RESUMO
AIMS: Metabolic dysfunction is involved in modulating the disease process in Huntington disease (HD) but the underlying mechanisms are not known. The aim of this study was to investigate if the metabolic regulators sirtuins are affected in HD. METHODS: Quantitative real-time polymerase chain reactions were used to assess levels of SIRT1-3 and downstream targets in post mortem brain tissue from HD patients and control cases as well as after selective hypothalamic expression of mutant huntingtin (HTT) using recombinant adeno-associated viral vectors in mice. RESULTS: We show that mRNA levels of the metabolic regulator SIRT1 are increased in the striatum and the cerebral cortex but not in the less affected cerebellum in post mortem HD brains. Levels of SIRT2 are only increased in the striatum and SIRT3 is not affected in HD. Interestingly, mRNA levels of SIRT1 are selectively increased in the lateral hypothalamic area (LHA) and ventromedial hypothalamus (VMH) in HD. Further analyses of the LHA and VMH confirmed pathological changes in these regions including effects on SIRT1 downstream targets and reduced mRNA levels of orexin (hypocretin), prodynorphin and melanin-concentrating hormone (MCH) in the LHA and of brain-derived neurotrophic factor (BDNF) in the VMH. Analyses after selective hypothalamic expression of mutant HTT suggest that effects on BDNF, orexin, dynorphin and MCH are early and direct, whereas changes in SIRT1 require more widespread expression of mutant HTT. CONCLUSIONS: We show that SIRT1 expression is increased in HD-affected brain regions and that metabolic pathways are altered in the HD hypothalamus.
Assuntos
Encéfalo/metabolismo , Doença de Huntington/metabolismo , Hipotálamo/metabolismo , Sirtuína 1/metabolismo , Idoso , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , Neurônios/patologiaAssuntos
Anafilaxia/etiologia , Recuperação Demorada da Anestesia/tratamento farmacológico , Complicações Intraoperatórias/induzido quimicamente , gama-Ciclodextrinas/efeitos adversos , Adolescente , Adulto , Sistemas de Notificação de Reações Adversas a Medicamentos , Idoso , Idoso de 80 Anos ou mais , Anafilaxia/diagnóstico , Anafilaxia/tratamento farmacológico , Anafilaxia/imunologia , Androstanóis/efeitos adversos , Androstanóis/antagonistas & inibidores , Causalidade , Criança , Hipersensibilidade a Drogas/etiologia , Hipersensibilidade a Drogas/imunologia , Epinefrina/uso terapêutico , Feminino , Humanos , Imunoglobulina E/imunologia , Complicações Intraoperatórias/diagnóstico , Complicações Intraoperatórias/imunologia , Masculino , Pessoa de Meia-Idade , Rocurônio , Testes Cutâneos , Sugammadex , Adulto Jovem , gama-Ciclodextrinas/imunologiaRESUMO
Rocuronium, a non-depolarizing neuromuscular blocking drug has a rapid onset of action, a comparatively low potency and, with a more favourable side effects profile than succinylcholine, it has become a popular alternative to that drug for rapid sequence inductions in anaesthesia. The rocuronium-binding cyclodextrin derivative sugammadex, prepared by per-6 substitution of the primary hydroxyls of γ-cyclodextrin with thiol ether-linked propionic acid side chains to extend the hydrophobic cavity to accommodate rocuronium, is used to reverse neuromuscular blockade by encapsulating the drug as an inclusion complex and removing it from the neuromuscular junction to the plasma. It has recently been suggested that sugammadex might also be of value in the management of rocuronium-induced anaphylaxis and this has been potentially supported by recent case reports. However, before sugammadex can be recommended for this purpose, it is important to establish whether or not the allergenic substituted ammonium groups at each end of the rocuronium molecule in the inclusion complex are masked within the cavity or left exposed for interaction with rocuronium-reactive IgE antibodies in the sera of rocuronium-allergic patients. Detailed experimental strategies and experimental protocols to investigate the allergenic potential of the sugammadex-rocuronium inclusion complex are presented and a possible explanation of the apparently rapid and successful reversal of anaphylaxis by administration of sugammadex is advanced and discussed.
