiple-dose study, moderate drug accumulation was noted, which was attributable to forvatriptan's long t1/2 of about 26.47 to 30.63 h. Gender differences were noticed in both single- and multiple-dose study; exposure PK parameters were consistently higher in female than in male. CONCLUSION: These pharmacokinetic evaluations in healthy Chinese subjects found that frovatriptan succinate tablet has an acceptable pharmacokinetic profile in Chinese subjects.
Assuntos
Povo Asiático , Carbazóis/administração & dosagem , Agonistas do Receptor de Serotonina/administração & dosagem , Triptaminas/administração & dosagem , Administração Oral , Adulto , Área Sob a Curva , Carbazóis/farmacocinética , Estudos Cross-Over , Relação Dose-Resposta a Droga , Feminino , Meia-Vida , Humanos , Masculino , Agonistas do Receptor de Serotonina/farmacocinética , Fatores Sexuais , Comprimidos , Fatores de Tempo , Triptaminas/farmacocinética , Adulto JovemRESUMO
Cluster headache is a debilitating primary headache disorder that affects approximately 0.1% of the population worldwide. Cluster headache attacks involve severe unilateral pain in the trigeminal distribution together with ipsilateral cranial autonomic features and a sense of agitation. Acute treatments are available and are effective in just over half of the patients. Until recently, preventive medications were borrowed from non-headache indications, so management of cluster headache is challenging. However, as our understanding of cluster headache pathophysiology has evolved on the basis of key bench and neuroimaging studies, crucial neuropeptides and brain structures have been identified as emerging treatment targets. In this Review, we provide an overview of what is known about the pathophysiology of cluster headache and discuss the existing treatment options and their mechanisms of action. Existing acute treatments include triptans and high-flow oxygen, interim treatment options include corticosteroids in oral form or for greater occipital nerve block, and preventive treatments include verapamil, lithium, melatonin and topiramate. We also consider emerging treatment options, including calcitonin gene-related peptide antibodies, non-invasive vagus nerve stimulation, sphenopalatine ganglion stimulation and somatostatin receptor agonists, discuss how evidence from trials of these emerging treatments provides insights into the pathophysiology of cluster headache and highlight areas for future research.
Assuntos
Encéfalo/fisiopatologia , Cefaleia Histamínica/fisiopatologia , Cefaleia Histamínica/terapia , Corticosteroides/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Biomarcadores/sangue , Encéfalo/efeitos dos fármacos , Cefaleia Histamínica/sangue , Terapia por Estimulação Elétrica/tendências , Humanos , Oxigenoterapia/tendências , Triptaminas/administração & dosagem , Estimulação do Nervo Vago/tendênciasRESUMO
PURPOSE: Zolmitriptan (ZT) is a selective serotonin agonist that is used for the treatment of migraine. It belongs to BCS class III with high solubility and low permeability. Besides, the drug is subjected to pre-systemic metabolism. Accordingly, new Zolmitriptan/chitosan nanostructured lipid carriers (ZT/CT NLCs) coated with Tween 80 (stealthy layer) have been developed to overcome such demerits. METHODS: The NLCs were developed by combining ultrasonication and double emulsion (w/o/w) techniques. The lipids were Gelucire and Labrasol. Herein, the quality by design (23 full factorial design) was scrupulously followed, where critical process parameters and critical quality attributes were predefined. The optimized formulation (F8) was fully characterized with respect to entrapment efficiency (%EE), percentage yield (% yield), particle size, size distribution (PDI), zeta potential (ZP), morphological appearance (TEM). In vitro release, stability study and pharmacodynamic evaluations were also assessed. The optimized freeze dried formula was dispensed in in situ gelling hard gelatin capsule encompassing pectin and guar gum for further in vitro and pharmacodynamic evaluations. RESULTS: The optimized spherical nanoparticles experienced high percentage EE and yield (78.14% and 60.19%, respectively), low particle size and PDI (343.87 nm and 0.209, respectively), as well as high negative ZP (-25.5 mV). It showed good physical stability at refrigerated conditions. The NLCs dispensed in in situ gelling hard gelatin capsule comprising pectin and guar gum experienced sustained release for 30 h and significantly maintained the pharmacological effect in mice up to 8 h (p < 0.001). CONCLUSION: ZT, a BCS class III drug that suffers from poor permeability and pre-systemic metabolism, was successfully maneuvered as nanostructured lipid carrier particles (NLCs). The incorporation of the NLCs in in situ gelling hard gelatin capsules fulfilled a dual function in increasing permeability, as well as sustaining the pharmacodynamic effect. This result would open new vistas in improving the efficacy of other class III drugs.
