RESUMO
The Food and Drug Administration has that "sponsors should enroll participants who reflect the characteristics of clinically relevant populations". Recent reports have noted that global Alzheimer's Disease trials have enrolled predominantly White subjects. However, a thorough analysis of industry-sponsored, United States-only Alzheimer's trials has yet to be performed. A search of the clinicaltrials.gov database and PubMed identified 101 industry-sponsored Alzheimer's trials, performed solely in the United States, with gender data. The percentage of male (46%) vs. female (54%) subjects was higher than expected compared to real-world data. There were 50 Alzheimer's trials with race data. There was a significant overrepresentation of White subjects (92%) compared to all other race groups. These data suggest that significant modifications of subject recruitment methods are needed to increase the enrollment of underrepresented populations into Alzheimer's trials of potential new therapeutic agents in the United States.
Assuntos
Doença de Alzheimer , Masculino , Humanos , Feminino , Estados Unidos , Doença de Alzheimer/tratamento farmacológico , DemografiaRESUMO
Antidepressants compete at several neurotransmitter receptor binding site, but drug affinities do not correlate with clinical efficacy. Long-term, but not short-term, antidepressant treatment decreases the numbers of both serotonin and beta-adrenergic receptors. The decrease in the number of receptor sites is most marked for [3H]spiroperidol-labeled serotonin receptors and is characteristic for antidepressants of several classes.
Assuntos
Antidepressivos/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Animais , Antidepressivos/administração & dosagem , Antidepressivos/metabolismo , Lobo Frontal/efeitos dos fármacos , Masculino , Ratos , Receptores Adrenérgicos alfa/metabolismo , Receptores Adrenérgicos beta/efeitos dos fármacos , Receptores Adrenérgicos beta/metabolismo , Receptores Dopaminérgicos/metabolismo , Receptores Histamínicos H1/metabolismo , Receptores Muscarínicos/metabolismo , Receptores de Serotonina/metabolismo , Espiperona/metabolismo , Fatores de TempoRESUMO
Two distinct serotonin (5-hydroxytryptamine) receptors designated serotonin 1 and serotonin 2 bind tritium-labeled serotonin and tritium-labeled spiroperidol, respectively. Drug potencies at serotonin 2 sites, but not at serotonin 1 sites, predict their effects on the "serotonin behavioral syndrome," indicating that serotonin 2 sites mediate these behaviors. The limited correlation of drug effects with regulation by guanine nucleotides suggests that serotonin 1 sites might be linked to adenylate cyclase. Drug specificities of serotonin-elicited synaptic inhibition and excitation may reflect serotonin 1 and serotonin 2 receptor interactions, respectively.
Assuntos
Comportamento Animal/fisiologia , Encéfalo/fisiologia , Receptores de Serotonina/fisiologia , Adenilil Ciclases/metabolismo , Animais , Nucleotídeos de Guanina/fisiologia , Cinética , Masculino , Ratos , Serotonina/metabolismo , Espiperona/metabolismo , Relação Estrutura-AtividadeRESUMO
Purified preparations of microvessels from bovine cerebral cortex contain substantial levels of alpha-adrenergic, beta-adrenergic, and histamine 1 receptor binding sites but only negligible serotonin, muscarinic cholinergic, opiate, and benzodiazepine receptor binding. Norepinephrine and histamine may be endogenous regulators of the cerebral microcirculation at the observed receptors.
Assuntos
Encéfalo/irrigação sanguínea , Neurotransmissores/metabolismo , Receptores Adrenérgicos/metabolismo , Receptores Histamínicos H1/metabolismo , Receptores Histamínicos/metabolismo , Animais , Bovinos , Ligantes , Microcirculação , Receptores Adrenérgicos alfa/metabolismo , Receptores Adrenérgicos beta/metabolismo , Receptores Colinérgicos/metabolismo , Receptores de Serotonina/metabolismoRESUMO
The long anticipated 'genetic revolution' in neuropsychiatry has yet to have an impact on the practice of clinical medicine. Excitement in the 1980s over major genetic breakthroughs in schizophrenia and manic depression, for example, has been replaced in the late 1990s by the sobering realization that most common neuropsychiatric disorders are multifactorial. Despite considerable effort and resources, no 'causative' genetic variation has been identified that plays a definitive major role in any common neuropsychiatric disorder.