Assuntos
Anafilaxia/induzido quimicamente , Androstanóis/administração & dosagem , Androstanóis/imunologia , Portadores de Fármacos/química , Fármacos Neuromusculares não Despolarizantes/administração & dosagem , Fármacos Neuromusculares não Despolarizantes/imunologia , gama-Ciclodextrinas/química , Alérgenos/administração & dosagem , Alérgenos/efeitos adversos , Alérgenos/química , Alérgenos/imunologia , Anafilaxia/imunologia , Androstanóis/efeitos adversos , Androstanóis/química , Animais , Portadores de Fármacos/metabolismo , Humanos , Imunoglobulina E/imunologia , Modelos Moleculares , Fármacos Neuromusculares não Despolarizantes/efeitos adversos , Fármacos Neuromusculares não Despolarizantes/química , Rocurônio , Sugammadex , gama-Ciclodextrinas/imunologiaRESUMO
Opioid analgesics are amongst the most commonly administered drugs in hospitals. Whether natural or synthetic, they show some common structural features, morphine-like pharmacological action and binding specificity for complementary opioid receptors. Tramadol differs from the other opioid analgesics in possessing monoaminergic activity in addition to its affinity for the µ opioid receptor. Many opioids are potent histamine releasers producing a variety of haemodynamic changes and anaphylactoid reactions, but the relationship of the appearance of these effects to the histamine plasma concentration is complex and there is no direct and invariable relationship between the two. Studies of the histamine-releasing effects, chiefly centred on morphine, reveal variable findings and conclusions often due to a range of factors including differences in technical measurements, dose, mode of administration, site of injection, the anatomical distribution of histamine receptors and heterogeneity of patient responses. Morphine itself has multiple direct effects on the vasculature and other haemodynamically-active mediators released along with histamine contribute to the variable responses to opioid drug administration. Despite their heavy use and occasional apparent anaphylactic-like side-effects, immunoglobulin E antibody-mediated immediate hypersensitivity reactions to the drugs are not often encountered. Uncertainties associated with skin testing with these known histamine-releasers, and the general unavailability of opioid drug-specific immunoglobulin E antibody tests contribute to the frequent failure to adequately investigate and establish underlying mechanisms of reactions by distinguishing anaphylactoid from true anaphylactic reactions. Clinical implications for diagnosis of reactions and some speculations on the rarity of true Type 1 allergies to these drugs are presented.
Assuntos
Analgésicos Opioides/efeitos adversos , Anafilaxia/induzido quimicamente , Hipersensibilidade a Drogas/etiologia , Liberação de Histamina/efeitos dos fármacos , Analgésicos Opioides/classificação , Analgésicos Opioides/imunologia , Anafilaxia/fisiopatologia , Animais , Humanos , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Receptores Histamínicos/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Cyclodextrins, oligosaccharides linked in a circular arrangement around a central cavity, are used extensively in the pharmaceutical industry to improve drug delivery. Their usefulness depends on their capacity to form a drug inclusion, or host-guest, complex within the cavity. In an attempt to improve the delivery of the widely used neuromuscular blocking drug (NMBD) rocuronium, a rocuronium inclusion complex was formed with a chemically modified γ-cyclodextrin. The high binding affinity and specificity of the modified carrier (named sugammadex) for rocuronium (and other aminosteroid NMBDs) led to its use in anaesthesia as an innovative and useful agent for rapid reversal of rocuronium-induced neuromuscular block by sequestering the drug as an inclusion complex. This, in turn, led to the suggestion that sugammadex might be useful to remove the NMBD from the circulation of patients experiencing rocuronium-induced anaphylaxis, a suggestion subsequently supported in case reports where traditional treatment had failed. Successful resuscitations suggested that sugammadex might be a valuable new treatment for such intractable cases but, given the inappropriateness of clinical trials, confirmation or refutation will have to await the slow accumulation of results of individual case reports. Important questions related to antibody accessibility of drug allergenic structures on the rocuronium-sugammadex inclusion complex, and the competition between sugammadex and IgE antibodies (both free and cell bound) for rocuronium, also remain and can be investigated in vitro. The sugammadex findings indicate that the use of carrier molecules such as the cyclodextrins to improve drug delivery will sometimes give rise to changed immunologic and allergenic behaviour of some drugs and this will have to be taken into account in preclinical drug safety assessments of drug-carrier complexes. The possibility of encapsulating and removing other allergenic drugs, e.g., penicillins and cephalosporins, in cases of difficult-to-reverse anaphylaxis to these drugs is discussed.