Assuntos
Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Lipídeos/química , Nanoestruturas/química , Oxazolidinonas/farmacocinética , Triptaminas/farmacocinética , Animais , Cápsulas , Quitosana/química , Portadores de Fármacos/administração & dosagem , Emulsões/química , Gelatina/química , Masculino , Camundongos , Nanopartículas/química , Oxazolidinonas/administração & dosagem , Oxazolidinonas/química , Tamanho da Partícula , Pectinas/química , Polissorbatos/química , Solubilidade , Triptaminas/administração & dosagem , Triptaminas/química , Ultrassom/métodosRESUMO
OBJECTIVE: This study describes the approaches, medications used, and time of care for migraineurs, who have been in emergency departments (ED) from 2 different regions of Brazil. METHODS: Retrospective, cross-sectional, observational, non-randomized study of migraine patients seen at 2 headache centers in Brazil. RESULTS: Eighty-four migraine patients (15 men and 69 women) were divided into 2 groups: chronic (19%, n = 16) and episodic migraineurs (81%, n = 68). In the ED, medications were used in the following order of frequency: dipyrone or metamizole (89.3%, 75/84), nonsteroidal anti-inflammatory drugs (57.1%; 48/84) opioids (51.1%; 43/84), metoclopramide (29.8%; 25/84), dexamethasone (28.6%; 24/84), chlorpromazine (13.1%; 11/84), and subcutaneous sumatriptan (7.1%; 6/84). The average time in the care center was 8.2 hours, but only 23 patients (27.4%) left the hospital with greater than 50% relief in headache severity. CONCLUSIONS: Dipyrone and nonsteroidal anti-inflammatories were the most used drugs, but nearly half received opioids. More efficient drugs were poorly used. Considering the number of patients leaving the hospital with headache relief, a changing treatment paradigm should be carried out in Brazil.
Assuntos
Analgésicos Opioides/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Dipirona/uso terapêutico , Antagonistas dos Receptores de Dopamina D2/uso terapêutico , Serviço Hospitalar de Emergência/estatística & dados numéricos , Glucocorticoides/uso terapêutico , Transtornos de Enxaqueca/tratamento farmacológico , Triptaminas/uso terapêutico , Adulto , Brasil , Doença Crônica , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Triptaminas/administração & dosagem , Adulto JovemRESUMO
The electrospinning process is a promising approach to produce various drug-loaded orodispersible films (ODFs) with a rapid onset of their actions. However, there is only limited number of studies comparing the pharmacological performances of electrospun ODFs (eODFs) with traditional casting films (CFs). In this study, rizatriptan benzoate (RB), a pain relieving agent was formulated with PVP and PVA into ODFs using electrospinning and casting methods. The ODFs were subsequently characterized with respect to their morphology, solid state properties and mechanical characteristics. The uniformity of the dosage units, disintegration behavior and dissolution patterns of the ODFs were also evaluated prior to the pharmacokinetic study. The obtained CFs and eODFs were semitransparent and white in appearance, respectively. The scanning electron microscopy revealed that the eODFs contained nanoporous structure, while the CFs showed no observable pores. RB was amorphously dispersed in both these films without drug-polymer interactions. The uniformity of dosage units for both eODFs and CFs was complied with European Pharmacopeia. As compared to the CFs, the eODFs were more flexible and lesser rigid in nature and showed faster disintegration and dissolution rates. In addition, the eODFs exhibited a higher bioavailability with a shorter Tmax relative to the CFs and commercial RB tablets. This study demonstrated that eODFs were superior to CFs with respect to in vivo pharmacological effects, which could be attributed to the submicron structure of eODFs obtained through the electrospinning process.
