RESUMO
NS11821 is a partial GABAA agonist with relatively dominant α2,3 and α5 subtype efficacy but negligible α1 agonism. This first-in-human study was performed in healthy male subjects using a single-dose, parallel, double blind, placebo-controlled, randomized, dose-escalation study design. In total six cohorts (N=48) were enrolled. The eight subjects of each cohort received NS11821 (10 mg, 30 mg, 75 mg, 150 mg, 300 mg or 600 mg) or placebo in a 6:2 ratio. At low dose levels, NS11821 had a relatively low exposure and a more-than-proportional increase of the area under the curve and maximum plasma concentrations, probably due to poor solubility. Saccadic peak velocity decreased in a dose-related manner while limited impairments were seen on body sway and the visual analogue scale for alertness. The most common adverse events were somnolence and dizziness, which were more prominent with the higher doses. Although no positive control was used in this study, the results were compared post hoc with a Centre for Human Drug Research dataset for lorazepam 2 mg. The maximum saccadic peak velocity effects seemed comparable to the typical effects of lorazepam, whereas the other central nervous system effects were smaller. These results support the pharmacological selectivity of NS11821 and show that pharmacodynamic effective doses of NS11821 were safe and well tolerated in healthy subjects.
Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Agonistas de Receptores de GABA-A/uso terapêutico , Receptores de GABA-A/metabolismo , Adolescente , Adulto , Método Duplo-Cego , Voluntários Saudáveis , Humanos , Lorazepam/uso terapêutico , Masculino , Adulto JovemRESUMO
Although personal melanoma risk factors are well established, the contribution of socioeconomic factors, including clothing styles, social norms, medical paradigms, perceptions of tanned skin, economic trends, and travel patterns, to melanoma incidence has not been fully explored. We analyzed artwork, advertisements, fashion trends, and data regarding leisure-time activities to estimate historical changes in UV skin exposure. We used data from national cancer registries to compare melanoma incidence rates with estimated skin exposure and found that they rose in parallel. Although firm conclusions about melanoma causation cannot be made in an analysis such as this, we provide a cross-disciplinary, historical framework in which to consider public health and educational measures that may ultimately help reverse melanoma incidence trends.
Assuntos
Melanoma/epidemiologia , Banho de Sol/estatística & dados numéricos , Adolescente , Adulto , Vestuário/história , Cultura , Feminino , Conhecimentos, Atitudes e Prática em Saúde , História do Século XX , Humanos , Incidência , Masculino , Melanoma/etiologia , Pele/efeitos da radiação , Banho de Sol/história , Bronzeado , Estados Unidos , Adulto JovemRESUMO
GAB(A) (γ-aminobutyric acid) is abundantly expressed within the brain, and spinal cord pain circuits where it acts as the principal mediator of fast inhibitory neurotransmission. However, drugs that target GABA(A) receptor function such as the classical benzodiazepines have not been optimised to promote analgesia, are limited by side effects and are not routinely used for this purpose in humans. Compounds such as NS11394, L-838,417, HZ166 and TPA023 all bind to the same benzodiazepine site on the GABA(A) receptor to allosterically modulate receptor function and enhance the actions of GABA. By virtue of their ability to activate selected subtypes of GABA(A) receptors (principally those containing α2, α3 and α5 subunits) these compounds have been shown to possess excellent tolerability profiles in animals. Importantly, a number of these molecules also mediate profound analgesia in animal models of inflammatory and neuropathic pain. Other modulators such as neurosteroids bind to distinct sites on GABA(A) receptor α subunits, possess a unique pharmacology and are capable of targeting alternative GABA(A) receptor expressing populations. Moreover, neurosteroids also have pronounced analgesic actions in animal pain models. The continuing call for novel mechanism of action analgesics to target specific pathologies, especially in clinical neuropathic conditions, emphasizes the need to test modulators of GABA(A) receptor function in both human experimental pain models and pain patients.