Assuntos
Anafilaxia/imunologia , Androstanóis/imunologia , Hipersensibilidade a Drogas/imunologia , Fármacos Neuromusculares não Despolarizantes/imunologia , gama-Ciclodextrinas/imunologia , Anafilaxia/tratamento farmacológico , Androstanóis/química , Ciclodextrinas/química , Ciclodextrinas/imunologia , Ciclodextrinas/uso terapêutico , Hipersensibilidade a Drogas/tratamento farmacológico , Interações Medicamentosas/imunologia , Humanos , Fármacos Neuromusculares não Despolarizantes/química , Período Perioperatório , Rocurônio , Sugammadex , gama-Ciclodextrinas/química , gama-Ciclodextrinas/uso terapêuticoRESUMO
BACKGROUND: The aim of this study was to ascertain whether anaesthetic induction-related anaphylactic bronchospasm could be distinguished from other types of bronchospasm by clinical features and response to treatment. Such features could then be used to identify a group of patients in whom skin testing is indicated. METHODS: We retrospectively studied data from 183 patients referred to an anaesthetic allergy clinic because of bronchospasm during induction. For the analysis, the patients were divided into two groups depending on whether there was evidence suggesting immunological anaphylaxis. RESULTS: When the patients in whom intradermal tests were positive were compared with those in whom intradermal tests were negative, the skin test-positive patients had significantly more severe reactions, and they were more commonly associated with other clinical signs. Mast cell tryptase (MCT) was an excellent discriminator between reactions likely to be allergic and those unlikely to be allergic. CONCLUSIONS: Anaphylactic bronchospasm related to induction of anaesthesia is more likely to be severe than bronchospasm due to non-immune causes. An allergic cause is more likely if there are associated features of anaphylaxis (skin changes, hypotension, angioedema) or elevated MCT. Patients with any of these features should undergo immuno-allergolical investigation.
Assuntos
Anafilaxia/fisiopatologia , Anestesia/efeitos adversos , Espasmo Brônquico/induzido quimicamente , Hipersensibilidade a Drogas/fisiopatologia , Adulto , Análise de Variância , Anafilaxia/diagnóstico , Espasmo Brônquico/classificação , Estudos de Coortes , Hipersensibilidade a Drogas/diagnóstico , Feminino , Liberação de Histamina/efeitos dos fármacos , Humanos , Masculino , Mastócitos/enzimologia , Pessoa de Meia-Idade , Testes Cutâneos , Resultado do Tratamento , Triptases/metabolismoRESUMO
Following the demonstration 25 years ago that substituted ammonium groups on neuromuscular blocking drugs (NMBDs) are the main allergenic structures recognized by IgE antibodies in the sera of some patients who experience anaphylaxis during anaesthesia, immunoassays for these drugs were quickly applied to supplement skin tests in the diagnostic assessment of suspected adverse reactions to anaesthetic agents. Many subjects who react to an NMBD do so on first exposure and this led to the speculation that the origin of allergic sensitization is an environmental agent(s) or another drug containing an ammonium ion. Direct antibody binding and hapten inhibition studies revealed that morphine, which contains a tertiary amino group, was strongly recognized by IgE in sera from anaphylactic patients and a morphine-solid phase immunoassay was found to be superior to NMBD-based assays for the detection of NMBD-reactive IgE antibodies. Extensive inhibition experiments indicate the likelihood of antibody combining site heterogeneity with recognition at the fine structural level of features additional, and adjacent to, ammonium ions. Further quantitative investigations are needed to identify these neighbouring groups on different NMBDs. Recent work has implicated the morphine analogue pholcodine as the sensitizing agent in Norway where, unlike Sweden, anaphylactic reactions to NMBDs are not uncommon and the medicament is available over-the-counter. This has led to the suggestion that allergenic sensitization to the ammonium group of pholcodine may account for the different incidences of anaphylaxis during anaesthesia in the two countries. This work is subjected to critical review and some alternative speculations on the nature and origin of the sensitizing agent(s) are presented.