Assuntos
Química Farmacêutica/métodos , Portadores de Fármacos/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Triazóis/metabolismo , Triptaminas/metabolismo , Administração Oral , Animais , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Agonistas do Receptor de Serotonina/administração & dosagem , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/metabolismo , Triazóis/administração & dosagem , Triazóis/química , Triptaminas/administração & dosagem , Triptaminas/química , Difração de Raios X/métodosRESUMO
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
Background: Eletriptan is a migraine-specific drug-containing the triptan group. In terms of drug safety, the present study aimed to investigate the genotoxic potential of eletriptan.Research design & methods: We conducted our study by using the cytokinesis-block micronucleus cytome (CBMN) assay, a comprehensive method for measuring micronucleus formation, and a sensitive method for detecting DNA-strand breaks. In the assay, cytokinesis-block proliferation index and the frequency of micronuclei were evaluated in lymphocytes treated with three different concentrations (1, 10 and 25 µg/ml) of eletriptan for 48 hours. In comet assays, DNA damage was evaluated in leucocytes treated with three different concentrations (1, 10 and 25 µg/ml) of eletriptan for an hour.Results: Eletriptan did not induce cytotoxicity nor any increased micronuclei frequencies. While the comet parameters % DNA in tail, tail moment, and the olive moment was found to be significantly increased at 10 and 25 µg/ml, the cytokinesis-block proliferation index values were not.Conclusion: These findings suggest that eletriptan is non-cytotoxic but potentially weakly genotoxic at higher concentrations (10 and 25 µg/ml).
Assuntos
Dano ao DNA/efeitos dos fármacos , Pirrolidinas/efeitos adversos , Agonistas do Receptor de Serotonina/efeitos adversos , Triptaminas/efeitos adversos , Adulto , Células Cultivadas , Ensaio Cometa , Citocinese/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Leucócitos/efeitos dos fármacos , Leucócitos/patologia , Linfócitos/efeitos dos fármacos , Linfócitos/patologia , Masculino , Testes para Micronúcleos , Pirrolidinas/administração & dosagem , Agonistas do Receptor de Serotonina/administração & dosagem , Triptaminas/administração & dosagemAssuntos
Analgésicos/uso terapêutico , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/uso terapêutico , Transtornos de Enxaqueca/tratamento farmacológico , Triptaminas/uso terapêutico , Terapia por Acupuntura , Adulto , Analgésicos/administração & dosagem , Analgésicos/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Antieméticos/efeitos adversos , Antieméticos/uso terapêutico , Interações Medicamentosas , Alcaloides de Claviceps/efeitos adversos , Alcaloides de Claviceps/uso terapêutico , Feminino , Humanos , Transtornos de Enxaqueca/prevenção & controle , Gravidez , Antagonistas do Receptor 5-HT1 de Serotonina/uso terapêutico , Triptaminas/administração & dosagem , Triptaminas/efeitos adversosRESUMO
BACKGROUND: Lasmiditan demonstrated superiority to placebo in the acute treatment of migraine in adults with moderate/severe migraine disability in two similarly designed Phase 3 trials, SAMURAI and SPARTAN. Post-hoc integrated analyses evaluated the efficacy of lasmiditan in patients who reported a good or insufficient response to triptans and in those who were triptan naïve. METHODS: Subgroups of patients reporting an overall response of "good" or "poor/none" to the most recent use of a triptan at baseline (defined as good or insufficient responders, respectively) and a triptan-naïve subpopulation were derived from combined study participants randomized to receive lasmiditan 50 mg (SPARTAN only), 100 mg or 200 mg, or placebo, as the first dose. Outcomes including headache pain-freedom, most bothersome symptom-freedom, and headache pain relief 2 hours post-first dose of lasmiditan were compared with placebo. Treatment-by-subgroup analyses additionally investigated whether therapeutic benefit varied according to prior triptan response (good or insufficient). RESULTS: Regardless of triptan response, lasmiditan showed higher efficacy than placebo (most comparisons were statistically significant). Treatment-by-subgroup analyses found that the benefit over placebo of lasmiditan did not vary significantly between patients with a good response and those with an insufficient response to triptans. Lasmiditan also showed higher efficacy than placebo in triptan-naïve patients. CONCLUSIONS: Lasmiditan demonstrated comparable efficacy in patients who reported a good or insufficient response to prior triptan use. Lasmiditan also showed efficacy in those who were triptan naïve. Lasmiditan may be a useful therapeutic option for patients with migraine. TRIAL REGISTRATION: SAMURAI (NCT02439320); SPARTAN (NCT02605174).