Assuntos
Psiquiatria Biológica , Genoma , Transtornos Mentais/genética , Mutação , Terapia Combinada , Humanos , Transtornos Mentais/terapia , FenótipoRESUMO
Radioligand binding studies were used to analyze the interactions of two novel anxiolytics, buspirone and TVX Q 7821, with a series of 10 neuronal membrane receptor sites. Buspirone (IC50 = 24 nM) and TVX Q 7821 (IC50 = 9.5 nM) display the highest affinity for 5-hydroxytryptamine1A (5-HT1A) binding sites labeled by 3H-8-hydroxy-2-(di-n-pro-pylamino) tetralin (DPAT). By contrast, buspirone is 16-fold weaker at dopamine (D2) receptors (IC50 = 380 nM), whereas TVX Q 7821 is 6-fold less potent at alpha-adrenergic1 sites (IC50 = 58 nM). At the other receptors studied, buspirone and TVX Q 7821 had similar pharmacological profiles. Both agents display moderate affinity for histamine (H1), alpha-adrenergic2, and 5-HT2 binding sites. The drugs are essentially inactive at 5-HT1B, calcium channel antagonist, muscarinic cholinergic, and benzodiazepine receptors. These results suggest that the anxiolytic effects of buspirone and TVX Q 7821 may be mediated by central 5-HT1A receptors.
Assuntos
Ansiolíticos/farmacologia , Encéfalo/efeitos dos fármacos , Pirimidinas/farmacologia , Receptores de Serotonina/efeitos dos fármacos , 8-Hidroxi-2-(di-n-propilamino)tetralina , Animais , Ligação Competitiva , Buspirona , Bovinos , Depressão Química , Diazepam/metabolismo , Flunitrazepam/metabolismo , Técnicas In Vitro , Lorazepam/metabolismo , Tetra-Hidronaftalenos/metabolismoRESUMO
The affinity of 1-(m-chlorophenyl)piperazine (mCPP) for 11 neurotransmitter receptor binding sites was determined in human brain membranes. mCPP is essentially equipotent at all 5-hydroxytryptamine (5-HT) receptor subtypes (IC50 values ranging from 360 to 1300 nM). The drug displays similar affinity (IC50 = 570 nM for alpha 2-adrenergic receptors labeled for 3H-rauwolscine. mCPP is less potent at alpha 1- and beta-adrenergic, dopamine, and muscarinic cholinergic receptors (IC50 values 2500-24,000 nM). mCPP is inactive at both benzodiazepine receptors and the 5-HT uptake sites at concentrations below 100,000 nM. These data demonstrate that mCPP displays similar potency for multiple neurotransmitter receptor binding sites in human brain.
Assuntos
Encéfalo/metabolismo , Piperazinas/metabolismo , Receptores de Neurotransmissores/metabolismo , Adulto , Idoso , Feminino , Lobo Frontal/metabolismo , Globo Pálido/metabolismo , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Ensaio Radioligante , Receptores Adrenérgicos alfa/metabolismo , Receptores de Serotonina/metabolismoRESUMO
Chronic administration of the neuroleptic haloperidol, the calcium channel antagonist nitrendipine, and the calcium channel antagonist neuroleptic pimozide produce differential effects on rat striatal 3H-spiperone binding. Following 7 days of 10 mg/kg i.p. administration, haloperidol significantly increases (p less than 0.01) dopamine D2 receptor binding to 123% +/- 6% of control values, whereas pimozide treatment significantly reduces (p less than 0.001) striatal 3H-spiperone binding to 46% +/- 6% of control values. Chronic administration of the calcium channel antagonist nitrendipine does not alter 3H-spiperone binding relative to control values. Saturation analysis reveals an increase in Bmax following chronic haloperidol and a decrease in Bmax following chronic pimozide treatment. No alterations in muscarinic cholinergic sites, dopamine uptake sites, or calcium channel antagonist sites result following chronic drug administration. These results are the first demonstration of a decrease in dopamine D2 binding sites after chronic neuroleptic treatment.