Assuntos
Formação de Anticorpos/imunologia , Especificidade de Anticorpos/imunologia , Imunoglobulina E/imunologia , Bloqueadores Neuromusculares/imunologia , Anafilaxia/imunologia , Reações Cruzadas/imunologia , Humanos , Hipersensibilidade/imunologia , Derivados da Morfina/imunologia , Bloqueadores Neuromusculares/química , Compostos de Amônio Quaternário/imunologiaRESUMO
BACKGROUND: Latex allergy has emerged as an important cause of allergic reactions particularly in health workers. Due to the lack of a standardized extract for objective skin testing a screening questionnaire was developed. METHODS: At the 1995 Australian Dental Association Conference, all attendees were invited to complete a questionnaire and undergo skin testing to assess the level of latex allergy in this population and to assess the performance of the questionnaire as a screening test for latex allergy. RESULTS: The questionnaire had high specificity but poor sensitivity compared to skin testing with latex extract. CONCLUSION: This study compares at risk individuals identified by a screening questionnaire with those identified by objective skin testing. A questionnaire designed to screen for latex allergy was reliable for identifying those with low risk while overestimating those at risk of true latex allergy, demonstrating the need for objective testing with reliable allergens.
Assuntos
Odontólogos , Hipersensibilidade ao Látex/diagnóstico , Programas de Rastreamento , Doenças Profissionais/diagnóstico , Adulto , Feminino , Hipersensibilidade Alimentar/diagnóstico , Humanos , Hipersensibilidade Imediata/diagnóstico , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Testes Cutâneos , Estatística como Assunto , Inquéritos e QuestionáriosRESUMO
BACKGROUND: An appreciation of the structural heterogeneity of allergenic determinants on penicillins and cephalosporins reveals the importance of side-chain groups and their involvement in many allergies to beta-lactam drugs. Although allergenic cross-reactions between penicillins and cephalosporins are known to occur, the precise molecular bases of such recognitions and cross-sensitivities have rarely been studied and identified. OBJECTIVES: The unexpected finding of a high incidence of positive IgE antibody reactions with both benzylpenicillin and cephalothin prompted serological and immunochemical studies to identify the chemical basis of antibody recognition of these drugs from the two different families of beta-lactam antibiotics. METHODS: Adsorption studies were employed to identify whether or not a single population of antibodies was involved in the recognition of benzylpenicillin and cephalothin. Identification of the fine structural features recognized by IgE antibodies was investigated by quantitative hapten inhibition studies employing carefully selected beta-lactam drugs, analogues and some other structurally related chemicals. RESULTS: Adsorption studies with penicilloic acid-solid phase clearly established that a single population of cross-reacting antibodies recognized both benzylpenicillin and cephalothin. Quantitative inhibition findings, especially with phenylacetic acid and 2-thiopheneacetic acid and with cephaloridine and cefoxitin, which have the same (2-thienyl)methyl side-chain as cephalothin, implicated the methylene group as the focus of the allergenic determinant recognized on benzylpenicillin and cephalothin. In addition to the methylene group, recognition graded into neighbouring structures including the amide group and extended weakly to the beta-lactam ring. CONCLUSIONS: Results confirmed that structural features as small as a methylene group may be allergenically important. In the present case, this group, making up only part of the different side-chains on benzylpenicillin and cephalothin, together with neighbouring structures extending toward the beta-lactam ring, accounted for the cross-reactivity seen between structures that, at first sight, appear to be not closely related. Such subtle, small, common structural features are likely to be immunologically recognized and implicated in allergic reactions to other drugs, including beta-lactam antibiotics.