Assuntos
Benzamidas/administração & dosagem , Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/tratamento farmacológico , Piperidinas/administração & dosagem , Piridinas/administração & dosagem , Agonistas do Receptor de Serotonina/administração & dosagem , Triptaminas/administração & dosagem , Adulto , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
INTRODUCTION: Migraine has recently become a major interest to the neuroscientists. Zolmitriptan is an effective medicine used in the treatment of migraine. The nasal spray was prepared from Zolmitriptan loaded chitosan nanoparticles and evaluated for pharmacokinetic properties. METHODS: In this study male Wistar albino rats weighing between 200 and 250â¯g were taken and divided into 4 groups with 6 rats in each group. Nasal spray containing Zolmitriptan loaded Chitosan nanoparticles were administered nasally (using specific inhalation mask) at a dose of 0.5â¯mg/kg as a test formulation and compared with the control groups which received either water for injection or marketed standard drug (Zolmist) or standard drug solution at a same dose. The pharmacokinetic parameters such as Cmax, Tmax, and brain tissue analyses for accumulation of drug were performed for Zolmitriptan by LC-MS method. RESULTS: Amount of drug in the plasma from the test formulation, standard marketed drug (Zolmist) and standard drug solution was found to be 41.37⯱â¯2.31, 34.76⯱â¯4.22 and 23.74⯱â¯2.42â¯ng/ml at 10â¯min respectively, which indicated significantly (pâ¯<â¯0.05) greater amount of drug being delivered from the test formulation compared to the both standard groups. The amount of the drug (Zolmitriptan) present in brain tissue (Olfactory lobe) was found to be 15⯱â¯0.08, 13⯱â¯0.14 and 8⯱â¯0.13â¯ng/g at 60â¯min for test formulation, marketed standard and standard drug solution respectively which indicates significantly (pâ¯<â¯0.05) higher amount of drug absorption in brain tissue from the test formulation compared to both the standard groups. CONCLUSION: Pharmacokinetics studies of nasal spray containing Zolmitriptan loaded chitosan nanoparticles proved rapid onset of action in animals and is promising in treatment of migraine.
Assuntos
Encéfalo/efeitos dos fármacos , Quitosana/farmacocinética , Nanopartículas/química , Oxazolidinonas/farmacocinética , Triptaminas/farmacocinética , Administração Intranasal/instrumentação , Administração Intranasal/métodos , Animais , Encéfalo/patologia , Quitosana/administração & dosagem , Cromatografia Líquida , Modelos Animais de Doenças , Masculino , Transtornos de Enxaqueca/tratamento farmacológico , Oxazolidinonas/administração & dosagem , Tamanho da Partícula , Ratos , Ratos Wistar , Espectrometria de Massas em Tandem , Triptaminas/administração & dosagemRESUMO
OBJECTIVE: To develop and evaluate zolmitriptan spanlastics (Zol SLs) as a brain-targeted antimigraine delivery system. Spanlastics (SLs) prepared using span 60: tween 80 (70:30%, respectively) gave the highest percentage of entrapment efficiency (EE%). MATERIALS AND METHODS: A total of 60 adult male Wistar albino rats were divided into six groups (n=10 rats/group). Group 1 (Control) comprised rats serving as a negative control. Group 2 was treated with glyceryl trinitrate (NTG) and served as the positive control. Groups 3 (NTG+Zol com), Group 4 (NTG+Zol sol) and Group 5 (NTG+Zol SLs) received commercial zolmitriptan orally, zolmitriptan solution intranasally and Zol SLs F5 intranasally, respectively, 30 min before NTG. Group 6 (Zol SLs) comprised normal rats that received only Zol SLs intranasally. RESULTS: We found decreased Tmax, increased Cmax, AUC0-6, AUC0-∞ and ameliorated behaviour in rats (head scratching) treated with intranasal SLs compared to oral commercial zolmitriptan. CONCLUSION: Our study substantiates the enhanced efficacy of Zol SLs in brain targeting for migraine treatment.
