RESUMO
"Migraine associated vertigo" is emerging as a popular diagnosis for patients with recurrent vertigo. However, in view of our current understanding of both migraine and vertigo, "migraine associated vertigo," in contrast to basilar artery migraine, is neither clinically nor biologically plausible as a migraine variant.
Assuntos
Transtornos de Enxaqueca/complicações , Transtornos de Enxaqueca/fisiopatologia , Vertigem/etiologia , Vertigem/fisiopatologia , Humanos , Transtornos de Enxaqueca/diagnóstico , Recidiva , Insuficiência Vertebrobasilar/complicações , Insuficiência Vertebrobasilar/diagnóstico , Insuficiência Vertebrobasilar/fisiopatologia , Vertigem/diagnósticoRESUMO
Glucagon-like peptide 1 (GLP-1) is a 30 or 31 amino acid peptide hormone that contributes to the physiological regulation of glucose homeostasis and food intake. Herein, we report the discovery of a novel class of 11 amino acid GLP-1 receptor agonists. These peptides consist of a structurally optimized 9-mer, which is closely related to the N-terminal 9 amino acids of GLP-1, linked to a substituted C-terminal biphenylalanine (BIP) dipeptide. SAR studies resulted in 11-mer GLP-1R agonists with similar in vitro potency to the native 30-mer. Peptides 21 and 22 acutely reduced plasma glucose excursions and increased plasma insulin concentrations in a mouse model of diabetes. These peptides also showed sustained exposures over several hours in mouse and dog models. The described 11-mer GLP-1 receptor agonists represent a new tool in further understanding GLP-1 receptor pharmacology that may lead to novel antidiabetic agents.
Assuntos
Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Receptores de Glucagon/agonistas , Sequência de Aminoácidos , Animais , Células CHO , Cricetinae , Cricetulus , Cães , Relação Dose-Resposta a Droga , Receptor do Peptídeo Semelhante ao Glucagon 1 , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacocinética , Masculino , Camundongos , Modelos Moleculares , Dados de Sequência Molecular , Oligopeptídeos/síntese química , Oligopeptídeos/farmacocinética , Conformação ProteicaRESUMO
BACKGROUND: The buildup time of migraine headaches has not been well delineated in publications to date and we are aware of patients whose migraines last well over 72 hours. More concentration on these factors in the assessment of patients might lead to more appropriate therapeutic choices. METHOD: Prospective ascertainment of such data through a questionnaire completed by 253 informed and willing patients with IHS migraine with or without aura consulting Canadian headache specialists. Data were electronically sent to a central computer from each center, tabulated and analyzed using standard statistical parameters. RESULTS: In 253 patients with migraine ascertained using applied IHS criteria, nausea was a feature in over 90% of cases, especially in those with aura. This inhibited the ingestion of oral medications in about a quarter of all subjects. The time to build from no pain to moderate/severe pain was shorter in subjects with auras and was less than 2 hours in 97% of those with and 86% of those without auras. However, we also identified a group of subjects with migraine (over 10% of all) in whom the build time to maximum pain is delayed for over 2 hours. Nausea was experienced by 91.7% of subjects, slightly but significantly later in those without auras. While most headaches in each group lasted from 4 to 72 hours, 24.3% of those with and 20.6% of those without aura expected to experience pain for more than 72 hours, while in untreated cases disability due to pain, nausea, or malaise usually persisted for over 3 days in 24.3% and 16.7% of those with and without aura, respectively. One-fifth of migraineurs may be in pain and/or disabled by accompanying symptoms for over 3 days in a typical migraine attack. Over half of our subjects reported that their medications worked well or excellently. CONCLUSIONS: Attacks of migraine in real-life clinical situations vary somewhat from the IHS criteria in that they are more often associated with nausea that interferes with oral therapy; can persist for over 72 hours; may have slow (>2 hours) buildup to maximum pain in 10% of cases; and may cause disability for over 3 days. Nevertheless, current therapeutic regimens (including prescribed medications) work well for a substantial majority.
Assuntos
Enxaqueca com Aura/fisiopatologia , Enxaqueca sem Aura/fisiopatologia , Adulto , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Enxaqueca com Aura/complicações , Enxaqueca com Aura/tratamento farmacológico , Enxaqueca sem Aura/complicações , Enxaqueca sem Aura/tratamento farmacológico , Náusea/epidemiologia , Náusea/etiologia , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: To report the clinical findings of 10 patients diagnosed with pseudomigraine with lymphocytic pleocytosis and the results of mutational analysis of the CACNA1A gene in 8 of these patients. BACKGROUND: Pseudomigraine with lymphocytic pleocytosis, also referred to as headache with neurologic deficits and cerebrospinal fluid lymphocytosis (HaNDL), is characterized by episodic transient neurologic dysfunction associated with moderate to severe headache and cerebrospinal fluid lymphocytic pleocytosis. Episodes are recurrent and the condition is self-limiting. The etiology of this sporadic condition remains unknown, but the episodic nature and its ability to be triggered by angiography is somewhat reminiscent of the phenotypic features of familial hemiplegic migraine, a condition caused by mutations in the CACNA1A gene. DESIGN/METHODS: Utilizing retrospective chart review, we describe the clinical features of pseudomigraine with lymphocytic pleocytosis in 10 patients. Whole blood was taken from 8 patients (2 were lost to follow-up) and used for DNA testing. The CACNA1A gene was screened for mutations using heteroduplex analysis and direct DNA sequencing. RESULTS: Clinical features of pseudomigraine with lymphocytic pleocytosis included transient episodes of weakness, sensory and visual symptoms, aphasia, and confusion lasting minutes up to 4 hours. Sensory symptoms, typically affecting the face and arm, were the most common presentation. Localization of symptoms did not conform to vascular territories. Headache was typically throbbing and most often bilateral. Genetic analysis did not identify any mutations in the CACNA1A gene. CONCLUSIONS: Similarities between familial hemiplegic migraine and pseudomigraine with lymphocytic pleocytosis include recurrent headache with reversible neurologic deficit, cerebrospinal fluid lymphocytic pleocytosis, and triggers such as angiography. Even so, heteroduplex analysis and DNA sequencing failed to identify any sporadic mutations or shared polymorphisms in the exons or the intron/exon boundaries of the CACNA1A gene. These results do not support a role of the CACNA1A gene in the etiology of pseudomigraine with lymphocytic pleocytosis.
Assuntos
Canais de Cálcio/genética , Cefaleia/genética , Linfocitose/líquido cefalorraquidiano , Enxaqueca com Aura/genética , Adulto , Feminino , Cefaleia/complicações , Cefaleia/etiologia , Humanos , Contagem de Linfócitos , Linfocitose/complicações , Masculino , Pessoa de Meia-Idade , Mutação , Doenças do Sistema Nervoso/etiologia , Polimorfismo Genético , Recidiva , Estudos RetrospectivosRESUMO
The headache history is discussed as a model for establishing effective doctor patient communication. A thorough knowledge regarding headache onset, course and current features provides a basis for diagnosis and management. The principles of acceptance, validation, empathy, respect and advocacy are explored.