Assuntos
Antibacterianos/imunologia , Cefalotina/imunologia , Hipersensibilidade a Drogas/imunologia , Epitopos/química , Imunoglobulina E/imunologia , Penicilina G/química , Adsorção , Idoso , Anticorpos/imunologia , Reações Cruzadas , Epitopos/imunologia , Humanos , Masculino , Penicilina G/imunologiaRESUMO
IgE antibodies in the sera of subjects allergic to beta-lactam antibiotics detect a spectrum of specificities ranging from side-chain groups to an entire penicillin or cephalosporin molecule. In addition to such structural heterogeneity of allergenic determinants, IgE antibodies in the sera of different allergic subjects show heterogeneous recognition responses. Detailed immunochemical studies were carried out on the sera of penicillin-allergic subjects that showed selective and unexpected reactions with the frequently prescribed penicillin, amoxicillin. Antibodies from one subject reacted only with the amoxicilloyl determinant while IgE from another subject showed multiple reactivity with penicilloyl and penicillanyl determinants of different penicillins but not with the amoxicilloyl determinant. Quantitative hapten inhibition studies revealed that the combining sites of the former antibodies were complementary to amoxicillin in a form that permits binding to the hydroxyaminobenzyl side-chain and the thiazolidine ring carboxyl. These conditions are satisfied with the drug in the '-oyl' but not in the '-anyl' form which involves linkage through the 2-carboxyl of the thiazolidine ring. With the second serum, adsorption studies showed that the wide-ranging reactivity of IgE was due to a single population of antibodies that detected a common specificity on the different penicillins. Combining site studies revealed clear recognition of the benzyl portion of the side-chain of benzylpenicilloyl, benzylpenicillanyl, ampicilloyl, ampicillanyl and amoxicillanyl determinants when free antibody access to the side-chain was possible but little or no recognition of the ring hydroxyl of amoxicillin. Such uninhibited access may not occur, however, when amoxicillin is conjugated in the '-oyl' form since opening the beta-lactam ring allows increased flexibility and rotation of the molecule and the possibility of close association of the hydroxyaminobenzyl side-chain of amoxicillin with the linked peptide carrier. In such close steric association, H-bonding involving the ring hydroxyl and amino acids of the carrier may prevent antibody access to the side-chain region of the amoxicilloyl determinant.
Assuntos
Amoxicilina/química , Amoxicilina/farmacologia , Hipersensibilidade/imunologia , Imunoglobulina E/química , Imunoglobulina E/imunologia , Rinite/imunologia , Adsorção , Adulto , Idoso , Antibacterianos/farmacologia , Afinidade de Anticorpos , Asma/imunologia , Asma/metabolismo , Sítios de Ligação , Relação Dose-Resposta a Droga , Feminino , Humanos , Ligação de Hidrogênio , Hipersensibilidade/metabolismo , Imunoglobulina E/sangue , Concentração Inibidora 50 , Masculino , Modelos Químicos , Modelos Moleculares , Osteoartrite/imunologia , Osteoartrite/metabolismo , Ligação Proteica , Radioimunoensaio , Rinite/metabolismoRESUMO
OBJECTIVE: To examine the clinical features, treatment, and outcome of anaphylactic and anaphylactoid reactions during cardiac surgery. DESIGN: Retrospective descriptive study. SETTING: A specialized referral anesthetic allergy clinic at a university teaching hospital. PARTICIPANTS: Twenty-three cardiac surgical patients referred after reactions resembling anaphylaxis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The database of the anesthetic allergy clinic was examined, and the data for patients who developed anaphylactic or anaphylactoid reactions were collated and summarized. Twenty-three cardiac surgical patients who experienced signs of anaphylactic or anaphylactoid reactions during anesthesia and surgery from 8 cardiac surgical centers in a major city were referred to the clinic. Cephalosporin antibiotics (30%) and gelatin solutions (Hemaccel) (26%) were the most common (56%) causes of the reactions. Most reactions occurred before the start of cardiopulmonary bypass. Although metaraminol was the first vasopressor used in 18 of 23 patients, it was not effective in 14 patients. Response to epinephrine was immediate and effective in 88% of cases. Rapid placement onto cardiopulmonary bypass facilitated a good outcome and permitted all but one operation to proceed as planned. No intraoperative or postoperative deaths were recorded. CONCLUSION: Of the anaphylactic and anaphylactoid reactions, 60% occurred before cardiopulmonary bypass, and these were caused by antibiotics and gelatin solution. The results from this limited database showed that cardiac surgery proceeded without complications after cardiovascular collapse caused by anaphylactic or anaphylactoid reactions. Rapid institution of cardiopulmonary bypass may be life-saving and should be considered.