Assuntos
Corpo Estriado/efeitos dos fármacos , Haloperidol/farmacologia , Nitrendipino/farmacologia , Pimozida/farmacologia , Receptores Dopaminérgicos/efeitos dos fármacos , Animais , Canais Iônicos/efeitos dos fármacos , Canais Iônicos/metabolismo , Masculino , Ratos , Ratos Endogâmicos , Receptores Dopaminérgicos/análise , Receptores de Dopamina D2 , Espiperona/metabolismoRESUMO
The interactions of tandospirone (formerly called SM-3997) with 5-HT and other neurotransmitter receptor binding sites were determined in brain homogenates. Tandospirone is most potent at the 5-HT1A receptor, displaying a Ki value of 27 +/- 5 nM. The agent is approximately two to three orders of magnitude less potent at 5-HT2, 5-HT1C, alpha 1-adrenergic, alpha 2-adrenergic, and dopamine D1 and D2 receptors (Ki values ranging from 1300 to 41000 nM). Tandospirone is essentially inactive at 5-HT1B receptors; 5-HT uptake sites; beta-adrenergic, muscarinic cholinergic, and benzodiazepine receptors. This pharmacological profile differs slightly from that of other novel anxiolytics such as buspirone, ipsapirone, and gepirone. Saturation and competition studies using 3H-tandospirone also suggest that the drug interacts with 5-HT1A receptor binding sites in rat cortical membranes (KD = 4.5 +/- 0.8 nM; Bmax = 2.2 +/- 0.6 pmol/g tissue). Based on adenylate cyclase studies which measure 5-HT1A receptor-mediated effects, tandospirone displays approximately 60% of the agonist effect of 8-OH-DPAT, a selective 5-HT1A agonist. Thus, the primary pharmacological effect of tandospirone appears to be partial agonism at the 5-HT1A receptor, an activity similar to other pyrimidinyl-piperazines which are being developed as novel anxiolytic agents.
Assuntos
Ansiolíticos/farmacocinética , Encéfalo/enzimologia , Piperazinas/farmacocinética , Pirimidinas/farmacocinética , Receptores de Serotonina/metabolismo , Adenilil Ciclases/metabolismo , Animais , Ligação Competitiva/fisiologia , Buspirona/farmacocinética , Isoindóis , Masculino , Ensaio Radioligante , Ratos , Ratos Endogâmicos , Receptores Adrenérgicos alfa/metabolismo , Receptores Adrenérgicos beta/metabolismo , Receptores Dopaminérgicos/metabolismoRESUMO
Molecular cloning studies have now identified six HTR genes encoding the biosynthesis of the structurally homologous human serotonin (5-hydroxytryptamine; 5-HT) receptors, namely 5-HTR1A, 5-HTR1B, 5-HTR1C, 5-HTR1D, 5-HTR2 and 5-HTRS31. Several of these receptors are encoded by intronless genes, and we now report the cloning of another intronless serotonergic HTR gene. This gene was cloned by a method using the polymerase chain reaction. The nucleotide sequence of this gene is most closely homologous to the 5-HTR1D gene; however, several stop codons, frame shifts and deletions are present in the coding region suggesting that this is a pseudogene which could not encode a functional receptor. Sequence analysis also revealed that the coding sequence of this pseudogene is disrupted by insertion of a 283-bp Alu repeat sequence.