Assuntos
Transtornos de Enxaqueca/tratamento farmacológico , Oxazolidinonas/uso terapêutico , Agonistas do Receptor 5-HT1 de Serotonina/uso terapêutico , Triptaminas/uso terapêutico , Administração Intranasal , Animais , Injeções Intraperitoneais , Masculino , Transtornos de Enxaqueca/induzido quimicamente , Nitroglicerina/administração & dosagem , Oxazolidinonas/administração & dosagem , Oxazolidinonas/sangue , Ratos , Ratos Wistar , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Agonistas do Receptor 5-HT1 de Serotonina/sangue , Triptaminas/administração & dosagem , Triptaminas/sangueRESUMO
Rizatriptan produces antimigraine activity by acting as selective agonist of 5-HT1B and 5-HT1D receptors present on intracranial and extracerebral blood vessels. Absorption from oral tablet is slow with Tmax of approximately 1-1.5â¯h. A few attempts have been made to promote rapid absorption such as oral or sublingual films with limited success. The aim of our study was to develop intranasal spray formulation of rizatriptan with quick onset of action. Solubility was enhanced by a co-solvent system where we studied solubility of rizatriptan benzoate in pure solvents, binary and ternary mixtures. Binary and ternary co-solvents using ethanol, water, propylene glycol and polyethylene glycol resulted rizatriptan equivalent base solubility more than 60â¯mg/mL. Same co-solvents were used at different level to make nasal spray formulations and evaluated pharmacokinetics using beagle dog animal model. Nasal spray formulation containing 20% w/w ethanol exhibited highest exposure, where Cmax (312â¯ng/mL) reached in 5â¯min and maintained higher concentration than oral dose for more than 30â¯min.
Assuntos
Composição de Medicamentos/métodos , Transtornos de Enxaqueca/tratamento farmacológico , Solventes/química , Triazóis/administração & dosagem , Triptaminas/administração & dosagem , Administração Intranasal , Administração Oral , Animais , Área Sob a Curva , Cápsulas , Cães , Etanol/química , Humanos , Modelos Animais , Polietilenoglicóis/química , Propilenoglicol/química , Solubilidade , Fatores de Tempo , Triazóis/química , Triazóis/farmacocinética , Triptaminas/química , Triptaminas/farmacocinética , Água/químicaAssuntos
Agonistas de Dopamina/administração & dosagem , Transtornos de Enxaqueca/tratamento farmacológico , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Administração por Inalação , Administração Intranasal/instrumentação , Administração Intranasal/tendências , Barreira Hematoencefálica/metabolismo , Di-Hidroergotamina/administração & dosagem , Agonistas de Dopamina/farmacocinética , Humanos , Inaladores Dosimetrados , Oxazolidinonas/administração & dosagem , Agonistas do Receptor 5-HT1 de Serotonina/farmacocinética , Triptaminas/administração & dosagemRESUMO
All patients with migraine merit acute treatment, which should optimally achieve a sustained pain-free response. Maximum acute treatment is associated with reduced risk of transformation of episodic to chronic migraine. The American Headache Society published the most recent complete evidence assessment of acute migraine treatments in 2015. Noninvasive neuromodulation represents a new, Food and Drug Administration-approved nonsignificant risk alternative for acute migraine therapy. The future of acute migraine treatment includes new devices and formulations of existing medications, new classes of acute medications, and new noninvasive nonsignificant risk neuromodulation devices, with many anticipated in the next few years.
