RESUMO
Recent experimental and theoretical results in cat primary visual cortex and in the whisker-barrel fields of rodent primary somatosensory cortex suggest common organizing principles for layer 4, the primary recipient of sensory input from the thalamus. Response tuning of layer 4 cells is largely determined by a local interplay of feed-forward excitation (directly from the thalamus) and inhibition (from layer 4 inhibitory interneurons driven by the thalamus). Feed-forward inhibition dominates excitation, inherits its tuning from the thalamic input, and sharpens the tuning of excitatory cells. Recurrent excitation enhances responses to effective stimuli.
Assuntos
Neocórtex/fisiologia , Potenciais de Ação/fisiologia , Vias Aferentes/fisiologia , Animais , Modelos Neurológicos , Inibição Neural/fisiologia , Córtex Somatossensorial/fisiologia , Tálamo/fisiologia , Vibrissas/fisiologia , Córtex Visual/fisiologiaRESUMO
Vinylogous hydroxamic acids (3-(N-hydroxy-N-alkylamino)-2-propen-1-ones, VHA) were prepared as antiinflammatory agents. The synthesis, chemical properties, and in vitro biological activities of these relatively unexplored compounds are described. The VHAs were prepared by condensation of the appropriate N-substituted hydroxylamine with any of the three reagents: a 1,3-dicarbonyl compound (method A); a vinylogous amide (method B); or an alkynone (method C). The VHAs exist as one or more tautomers in solution with the relative proportions of each being dependent upon the structure of the VHA, solvent, and pH. VHAs undergo some of the typical reactions of hydroxamic acids as well as those of vinylogous amides. VHAs are active as inhibitors of 5-lipoxygenase and of IL-1 biosynthesis in vitro, which do not inhibit other enzymes of the arachidonic acid cascade. They have been shown by ESR studies to bring about inhibition of soybean type 1 15-lipoxygenase by reduction of the active site iron.
Assuntos
Ácidos Hidroxâmicos/síntese química , Interleucina-1/biossíntese , Inibidores de Lipoxigenase/síntese química , Compostos de Vinila/síntese química , Animais , Humanos , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Técnicas In Vitro , Inibidores de Lipoxigenase/química , Inibidores de Lipoxigenase/farmacologia , Ratos , Glycine max , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Compostos de Vinila/química , Compostos de Vinila/farmacologiaRESUMO
Using the isoxazoline as a common structural feature, three series of glycoprotein IIb/IIIa receptor antagonists were evaluated, culminating in the discovery of XR299 (30). In an in vitro assay of platelet inhibition, XR299 had an IC50 of 0.24 microM and was a potent antiplatelet agent when dosed intravenously in a canine model. It was shown through X-ray studies of the cinchonidine salt 49 that the receptor required the 5(R)-stereochemistry for high potency. The ethyl ester prodrug of XR299, XR300 (29), was orally active in the dog.
Assuntos
Isoxazóis/química , Isoxazóis/síntese química , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Animais , Cristalografia por Raios X , Cães , Isoxazóis/metabolismo , Conformação ProteicaRESUMO
Factor Xa (fXa) plays a critical role in the coagulation cascade, serving as the point of convergence of the intrinsic and extrinsic pathways. Together with nonenzymatic cofactor Va and Ca2+ on the phospholipid surface of platelets or endothelial cells, factor Xa forms the prothrombinase complex, which is responsible for the proteolysis of prothrombin to catalytically active thrombin. Thrombin, in turn, catalyzes the cleavage of fibrinogen to fibrin, thus initiating a process that ultimately leads to clot formation. Recently, we reported on a series of isoxazoline and isoxazole monobasic noncovalent inhibitors of factor Xa which show good potency in animal models of thrombosis. In this paper, we wish to report on the optimization of the heterocyclic core, which ultimately led to the discovery of a novel pyrazole SN429 (2b; fXa K(i) = 13 pM). We also report on our efforts to improve the oral bioavailability and pharmacokinetic profile of this series while maintaining subnanomolar potency and in vitro selectivity. This was achieved by replacing the highly basic benzamidine P1 with a less basic benzylamine moiety. Further optimization of the pyrazole core substitution and the biphenyl P4 culminated in the discovery of DPC423 (17h), a highly potent, selective, and orally active factor Xa inhibitor which was chosen for clinical development.