Assuntos
Anafilaxia/etiologia , Procedimentos Cirúrgicos Cardíacos , Complicações Intraoperatórias , Adolescente , Adulto , Idoso , Anafilaxia/diagnóstico , Anafilaxia/terapia , Antibacterianos/efeitos adversos , Epinefrina/uso terapêutico , Feminino , Humanos , Masculino , Metaraminol/uso terapêutico , Pessoa de Meia-Idade , Bloqueadores Neuromusculares/efeitos adversos , Plasma , Transfusão de Plaquetas/efeitos adversos , Protaminas/efeitos adversos , Ressuscitação , Estudos Retrospectivos , Vasoconstritores/uso terapêuticoRESUMO
The hypocretins (orexins) are a newly identified peptide family comprised of two peptides, hypocretin-1 and hypocretin-2. Recent observations suggest an involvement of these peptides in the regulation of behavioral state. For example, these peptides are found in a variety of brain regions associated with the regulation of forebrain neuronal and behavioral activity states. Furthermore, when infused into the lateral ventricles in awake animals, hypocretin-1 elicits increased duration of waking beyond that observed in vehicle-treated animals. Previous studies have been limited to an examination of the sleep-wake effects of hypocretin-1 in awake animals. Currently, the sleep-wake effects of hypocretin-2 and the extent to which hypocretins can initiate waking in the sleeping animal remain unclear. To better characterize the wake-promoting actions of the hypocretins, the current studies examined the sleep-wake effects of varying doses (0.007, 0.07 and 0.7 nmol) of hypocretin-1 and hypocretin-2 when administered into sleeping rats (e.g. remote-controlled infusions). Infusions of hypocretin-1 and hypocretin-2 into the lateral ventricles elicited a short latency (0.7 nmol hypocretin-1; 93+/-30 s from the start of the 120-s infusion) increase in electroencephalographic, electromyographic, and behavioral indices of waking. These infusions also produced substantial decreases in slow-wave and rapid-eye movement sleep. Hypocretin-1 was more potent than hypocretin-2 in these actions. Interestingly, hypocretin-1 infused into the fourth ventricle elicited less robust waking which occurred with a longer latency than infusions into the lateral ventricles. These latter observations suggest a forebrain site of action participates in hypocretin-1-induced waking. Within the forebrain, a variety of basal forebrain structures, including the medial preoptic area, the medial septal area and the substantia innominata, receive a moderate hypocretin innervation. Therefore, additional studies examined the sleep-wake effects of bilateral hypocretin-1 infusions into these basal forebrain structures. Robust increases in waking were observed following infusions into, but not outside, the medial septal area, the medial preoptic area and the substantia innominata. These results indicate a potentially prominent role of hypocretins in sleep-wake regulation via actions within certain basal forebrain structures and are consistent with studies indicating a prominent role of hypocretins in sleep/arousal disorders.