Assuntos
Manejo da Dor/métodos , Dor/tratamento farmacológico , Receptores de GABA-A/metabolismo , Analgesia , Animais , Humanos , Dor/complicações , Receptores de GABA-A/química , Pesquisa Translacional Biomédica , Ferimentos e Lesões/complicaçõesRESUMO
GABA-A receptor positive allosteric modulators (PAMs) mediate robust analgesia in animal models of pathological pain, in part via enhancing injury-induced loss of GABA-A-α2 and -α3 receptor function within the spinal cord. As yet, a lack of clinically suitable tool compounds has prevented this concept being tested in humans. Prior to assessing the efficacy of GABA-A receptor PAMs in a human volunteer pain model we have compared compounds capable of variously modulating GABA-A receptor function in comparable rat models of capsaicin-induced acute nocifensive flinching behaviour and secondary mechanical hypersensitivity. The subtype-selective PAM NS11394 (0.3-10 mg/kg), and the non-selective PAM diazepam (1-5 mg/kg) variously reduced capsaicin-induced secondary mechanical hypersensitivity (180 min post-injection). However, the low efficacy subtype-selective PAM TPA023 (3-30 mg/kg) was completely ineffective. This was surprising as both NS11394 and TPA023 robustly attenuated late phase (6-30 min post-injection) capsaicin-induced flinching, a pain-like behaviour that is putatively driven by peripheral and central sensitizing mechanisms. Diazepam also attenuated capsaicin-induced nocifensive behaviours, albeit at doses previously shown to impair locomotor function. Our data indicate that GABA-A receptor PAMs with optimal selectivity and efficacy profiles reduce centrally-mediated mechanical hypersensitivity in capsaicin-injected rats, an observation that we expect can translate directly to human volunteer studies.
Assuntos
Capsaicina , Moduladores GABAérgicos/química , Moduladores GABAérgicos/farmacologia , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Receptores de GABA-A/química , Receptores de GABA-A/efeitos dos fármacos , Aminas/farmacologia , Analgésicos Opioides/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Benzimidazóis/farmacologia , Ácidos Cicloexanocarboxílicos/farmacologia , Diazepam/farmacologia , Determinação de Ponto Final , Antagonistas GABAérgicos/farmacologia , Gabapentina , Hiperalgesia/psicologia , Masculino , Dor/psicologia , Estimulação Física , Piridazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/metabolismo , Triazóis/farmacologia , Ácido gama-Aminobutírico/farmacologiaRESUMO
BACKGROUND: Within the GABA(A)-receptor field, two important questions are what molecular mechanisms underlie benzodiazepine tolerance, and whether tolerance can be ascribed to certain GABA(A)-receptor subtypes. METHODS: We investigated tolerance to acute anxiolytic, hypothermic and sedative effects of diazepam in mice exposed for 28-days to non-selective/selective GABA(A)-receptor positive allosteric modulators: diazepam (non-selective), bretazenil (partial non-selective), zolpidem (α(1) selective) and TPA023 (α(2/3) selective). In-vivo binding studies with [(3)H]flumazenil confirmed compounds occupied CNS GABA(A) receptors. RESULTS: Chronic diazepam treatment resulted in tolerance to diazepam's acute anxiolytic, hypothermic and sedative effects. In mice treated chronically with bretazenil, tolerance to diazepam's anxiolytic and hypothermic, but not sedative, effects was seen. Chronic zolpidem treatment resulted in tolerance to diazepam's hypothermic effect, but partial anxiolytic tolerance and no sedative tolerance. Chronic TPA023 treatment did not result in tolerance to diazepam's hypothermic, anxiolytic or sedative effects. CONCLUSIONS: OUR DATA INDICATE THAT: (i) GABA(A)-α(2)/α(3) subtype selective drugs might not induce tolerance; (ii) in rodents quantitative and temporal variations in tolerance development occur dependent on the endpoint assessed, consistent with clinical experience with benzodiazepines (e.g., differential tolerance to antiepileptic and anxiolytic actions); (iii) tolerance to diazepam's sedative actions needs concomitant activation of GABA(A)-α(1)/GABA(A)-α(5) receptors. Regarding mechanism, in-situ hybridization studies indicated no gross changes in expression levels of GABA(A) α(1), α(2) or α(5) subunit mRNA in hippocampus or cortex. Since selective chronic activation of either GABA(A) α(2), or α(3) receptors does not engender tolerance development, subtype-selective GABA(A) drugs might constitute a promising class of novel drugs.