Assuntos
Inibidores do Fator Xa , Fibrinolíticos/síntese química , Pirazóis/síntese química , Inibidores de Serina Proteinase/síntese química , Sulfonas/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Cães , Fibrinolíticos/química , Fibrinolíticos/farmacocinética , Fibrinolíticos/farmacologia , Modelos Moleculares , Pirazóis/química , Pirazóis/farmacocinética , Pirazóis/farmacologia , Ratos , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/farmacocinética , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/farmacocinética , Sulfonas/farmacologiaRESUMO
Modification of the alpha-carbamate substituent of isoxazoline GPIIb/IIIa (alphaIIb beta3) antagonist DMP 754 (7) led to a series of alpha-sulfonamide and alpha-sulfamide diaminopropionate isoxazolinylacetamides which were found to be potent inhibitors of in vitro platelet aggregation. Aryl- and heteroaryl-alpha-sulfonamide groups, in conjunction with (5R)-isoxazoline (2S)-diaminopropionate stereochemistry, were found to impart a pronounced duration of antiplatelet effect in dogs, potentially due to high affinity for unactivated platelets. Isoxazolylsulfonamide 34b (DMP 802), a highly selective GPIIb/IIIa antagonist, demonstrated a prolonged duration of action after iv and po dosing and high affinity for resting and activated platelets. The prolonged antiplatelet profile of DMP 802 in dogs and the high affinity of DMP 802 for human platelets may be predictive of clinical utility as a once-daily antiplatelet agent.
Assuntos
Isoxazóis/síntese química , Inibidores da Agregação Plaquetária/síntese química , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Sulfonamidas/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Cães , Humanos , Técnicas In Vitro , Injeções Intravenosas , Isoxazóis/química , Isoxazóis/metabolismo , Isoxazóis/farmacologia , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/metabolismo , Inibidores da Agregação Plaquetária/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/metabolismo , Sulfonamidas/farmacologia , Fatores de TempoRESUMO
Using isoxazoline XR299 (1a) as a starting point for the design of highly potent, long-duration GPIIb/IIIa antagonists, the effect of placing lipophilic substituents at positions alpha and beta to the carboxylate moiety was evaluated. Of the compounds studied, it was found that the n-butyl carbamate 24u exhibited superior potency and duration of ex vivo antiplatelet effects in dogs. Replacement of the benzamidin-4-yl moiety with alternative basic groups, elimination of the isoxazoline stereocenter, and reversal of the orientation of the isoxazoline ring resulted in lowered potency and/or duration of action.
Assuntos
Isoxazóis/química , Inibidores da Agregação Plaquetária/síntese química , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Administração Oral , Animais , Plaquetas/efeitos dos fármacos , Cães , Desenho de Fármacos , Feminino , Isoxazóis/administração & dosagem , Isoxazóis/farmacologia , Macaca mulatta , Masculino , Modelos Químicos , Papio , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/farmacologiaAssuntos
Abscesso/terapia , Miosite/terapia , Abscesso/cirurgia , Adolescente , Adulto , Idoso , Antibacterianos/uso terapêutico , Criança , Pré-Escolar , Drenagem , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Miosite/tratamento farmacológico , Miosite/cirurgia , Estudos Prospectivos , Infecções Estafilocócicas/tratamento farmacológicoAssuntos
Úlcera Duodenal/cirurgia , Insulina , Úlcera Gástrica/cirurgia , Vagotomia , Glicemia/metabolismo , Úlcera Duodenal/diagnóstico , Feminino , Determinação da Acidez Gástrica , Gastrite/diagnóstico , Humanos , Infusões Parenterais , Insulina/administração & dosagem , Insulina/efeitos adversos , Masculino , Úlcera Gástrica/diagnósticoAssuntos
Fibrinogênio/metabolismo , Radioisótopos do Iodo , Tromboflebite/diagnóstico , Idoso , Humanos , Perna (Membro) , Pessoa de Meia-Idade , Ortopedia , Flebografia , Adesividade Plaquetária , Complicações Pós-Operatórias , Estudos Prospectivos , Radiometria , Tromboflebite/diagnóstico por imagem , Tromboflebite/metabolismoRESUMO
BACKGROUND: Apixaban is an oral, direct and highly selective factor Xa (FXa) inhibitor in late-stage clinical development for the prevention and treatment of thromboembolic diseases. OBJECTIVE: We evaluated the in vitro properties of apixaban and its in vivo activities in rabbit models of thrombosis and hemostasis. METHODS: Studies were conducted in arteriovenous-shunt thrombosis (AVST), venous thrombosis (VT), electrically mediated carotid arterial thrombosis (ECAT) and cuticle bleeding time (BT) models. RESULTS: In vitro, apixaban is potent and selective, with a K(i) of 0.08 nm for human FXa. It exhibited species difference in FXa inhibition [FXa K(i) (nm): 0.16, rabbit; 1.3, rat; 1.7, dog] and anticoagulation [EC(2x) (microm, concentration required to double the prothrombin time): 3.6, human; 2.3, rabbit; 7.9, rat; 6.7, dog]. Apixaban at 10 microm did not alter human and rabbit platelet aggregation to ADP, gamma-thrombin, and collagen. In vivo, the values for antithrombotic ED(50) (dose that reduced thrombus weight or increased blood flow by 50% of the control) in AVST, VT and ECAT and the values for BT ED(3x) (dose that increased BT by 3-fold) were 0.27 +/- 0.03, 0.11 +/- 0.03, 0.07 +/- 0.02 and > 3 mg kg(-1) h(-1) i.v. for apixaban, 0.05 +/- 0.01, 0.05 +/- 0.01, 0.27 +/- 0.08 and > 3 mg kg(-1) h(-1) i.v. for the indirect FXa inhibitor fondaparinux, and 0.53 +/- 0.04, 0.27 +/- 0.01, 0.08 +/- 0.01 and 0.70 +/- 0.07 mg kg(-1) day(-1) p.o. for the oral anticoagulant warfarin, respectively. CONCLUSIONS: In summary, apixaban was effective in the prevention of experimental thrombosis at doses that preserve hemostasis in rabbits.