Assuntos
Pseudogenes , Receptores de Serotonina/genética , Sequências Repetitivas de Ácido Nucleico , Sequência de Aminoácidos , Animais , Sequência de Bases , Northern Blotting , Southern Blotting , Clonagem Molecular , Humanos , Dados de Sequência Molecular , Pan troglodytes , Reação em Cadeia da Polimerase , Ratos , Homologia de Sequência de Aminoácidos , Homologia de Sequência do Ácido Nucleico , Especificidade da EspécieRESUMO
The authors examined the potencies of 22 neuroleptic drugs competing for binding sites associated with dopamine, serotonin, alpha-adrenergic, and histamine receptors in brain membranes. They found that although many neuroleptics are quite potent in competing at several of these receptor sites, the average antipsychotic clinical potency correlates closely only with the drug affinity for dopamine receptors labeled by 3H-spiroperidol At clinically effective doses, however, substantial occupancy of serotonin, alpha-adrenergic, and histamine receptors often occurs and may account for some of the auxiliary actions of neuroleptics.
Assuntos
Antipsicóticos/farmacologia , Encéfalo/efeitos dos fármacos , Receptores de Neurotransmissores/efeitos dos fármacos , Animais , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Masculino , Ratos , Receptores Adrenérgicos alfa/efeitos dos fármacos , Receptores Dopaminérgicos/efeitos dos fármacos , Receptores Histamínicos/efeitos dos fármacos , Receptores de Serotonina/efeitos dos fármacos , Serotonina/metabolismoRESUMO
Multiple 5-hydroxytryptamine (5-HT) receptors have been identified in the human nervous system. A subgroup of these receptors, designated 5-HT1 receptors, appears to be involved in the mechanism of action of acute antimigraine agents. This review summarizes data indicating that compounds with proven efficacy in the acute treatment of migraine are agonist at human 5-HT1 receptors. Further studies are cited to support two possible mechanisms of action for the efficacy of 5-HT1 agonists in treating migraine. It seems likely that a single 5-HT1 receptor subtype may be found in the near future to be the final common pathway in the mechanism of action of acute antimigraine agents.
Assuntos
Transtornos de Enxaqueca/tratamento farmacológico , Receptores de Serotonina/efeitos dos fármacos , Adenilil Ciclases/metabolismo , Di-Hidroergotamina/uso terapêutico , Humanos , Indóis/uso terapêutico , Receptores de Serotonina/classificação , Agonistas do Receptor de Serotonina/uso terapêutico , Sulfonamidas/uso terapêutico , SumatriptanaRESUMO
This review summarizes a growing body of biological, pharmacologic, and genetic data that support a role for dopamine in the pathophysiology of certain subtypes of migraine. Most migraine symptoms can be induced by dopaminergic stimulation. Moreover, there is dopamine receptor hypersensitivity in migraineurs, as demonstrated by the induction of yawning, nausea, vomiting, hypotension, and other symptoms of a migraine attack by dopaminergic agonists at doses that do not affect nonmigraineurs. Conversely, dopamine receptor antagonists are effective therapeutic agents in migraine. Recent genetic data suggest that molecular variations within dopamine receptor genes play a modifying role in the pathophysiology of migraine with aura. Therefore, modulation of dopaminergic neurotransmission should be considered in the therapeutic management of migraine.
Assuntos
Dopamina/fisiologia , Transtornos de Enxaqueca/fisiopatologia , Animais , Apomorfina/farmacologia , Dopamina/genética , Antagonistas de Dopamina/uso terapêutico , Humanos , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/genética , Náusea/fisiopatologia , Receptores Dopaminérgicos/genética , Receptores Dopaminérgicos/fisiologia , Transmissão Sináptica/fisiologia , Vômito/fisiopatologia , Bocejo/efeitos dos fármacosRESUMO
Cyproheptadine is equipotent (IC50 = 41 to 45 nM) in blocking contractions of canine basilar artery segments induced by serotonin, norepinephrine, potassium, or calcium. Methysergide and amitriptyline display variable potencies in inhibiting contractions depending on the initiating agent. Propranolol, at concentrations to 10 micromolar, had minimal effect on vessel contractions. We conclude that the primary action of cyproheptadine in preventing induced contractions of the canine basilar artery is antagonism of calcium channels. This action is unique among drugs used for migraine prophylaxis and may have important implications for the treatment of headache and other neurologic disorders.