Assuntos
Ansiolíticos/farmacologia , Encéfalo/metabolismo , Diazepam/farmacologia , Tolerância a Medicamentos/fisiologia , Hipnóticos e Sedativos/farmacologia , Receptores de GABA-A/metabolismo , Análise de Variância , Animais , Ansiolíticos/administração & dosagem , Benzodiazepinonas/metabolismo , Benzodiazepinonas/farmacologia , Temperatura Corporal , Primers do DNA/genética , Diazepam/administração & dosagem , Tolerância a Medicamentos/genética , Flumazenil/metabolismo , Hipnóticos e Sedativos/administração & dosagem , Hibridização In Situ , Masculino , Camundongos , Camundongos Mutantes , Piridazinas/metabolismo , Piridazinas/farmacologia , Piridinas/metabolismo , Piridinas/farmacologia , Triazóis/metabolismo , Triazóis/farmacologia , ZolpidemRESUMO
Currently, there are no effective pharmacological therapies for chronic tinnitus despite a number of efforts from clinical studies and more recently, studies in animals using compounds to enhance endogenous inhibition or reduce central hyperactivity. The purpose of the current study was to evaluate the therapeutic efficacy of a novel anxiolytic with potassium channel activity in suppressing salicylate induced tinnitus in animals. Kv7 potassium channels are present in the peripheral and central auditory system where they are believed to modulate neural activity. Maxipost, a compound which attenuates hyperexcitability via positive modulation of Kv7.2-Kv7.5 channels, was administered to rats with behavioral evidence of salicylate induced tinnitus. Tinnitus was measured using our previously established animal model, Schedule Induced Polydipsia Avoidance Conditioning, a paradigm where rats were conditioned to drink only during quiet and suppress drinking in the presence of sound. Salicylate alone significantly suppressed licks in quiet but had no effect on licks in sound; results consistent with the presence of tinnitus. Maxipost at 10 mg/kg suppressed behavioral evidence of tinnitus as it completely reversed salicylate's suppression of licks in quiet. Unexpectedly, the R-enantiomer of Maxipost, R-Maxipost, which has no anxiolytic effects and negatively modulates Kv7.2-Kv7.5, also suppressed behavioral evidence of tinnitus. Our original hypothesis was that Kv7.2-Kv7.5 channels might play a key role in tinnitus generation and that Maxipost but not R-Maxipost would suppress tinnitus; however, it appears that a shared mechanism between Maxipost and R-xMaxipost, such as inhibition of Kv7.1 channels or activation of BK channels or some novel mechanism common to both compounds, underlies salicylate induced tinnitus as both compounds completely abolished behavioral evidence of tinnitus in a dose-dependent manner. Further studies with specific BK channel agonists/antagonists are necessary to determine the contribution of these channels to other forms of tinnitus or determine novel targets that could be related to tinnitus.
Assuntos
Anti-Inflamatórios não Esteroides/toxicidade , Indóis/uso terapêutico , Bloqueadores dos Canais de Potássio/uso terapêutico , Salicilatos/toxicidade , Zumbido/induzido quimicamente , Zumbido/tratamento farmacológico , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Interações Medicamentosas , Indóis/química , Masculino , Polissorbatos/farmacologia , Ratos , Ratos Sprague-Dawley , Tensoativos/farmacologiaRESUMO
After injury GABA(A) receptor positive allosteric modulators (PAMs) mediate robust analgesia in animals via putative restoration of post-synaptic GABA(A)-α2 and -α3 receptor function within the spinal cord. GABA can also act at GABA(A) receptors localized on primary afferent neurones to inhibit presynaptic neurotransmitter release and produce analgesia via a process called primary afferent depolarization (PAD). Some forms of injury might sufficiently enhance PAD to shift it into a net excitatory process. Thus, negative allosteric modulators (NAMs) might also possess analgesic activity. We have compared compounds capable of either positively or negatively modulating GABA(A) receptors in rat models associated with injury-induced central sensitization. The subtype-selective PAMs NS11394 (1-10 mg/kg) and TPA023 (3-30 mg/kg) attenuated formalin-induced nocifensive behaviours. Similarly, both compounds reversed hindpaw mechanical hypersensitivity and weight bearing deficits in carrageenan-inflamed and nerve-injured rats. The non-selective PAM diazepam (1-5 mg/kg) was ineffective in all models. Surprisingly, both the non-selective NAM FG-7142 (3-30 mg/kg) and the α5-selective NAM α5IA-II (10-60 mg/kg) also attenuated formalin-induced nocifensive behaviours. In carrageenan-inflamed rats α5IA-II reversed mechanical hypersensitivity and weight bearing deficits whilst FG-7142 only attenuated weight bearing deficits. This picture was essentially reversed in nerve-injured rats for these two NAMs. With the exception of NS11394, all compounds attenuated exploratory motility behaviour in rats, either as a consequence of sedative or anxiogenic-like side-effects. These data indicate that the preferred selectivity and activity profiles for mediating analgesia upon activation of GABA(A) receptors might be more complex than previously anticipated, and is worthy of further exploration.