Assuntos
Proteínas de Transporte/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular , Neurônios/efeitos dos fármacos , Neuropeptídeos/farmacologia , Prosencéfalo/efeitos dos fármacos , Sono/efeitos dos fármacos , Vigília/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Relação Dose-Resposta a Droga , Eletroencefalografia/efeitos dos fármacos , Eletromiografia/efeitos dos fármacos , Quarto Ventrículo/efeitos dos fármacos , Quarto Ventrículo/fisiologia , Imuno-Histoquímica , Injeções Intraventriculares , Ventrículos Laterais/efeitos dos fármacos , Ventrículos Laterais/fisiologia , Masculino , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Neurônios/citologia , Neurônios/metabolismo , Orexinas , Área Pré-Óptica/citologia , Área Pré-Óptica/efeitos dos fármacos , Área Pré-Óptica/metabolismo , Prosencéfalo/citologia , Prosencéfalo/metabolismo , Ratos , Ratos Sprague-Dawley , Núcleos Septais/citologia , Núcleos Septais/efeitos dos fármacos , Núcleos Septais/metabolismo , Sono/fisiologia , Substância Inominada/citologia , Substância Inominada/efeitos dos fármacos , Substância Inominada/metabolismo , Vigília/fisiologiaRESUMO
Amylin, a calcitonin gene-related peptide-like peptide coreleased with insulin, exerts anorexic effects on central administration. Because previous studies revealed dense amylin binding in the nucleus accumbens (Acb), we investigated the behavioral effects of amylin infusions (10, 30, and 100 ng/side) into Acb subregions. Intra-Acb shell amylin infusions decreased ambulation, rearing, feeding, and drinking in either food-deprived rats or water-deprived rats; motor activity was affected more potently than ingestive behavior. Moreover, intra-Acb shell amylin reduced motor activity in nondeprived rats tested in the absence of food or water, indicating that the expression of amylin's effects is independent of drive or proximal incentives. Intra-Acb core amylin infusions in water-deprived rats also decreased ambulation and water intake, although anterior Acb placements were associated with smaller motor effects, regardless of Acb subregion. In contrast to amylin's effects, intra-Acb shell infusions of orexin-A (50, 100, and 500 ng/side) had no effects on motor activity, feeding, or drinking. Hence the Acb may be a target for behavioral regulation by satiety-related peptides like amylin.
Assuntos
Amiloide/administração & dosagem , Comportamento Alimentar/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular , Atividade Motora/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Proteínas de Transporte/administração & dosagem , Relação Dose-Resposta a Droga , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Privação de Alimentos , Infusões Parenterais , Polipeptídeo Amiloide das Ilhotas Pancreáticas , Masculino , Microinjeções , Neuropeptídeos/administração & dosagem , Núcleo Accumbens/anatomia & histologia , Orexinas , Ratos , Ratos Sprague-Dawley , Privação de ÁguaRESUMO
The multiple drug allergy syndrome, that is, allergic recognition of a variety of drugs that may be both pharmacologically and structurally different, has been little studied and, consequently, the underlying mechanism(s) is unknown. The molecular basis of drug recognition by IgE antibodies found in the sera of subjects exhibiting multiple allergic drug sensitivities was studied by direct binding and quantitative hapten inhibition assays in experiments employing a wide range of carefully selected drugs and other chemicals. Drug recognition was shown to be related to the presence of tertiary and quaternary mono-, di- and trialkyl amino groups, but only if the alkyl groups were 'small' viz., methyl or, perhaps, ethyl. Primary, secondary, and tertiary (with R = 'large' alkyl) groups showed no direct antibody binding or antibody inhibitory activities. Near-neighbour effects of amide and hydroxyl groups appeared to promote weaker antigenic recognition. Results indicate that the antibody recognition and clinical drug allergy spectra of at least some subjects with multiple drug allergies are due to wide ranging immunological cross-reactivities with drugs containing tertiary amino and quaternary ammonium groups which are present in many different pharmacologically active agents. Separate populations of antibodies to other non-cross reacting drugs, for example, beta-lactam antibiotics, may also be present in the sera of such subjects.