Assuntos
Artéria Basilar/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Ciproeptadina/farmacologia , Vasoconstrição/efeitos dos fármacos , Animais , Cloreto de Cálcio/farmacologia , Ciproeptadina/uso terapêutico , Cães , Feminino , Masculino , Transtornos de Enxaqueca/prevenção & controle , Norepinefrina/farmacologia , Cloreto de Potássio/farmacologia , Serotonina/farmacologiaRESUMO
Migraine has a major genetic component. Although most recent scientific studies have focused on the role of 5-hydroxytryptamine and neuropeptides in migraine, dopaminergic systems are also implicated in the pathogenesis. Therefore, the dopamine D2 receptor (DRD2) was analyzed as a candidate gene since antagonists of this receptor have been reported to be effective in the acute treatment of migraine. Individuals with migraine with aura (n = 52) have an increased frequency (0.84) of the DRD2 NcoI C allele (chi-square = 6.47; p < 0.005) compared with control individuals (n = 121; C allele frequency = 0.71). Individuals with migraine without aura (n = 77) showed the same DRD2 T allele frequency (0.70) as the control group. Migraine with aura was present in 27% of the C/C individuals, 16% of the C/T individuals, and 5.2% of the T/T individuals. These data suggest that activation of the DRD2 receptor plays a modifying role in the pathophysiology of migraine with aura. As a result, these data provide a molecular rationale for the documented efficacy of DRD2 antagonists in the treatment of migraine with aura.
Assuntos
Alelos , Transtornos de Enxaqueca/fisiopatologia , Receptores de Dopamina D2/genética , Adulto , Feminino , Genótipo , Haloperidol/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/genéticaRESUMO
We studied mortality after pertussis immunization in the mouse. Without treatment, 73 of 92 animals (80%) died after injection of bovine serum albumin (BSA) on day +7 of pertussis immunization. After pretreatment with 3 mg of cyproheptadine, 2 mg mianserin, or 2 mg chlorpheniramine, only 5 of 105 animals (5%) died after receiving BSA on day +7 (p less than 0.001). Blockade of histamine H1 receptors may reduce mortality in pertussis immunization-induced encephalopathy in mice.
Assuntos
Encefalopatias/tratamento farmacológico , Ciproeptadina/uso terapêutico , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Vacina contra Coqueluche/efeitos adversos , Animais , Encefalopatias/induzido quimicamente , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos BALB C , Soroalbumina Bovina/efeitos adversosRESUMO
Twenty-four patients with classic migraine attacks were treated with either nifedipine or placebo for up to 12 weeks. No significant differences were observed between the nifedipine (2.1 +/- 0.2) and placebo (2.3 +/- 0.2) treatment groups in the monthly frequency of headaches. However, the incidence of side effects was significantly greater (p less than 0.001) in the nifedipine (54% of patients) than in the placebo (8% of patients) treatment groups.