Assuntos
Analgésicos/uso terapêutico , Neuralgia/tratamento farmacológico , Medição da Dor/efeitos dos fármacos , Subunidades Proteicas/fisiologia , Receptores de GABA-A/fisiologia , Regulação Alostérica/fisiologia , Analgésicos/farmacologia , Animais , Diazepam/farmacologia , Diazepam/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Masculino , Neuralgia/fisiopatologia , Medição da Dor/métodos , Subunidades Proteicas/agonistas , Piridazinas/farmacologia , Piridazinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento , Triazóis/farmacologia , Triazóis/uso terapêuticoRESUMO
Nicotine increases serotonergic and noradrenergic neuronal activity and facilitates serotonin and noradrenaline release. Accordingly, nicotine enhances antidepressant-like actions of reuptake inhibitors selective for serotonin or noradrenaline in the mouse forced swim test and the mouse tail suspension test. Both high-affinity α4ß2 and low-affinity α7 nicotinic acetylcholine receptor subtypes are implicated in nicotine-mediated release of serotonin and noradrenaline. The present study therefore investigated whether selective agonism of α4ß2 or α7 nicotinic acetylcholine receptors would affect the mouse forced swim test activity of two antidepressants with distinct mechanisms of action, namely the selective serotonin reuptake inhibitor citalopram and the noradrenaline reuptake inhibitor reboxetine. Subthreshold and threshold doses of citalopram (3 and 10 mg/kg) or reboxetine (10 and 20 mg/kg) were tested alone and in combination with the novel α4ß2-selective partial nicotinic acetylcholine receptor agonist, NS3956 (0.3 and 1.0 mg/kg) or the α7-selective nicotinic acetylcholine receptor agonist, PNU-282987 (10 and 30 mg/kg). Alone, NS3956 and PNU-282987 were devoid of activity in the mouse forced swim test, but both 1.0 mg/kg NS3956 and 30 mg/kg PNU-282987 enhanced the effect of citalopram and also reboxetine. The data suggest that the activity of citalopram and reboxetine in the mouse forced swim test can be enhanced by agonists at either α4ß2 or α7 nicotinic acetylcholine receptors, suggesting that both nicotinic acetylcholine receptor subtypes may be involved in the nicotine-enhanced action of antidepressants.
Assuntos
Antidepressivos/farmacologia , Azepinas/farmacologia , Citalopram/farmacologia , Morfolinas/farmacologia , Agonistas Nicotínicos/farmacologia , Piridinas/farmacologia , Receptores Nicotínicos/fisiologia , Animais , Benzamidas/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Feminino , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Wistar , Reboxetina , Natação , Xenopus laevis , Receptor Nicotínico de Acetilcolina alfa7RESUMO
IMPORTANCE OF THE FIELD: Cognitive impairments associated with schizophrenia include neuropsychological deficits in attention, working memory, learning and executive function. Because these cognitive deficits precede the onset of psychosis, are present in non-affected relatives and constitute the best predictor of functional outcome, they are a cardinal clinical feature in schizophrenia. Currently, no effective treatment for the cognitive symptoms in schizophrenia exists. AREAS COVERED IN THIS REVIEW: There is evidence that the inhibitory GABA system is affected in schizophrenia, suggesting that cognitive impairments associated with schizophrenia may be effectively treated by drugs that modulate the GABA(A) receptor. However, classical benzodiazepines produce cognitive impairments and are associated with numerous side effects. The recent development of compounds with selective efficacy for different α subunits at the benzodiazepine site of the GABA(A) receptor has renewed interest for the therapeutic potential of GABAergic drugs. WHAT THE READER WILL GAIN: This review summarizes the involvement of the inhibitory GABA system in the cognitive abnormalities of schizophrenia and discusses putative (selective) GABAergic cognition-enhancing drugs for schizophrenia. TAKE HOME MESSAGE: If cognitive abnormalities in schizophrenic individuals are the result of GABAergic dysfunction, selectively modulating the GABA system could comprise a promising therapeutic intervention for cognitive symptoms in schizophrenia.