Assuntos
Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/tratamento farmacológico , Medidas de Resultados Relatados pelo Paciente , Analgésicos/administração & dosagem , Quimioterapia Combinada , Humanos , Resultado do Tratamento , Triptaminas/administração & dosagemRESUMO
This article outlines key features of diagnosis and treatment of migraine in children and adolescents. It emphasizes techniques that can be used by clinicians to optimize history taking in this population, as well as recognition of episodic conditions that may be associated with migraine and present in childhood. Acute treatment strategies include use of over-the-counter analgesics and triptan medications that have been approved by the US Food and Drug Administration for use in children and adolescents. Preventive treatment approach includes lifestyle modifications, behavioral strategies, and consideration of preventive medications with the lowest side effect profiles.
Assuntos
Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/terapia , Adolescente , Analgésicos/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Terapia Comportamental/métodos , Criança , Humanos , Transtornos de Enxaqueca/psicologia , Triptaminas/administração & dosagemRESUMO
The aim of the present study was to investigate and compare the effects of acute and chronic (21-day) administration of agonist (WAY-181187) and antagonist (SB-742457) of the 5-hydroxytryptamine 6 receptor (5-HT6R) on MK-801-induced memory impairments in novel object recognition (NORT) and Y-maze continuous spontaneous alternation tests (Y-CAT). Further, the expression of the brain-derived neurotrophic factor (BDNF) in rat hippocampus was measured after 21-day administration to investigate BDNF participation in the pro-cognitive effects of 5-HT6R ligands. We found that acute administration of WAY-181187, as well as SB-742457, reversed the effects of MK-801 in NORT and Y-CAT, and that this influence persisted after prolonged application in NORT but not in Y-CAT. Both 5-HT6R ligands increased hippocampal BDNF protein expression, but WAY-181187 was much more potent than SB-742457 and alleviated the MK-801-induced inhibition of BDNF signaling pathways better, which seems to translate into a stronger WAY-181187 effect in behavioral tests. Collectively, both the 5-HT6R agonist and the antagonist, administered acutely and chronically, prevent memory impairments and alterations in BDNF signaling induced by MK-801 in rats. The present results confirm the pro-cognitive properties of both types of 5-HT6R ligands and suggest that BDNF pathways may be involved in their mechanism of action.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Memória/efeitos dos fármacos , Memória/fisiologia , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/administração & dosagem , Agonistas do Receptor de Serotonina/administração & dosagem , Animais , Maleato de Dizocilpina/administração & dosagem , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Masculino , Quinolinas/administração & dosagem , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Sulfonas/administração & dosagem , Tiazóis/administração & dosagem , Triptaminas/administração & dosagemRESUMO
OBJECTIVES: This study aimed to establish a pharmacodynamic model to quantitatively compare the efficacy characteristics of seven kinds of triptans and their different dosage forms in the treatment of acute migraines. METHODS: Clinical studies of triptans in the treatment of acute migraines were comprehensively searched in the public databases. Pharmacodynamic models were established to describe the dose-effect and time-course of each kind of triptan for the proportion of patients who became pain free or had pain relief. RESULTS: A total of 92 articles involving 47,376 subjects were included in the analysis. After eliminating the placebo effect, oral eletriptan (40 mg) had the highest efficacy among all oral drugs at the maximum approved dose, and the proportion of patients who became pain free and had pain relief were 30.9% and 37.9% at 2 h, respectively. However, oral naratriptan (2.5 mg) had the lowest efficacy, and the proportion of patients who became pain free and had pain relief was 10.3% and 21.6% at 2 h, respectively. The efficacy of subcutaneous administration was significantly higher than that of oral administration, and the efficacy of nasal spray administration was comparable to that of oral administration. Regarding the dose-effect, the efficacy of the sumatriptan nasal spray significantly increased within the FDA (Food and Drug Administration)-approved dose range. When the dose was increased from 5 to 20 mg of sumatriptan nasal spray, the proportion of patients who became pain free and had pain relief increased by 16.8% and 18.3% at 2 h, respectively. Regarding the time-course, the time of onset of subcutaneous sumatriptan (6 mg) was the fastest, and the fraction of patients who were pain free at 2 h accounted for 90.6% of that at 4 h. CONCLUSIONS: This study evaluated the efficacy characteristics of seven kinds of triptans and their different dosage forms. The present findings provide necessary quantitative information for migraine medication guidelines.