Assuntos
Transtornos de Enxaqueca/prevenção & controle , Nifedipino/uso terapêutico , Ensaios Clínicos como Assunto , Método Duplo-Cego , Humanos , Transtornos de Enxaqueca/fisiopatologia , Nifedipino/efeitos adversos , PlacebosRESUMO
Nerve growth factor (NGF) plays a biologic role in the development and maintenance of sympathetic and small sensory neurons. Because it facilitates nerve fiber regeneration, lowers heat-pain threshold (hyperalgesia), and prevents or improves nerve dysfunction in experimental neuropathy, it is being considered as a putative treatment for certain human polyneuropathies. In 16 healthy subjects, we tested whether intradermal injection of minute doses of recombinant human NGF (1 or 3 micrograms) compared with saline induces hyperalgesia or alters cutaneous sensation (at the site of injection) as measured by symptom scores, clinical examination, or quantitative sensory testing with Computer Assisted Sensory Examination (CASE IV). Most subjects had, as their only symptom, localized tenderness of the NGF-injected site and only when the site was bumped or compressed. Slight discomfort developed in volar wrist structures (with flexion of fingers) or tenderness of deep structures to palpation over the bicipital groove or supraclavicular region. The Neuropathy Symptoms and Change questionnaire indicated that pressure allodynia was significantly localized to the NGF-injected side from 3 hours to 21 days after injections. Light stroking of the skin did not induce tactile allodynia. Compression of injected sites induced pressure allodynia that occurred more frequently and significantly on the NGF-injected side after 3 hours and was maintained for several weeks. No abnormality of vibratory or cooling detection threshold developed from NGF injection. By contrast, heat-pain threshold (HP 0.5, p = 0.003) and an intermediate level of heat-pain (HP 5.0, p < 0.001) were significantly lowered 1, 3, and 7 days (and in some cases at 3 hours and 14 and 21 days) after NGF injection. The time course of pressure allodynia and heat-pain hyperalgesia is too rapid to be explained by uptake of NGF by nociception terminals, retrograde transport, and upregulation of pain modulators. Local tissue mechanisms appear to be implicated. It remains to be tested whether recombinant human NGF prevents, stabilizes, or ameliorates small fiber human neuropathies.
Assuntos
Temperatura Alta , Fatores de Crescimento Neural/farmacologia , Limiar da Dor/efeitos dos fármacos , Limiar Sensorial/efeitos dos fármacos , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Crescimento Neural/efeitos adversos , Fatores de Crescimento Neural/uso terapêutico , Dor/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Transtornos de Sensação/induzido quimicamenteRESUMO
We conducted a multicenter, double-blind, parallel-group study to compare the efficacy and safety of dihydroergotamine (DHE) nasal spray and placebo over 4 hours in the treatment of migraine. Of the 112 patients enrolled, 100 were included in the "intent-to-treat" efficacy analysis. The patients self-administered either 2.0 mg DHE (0.5 mg per nostril, repeated after 15 minutes) or placebo at the onset of two separate headaches and rated hourly the drugs' effects on pain severity, pain relief, nausea, and vomiting. The physicians assessed the overall effectiveness of the drugs in relieving headache pain, nausea, and vomiting. Both the patients' and physicians' ratings indicated that DHE was significantly superior to placebo in improving headache and nausea; according to the patients' ratings, these between-group differences were already significant at the first (hour 1) evaluation. There were no significant differential treatment effects with respect to relief of vomiting. Most adverse events were mild or moderate, confined to the nasopharyngeal area, and probably related to the route of administration. We conclude that DHE nasal spray is a safe and effective treatment for the pain and nausea of migraine attacks.
Assuntos
Di-Hidroergotamina/uso terapêutico , Transtornos de Enxaqueca/tratamento farmacológico , Administração Intranasal , Adolescente , Adulto , Di-Hidroergotamina/administração & dosagem , Di-Hidroergotamina/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The hallucinogenic agent d-lysergic acid diethylamide (d-LSD) interacts with a number of serotonin (5-hydroxytryptamine [5-HT]) receptor subtypes in the central nervous system. It has been hypothesized that hallucinosis is produced by agonist activity at 5-HT2 receptors. There exist, however, numerous data from radioligand binding, cellular, smooth muscle, and behavioral studies that suggest that d-LSD is a potent 5-HT2 antagonist. These data are reviewed in this report. In addition, d-LSD displays agonist activity at 5-HT1A and 5-HT1C receptor subtypes, as determined in biochemical studies. At the present time, agonist interactions at 5-HT1C receptors, as opposed to 5-HT2 receptors, appears to be a more likely "common mechanism of action" of hallucinogenic agents.