Assuntos
GABAérgicos/uso terapêutico , Esquizofrenia/tratamento farmacológico , Atenção/efeitos dos fármacos , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Drogas em Investigação/metabolismo , Drogas em Investigação/farmacologia , Drogas em Investigação/uso terapêutico , Feminino , GABAérgicos/metabolismo , GABAérgicos/farmacologia , Agonistas de Receptores de GABA-A/farmacologia , Agonistas de Receptores de GABA-A/uso terapêutico , Humanos , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/fisiopatologia , Receptores de GABA/metabolismo , Esquizofrenia/metabolismoRESUMO
Recent GABA(A) receptor drug discovery efforts have culminated in the development of transgenic mice and subtype-selective pharmacological tools, enhancing our understanding of the major inhibitory neural system in the central nervous system. Notably, subtype-selective tools have demonstrated in both preclinical studies and, to some extent, in man that it is possible to develop drugs that share the clinical benefits of benzodiazepines (e.g., anxiolysis) while obviating some adverse effects of these clinically important drugs. Here, we highlight chronic pain as another therapeutic area in which subtype-selective GABA(A) receptor drugs might have clinical utility. Specifically, based on research in animal models of inflammatory/neuropathic pain, we suggest that subtype-selective positive modulators of GABA(A) alpha(2/3) receptors might reverse a loss of postsynaptic GABA(A) receptor-mediated inhibitory function in spinal cord, leading to analgesia. However, alteration of presynaptic inhibitory neural transmission in chronic pain suggests that drugs that negatively modulate GABA(A) receptors might also be effective analgesics. For example, the non-selective negative allosteric modulator FG-7142 reverses allodynia in an animal model of neuropathic pain. Importantly, these two mechanisms are not mutually exclusive. Further clinical exploration in pain of available positive and negative subtype-selective modulators that have been administered to humans would considerably aid back translation, allowing for improved therapeutic development.
Assuntos
Analgésicos/farmacologia , Moduladores GABAérgicos/farmacologia , Receptores de GABA-A/efeitos dos fármacos , Regulação Alostérica , Animais , Descoberta de Drogas , Humanos , Dor/tratamento farmacológico , Dor/fisiopatologia , Receptores de GABA-A/classificação , Receptores de GABA-A/fisiologiaRESUMO
BACKGROUND: In chronic studies, the classical benzodiazepine chlordiazepoxide (CDP) is often the preferred drug because, unlike other benzodiazepines, it is soluble in water. However, rapid CDP hydrolysis in solution has been described. This would diminish plasma levels in chronic minipump studies and introduce the corelease of active compounds. METHODS: Therefore, the present study aimed to explore the putative hydrolysis of CDP in aqueous solution over time and to identify the hydrolysis products. Moreover, we aimed to characterize the hydrolysis products for their in vitro (3H-flunitrazepam binding and oocyte electrophysiology) and in vivo (stress-induced hyperthermia paradigm) GABAA receptor potency. RESULTS: CDP in solution hydrolyzed to the ketone structure demoxepam which was confirmed using mass spectrometry. The hydrolysis was concentration dependent (first-order kinetics) and temperature dependent. CDP exerted greater potency compared to demoxepam in vitro (increased activity at GABAA receptors containing α1 subunits) and in vivo (stress-induced hyperthermia), although 3H-flunitrazepam binding was comparable. CONCLUSIONS: The classical benzodiazepine CDP is rapidly hydrolyzed in solution to the active compound demoxepam which possesses a reduced activity at the GABAA receptor. Chronic studies that use CDP in aqueous solution should thus be interpreted with caution. It is therefore important to consider drug stability in chronic minipump applications.