Assuntos
Hipersensibilidade a Drogas/imunologia , Adolescente , Adulto , Autoanticorpos/sangue , Hipersensibilidade a Drogas/sangue , Hipersensibilidade a Drogas/fisiopatologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Imunoglobulina E/imunologia , Masculino , Pessoa de Meia-Idade , Relação Estrutura-AtividadeRESUMO
Allergies to antibiotics, mainly the beta-lactam antibiotics (penicillins and cephalosporins), are a common, costly, and potentially dangerous clinical problem encountered in everyday practice. Although studies on the role of non-beta-lactam antibiotics in allergic diseases, particularly the development of specific diagnostic tests and the immunochemical identification of allergenic structures, have been too few and relatively superficial, the situation with the beta-lactam antibiotics is much more advanced. Good progress has been made in identifying the spectra of allergenic determinants recognized by IgE antibodies in the sera of subjects sensitized to penicillins and cephalosporins, and this is aiding the development of an appropriate battery of drug conjugates for use as diagnostic agents. Patient-sensitivity responses to the beta-lactam antibiotics are frequently heterogeneous, and this factor must be taken into account for any diagnostic strategy or future therapy with a penicillin or cephalosporin.
Assuntos
Antibacterianos/efeitos adversos , Epitopos/imunologia , Alérgenos/imunologia , Alérgenos/uso terapêutico , Hipersensibilidade a Drogas/etiologia , Humanos , Hipersensibilidade Imediata/diagnóstico , Hipersensibilidade Imediata/imunologia , Lactamas , Estados Unidos/epidemiologiaRESUMO
Of the very large number and variety of drugs used in medicine, those that are frequently implicated in immediate allergic reactions are relatively small in number and include neuromuscular blocking drugs used in anaesthesia, beta-lactam antibiotics, some other antibacterial agents including broad-spectrum antibiotics and quinolones and, less often, some narcotics. Structure-activity and immunochemical investigations have been most numerous and detailed for neuromuscular blocking drugs and beta-lactams, particularly penicillins. For the former group of drugs, morphine is proving to be a useful agent for the in-vitro detection of clinically relevant neuromuscular blocking drug-- as well as morphine- and fentanyl-reactive IgE antibodies. The employment of so-called 'major' and 'minor' determinants for a range of different penicillins and cephalosporins has revealed previously unsuspected heterogeneity in patient recognition responses, and has reinforced findings on the allergenic importance of side-chain groups. Many reports have been published on anaphylaxis to chlorhexidine, and progress in identifying allergenic determinants is reviewed together with the still inadequately understood subject of IgE antibody recognition of quinolone antibacterial agents.
Assuntos
Alérgenos/química , Hipersensibilidade a Drogas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Hipersensibilidade Imediata , Preparações Farmacêuticas/química , Alérgenos/efeitos adversos , Alérgenos/imunologia , Antibacterianos/química , Antibacterianos/imunologia , Humanos , Morfina/química , Morfina/imunologia , Entorpecentes/química , Entorpecentes/imunologia , Bloqueadores Neuromusculares/química , Bloqueadores Neuromusculares/imunologiaRESUMO
The "jack jumper" ant (Myrmecia pilosula) is a major cause of anaphylaxis in Tasmania. We describe four deaths attributed to stings by this ant between 1980 and 1999. All victims were men aged 40 years or over with significant comorbidities; two were taking angiotensin-converting enzyme inhibitors, which may increase risk of severe anaphylaxis. Three victims had known ant-sting allergy, but only one carried adrenaline, which he did not use. Another believed he was protected by previous attempts at hyposensitisation with whole ant-body extract. There is potential to prevent deaths by careful education of people with known allergy, prescribing of adrenaline for auto-injection and development of an effective hyposensitisation therapy.