Assuntos
Benzodiazepinas/farmacologia , Clordiazepóxido/farmacocinética , Bombas de Infusão Implantáveis , Animais , Benzodiazepinas/química , Temperatura Corporal/efeitos dos fármacos , Clordiazepóxido/química , Clordiazepóxido/farmacologia , Cromatografia Líquida/métodos , Estabilidade de Medicamentos , Febre , Hidrólise , Masculino , Espectrometria de Massas/métodos , Camundongos , Camundongos da Linhagem 129 , Oócitos/efeitos dos fármacos , Oócitos/fisiologia , Técnicas de Patch-Clamp/métodos , Ensaio Radioligante/métodos , Receptores de GABA-A/metabolismo , Fatores de Tempo , TrítioRESUMO
The use of genetically-engineered mice has identified alpha2- and alpha3-subunit containing GABA(A) receptors as principal contributors to the spinal disinhibition that occurs after inflammation and neuropathic injury. Pharmacological comparison of subtype selective allosteric modulators such as NS11394 and L838417 with either non-selective or full GABA(A) receptor modulators indicates that in addition to involvement of specific subunits per se, the level of efficacy at individual alpha subunits appears to be a critical determinant of analgesic activity. Combined, these complementary approaches identify the restoration of spinal inhibition after inflammatory, and especially neuropathic injury (the primary focus of this article), as a possible unifying mechanism for providing analgesia in patients with chronic pain.
Assuntos
Analgésicos/farmacologia , Neuralgia/tratamento farmacológico , Receptores de GABA-A/efeitos dos fármacos , Regulação Alostérica , Animais , Doença Crônica , Sistemas de Liberação de Medicamentos , Desenho de Fármacos , Humanos , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Camundongos , Neuralgia/fisiopatologia , Receptores de GABA-A/metabolismo , Medula Espinal/efeitos dos fármacosRESUMO
Letters to the Editor are welcomed for publication (subject to editing). Letters must be signed by all authors, and must not exceed two pages of text including references. Letters should not duplicate material submitted or published in other journals. Prepublication proofs will not be provided.
Assuntos
Imunoglobulina G/efeitos adversos , Imunossupressores/efeitos adversos , Líquen Plano/induzido quimicamente , Psoríase/tratamento farmacológico , Criança , Etanercepte , Humanos , Imunoglobulina G/administração & dosagem , Imunossupressores/administração & dosagem , Masculino , Receptores do Fator de Necrose Tumoral/administração & dosagem , Índice de Gravidade de DoençaRESUMO
A 39-year-old man with human immunodeficiency virus infection and Kaposi sarcoma on HAART therapy and doxorubicin presented in 2007 with a hyperpigmented tongue. Physical examination also showed hyperpigmented patches on the mucosal aspects of the lips and longitudinal dark bands on multiple nails. A skin biopsy specimen showed pigmentary alteration. Such hyperpigmentation has been described in numerous case reports and case series and has been reported to resolve within weeks to months of cessation of doxorubicin.
Assuntos
Antineoplásicos/efeitos adversos , Doxorrubicina/efeitos adversos , Doenças Labiais/induzido quimicamente , Melanose/induzido quimicamente , Unhas Malformadas/induzido quimicamente , Sarcoma de Kaposi/tratamento farmacológico , Doenças da Língua/induzido quimicamente , Síndrome da Imunodeficiência Adquirida/complicações , Adulto , Fármacos Anti-HIV/uso terapêutico , Antineoplásicos/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Carbamatos/uso terapêutico , Doxorrubicina/uso terapêutico , Combinação de Medicamentos , Furanos , Humanos , Lamivudina/uso terapêutico , Masculino , Organofosfatos/uso terapêutico , Ritonavir/uso terapêutico , Sarcoma de Kaposi/complicações , Sulfonamidas/uso terapêutico , Zidovudina/uso terapêuticoRESUMO
OBJECTIVE: To determine the utility of the current diameter criterion of larger than 6 mm of the ABCDE acronym for the early diagnosis of cutaneous melanoma. DESIGN: Cohort study. SETTING: Dermatology hospital-based clinics and community practice offices. Patients A total of 1323 patients undergoing skin biopsies of 1657 pigmented lesions suggestive of melanoma. MAIN OUTCOME MEASURE: The maximum lesion dimension (diameter) of each skin lesion was calculated before biopsy using a novel computerized skin imaging system. RESULTS: Of 1657 biopsied lesions, 853 (51.5%) were 6 mm or smaller in diameter. Invasive melanomas were diagnosed in 13 of 853 lesions (1.5%) that were 6 mm or smaller in diameter and in 41 of 804 lesions (5.1%) that were larger than 6 mm in diameter. In situ melanomas were diagnosed in 22 of 853 lesions (2.6%) that were 6 mm or smaller in diameter and in 62 of 804 lesions (7.7%) that were larger than 6 mm in diameter. Conclusion The diameter guideline of larger than 6 mm provides a useful parameter for physicians and should continue to be used in combination with the A, B, C, and E criteria previously established in the selection of atypical lesions for skin biopsy.
Assuntos
Inteligência Artificial , Dermoscopia/instrumentação , Diagnóstico por Computador/instrumentação , Processamento de Imagem Assistida por Computador/instrumentação , Melanoma/diagnóstico , Neoplasias Cutâneas/diagnóstico , Pele/patologia , Adulto , Idoso , Biópsia , Carcinoma in Situ/diagnóstico , Carcinoma in Situ/patologia , Estudos de Coortes , Diagnóstico Diferencial , Síndrome do Nevo Displásico/diagnóstico , Síndrome do Nevo Displásico/patologia , Feminino , Humanos , Ceratose/diagnóstico , Ceratose/patologia , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Nevo Pigmentado/diagnóstico , Nevo Pigmentado/patologia , Guias de Prática Clínica como Assunto , Valor Preditivo dos Testes , Curva ROC , Neoplasias Cutâneas/patologiaRESUMO
Signs and symptoms of persistent pain are associated with neuronal hyperexcitability within nociceptive pathways. This manifests behaviourally as a decrease in the nociceptive threshold to sensory stimulation, and is closely correlated with altered affective pain processing and increased expression of anxiety-like symptoms. Anticonvulsant drugs can have marked analgesic actions in animals and humans, and some have also been reported to possess anxiolytic-like properties in animals. In the current study, we have compared the antinociceptive actions of diazepam (allosteric GABA(A) receptor modulator), gabapentin (binds to alpha(2)delta Ca(2+) channel subunit), lamotrigine, riluzole and phenytoin (Na(+) channel blockers), levetiracetam (unknown mechanism), sodium valproate (potentiates GABA-mediated inhibition), ethosuximide (T-type Ca(2+) channel blocker) and retigabine (K(v)7 channel opener) in the rat formalin test, with their anxiolytic actions in the rat conditioned emotional response (CER) model of anxiety. Lamotrigine, gabapentin, riluzole, retigabine and ethosuximide attenuated second phase nociceptive responses in the formalin test. Lamotrigine, gabapentin and riluzole also displayed an anxiolytic-like profile in the CER model. Notably, the minimum doses of these drugs required to attenuate anxiety behaviour were similar to, or considerably lower than those needed to reverse pain-like behaviours. Diazepam was anxiolytic but only attenuated pain-like behaviours at sedative doses. The other drugs tested were inactive in both models. Our data suggests: (i) an antiepileptic mechanism of action per se is not necessarily sufficient for a compound to display antinociceptive and/or anxiolytic actions; and (ii) the combined antinociceptive and anxiolytic-like profiles of lamotrigine, gabapentin and riluzole suggests that these compounds likely modulate both sensory and affective dimensions of pain.
Assuntos
Anticonvulsivantes/uso terapêutico , Ansiedade/tratamento farmacológico , Dor/tratamento farmacológico , Analgésicos/farmacologia , Animais , Ansiedade/psicologia , Doença Crônica , Condicionamento Operante/efeitos dos fármacos , Eletrochoque , Emoções/efeitos dos fármacos , Comportamento Exploratório/efeitos dos fármacos , Formaldeído , Masculino , Atividade Motora/efeitos dos fármacos , Dor/psicologia , Medição da Dor/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
An 80-year-old man presented with a 50-year history of asymptomatic, subcutaneous masses on the arms, trunk, and legs. His father and maternal grandmother had had similar lesions. Histopathologic examination showed a benign angiolipoma; the same diagnosis has been made on several previous biopsy specimens. This patient's history and physical examination support the diagnosis of familial angiolipomatosis, which is a benign, autosomal-dominant condition that may be regarded as a subtype of familial multiple lipomatosis (FML) or as a distinct entity. Management of this condition may include liposuction or surgery to reduce the tumor burden.