Assuntos
Pirazóis/farmacologia , Piridonas/farmacologia , Trombose/tratamento farmacológico , Animais , Trombose das Artérias Carótidas , Modelos Animais de Doenças , Cães , Inibidores do Fator Xa , Hemostasia/efeitos dos fármacos , Humanos , Agregação Plaquetária/efeitos dos fármacos , Pirazóis/administração & dosagem , Piridonas/administração & dosagem , Coelhos , Ratos , Trombose/prevenção & controle , Trombose VenosaRESUMO
A prospective randomised trial was carried out on 263 patients admitted for appendicectomy. In those patients with normal or inflamed appendix only, wound sepsis occurred in five (5%) of the 96 patients receiving metronidazole compared with seven (7%) of the 91 controls. In patients with gangrenous or perforated appendices, however, 15 of the 32 patients (47%) receiving ampicillin and five (16%) of 31 patients receiving metronidazole developed a wound infection (p less than 0.025). Therapeutic courses of metronidazole significantly reduced wound sepsis rate in those with gangrenous or perforated appendices. Together with another antibiotic it should form part of the management of such patients, but antibiotics are unlikely to reduce further the low rate of wound infection in patients with normal or inflamed appendices.
Assuntos
Ampicilina/uso terapêutico , Apendicectomia , Metronidazol/uso terapêutico , Infecção da Ferida Cirúrgica/prevenção & controle , Adolescente , Adulto , Idoso , Apendicite/patologia , Apendicite/cirurgia , Criança , Pré-Escolar , Feminino , Gangrena , Humanos , Perfuração Intestinal/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Distribuição AleatóriaRESUMO
Previous experimental studies of both cortical barrel and thalamic barreloid neuron responses in rodent somatosensory cortex have indicated an active role for barrel circuitry in processing thalamic signals. Previous modeling studies of the same system have suggested that a major function of the barrel circuit is to render the response magnitude of barrel neurons particularly sensitive to the temporal distribution of thalamic input. Specifically, thalamic inputs that are initially synchronous strongly engage recurrent excitatory connections in the barrel and generate a response that briefly withstands the strong damping effects of inhibitory circuitry. To test this experimentally, we recorded responses from 40 cortical barrel neurons and 63 thalamic barreloid neurons evoked by whisker deflections varying in velocity and amplitude. This stimulus evoked thalamic response profiles that varied in terms of both their magnitude and timing. The magnitude of the thalamic population response, measured as the average number of evoked spikes per stimulus, increased with both deflection velocity and amplitude. On the other hand, the degree of initial synchrony, measured from population peristimulus time histograms, was highly correlated with the velocity of whisker deflection, deflection amplitude having little or no effect on thalamic synchrony. Consistent with the predictions of the model, the cortical population response was determined largely by whisker velocity and was highly correlated with the degree of initial synchrony among thalamic neurons (R(2) = 0.91), as compared with the average number of evoked thalamic spikes (R(2) = 0.38). Individually, the response of nearly all cortical cells displayed a positive correlation with deflection velocity; this homogeneity is consistent with the dependence of the cortical response on local circuit interactions as proposed by the model. By contrast, the response of individual thalamic neurons varied widely. These findings validate the predictions of the modeling studies and, more importantly, demonstrate that the mechanism by which the cortex processes an afferent signal is inextricably linked with, and in fact determines, the saliency of neural codes embedded in the thalamic response.
Assuntos
Rede Nervosa/fisiologia , Córtex Somatossensorial/fisiologia , Vibrissas/inervação , Animais , Eletrofisiologia , Feminino , Potenciais da Membrana/fisiologia , Rede Nervosa/citologia , Neurônios/fisiologia , Técnicas de Patch-Clamp , Estimulação Física , Núcleos Posteriores do Tálamo/citologia , Núcleos Posteriores do Tálamo/fisiologia , Ratos , Córtex Somatossensorial/citologia , Tálamo/citologia , Tálamo/fisiologiaRESUMO
1. Extracellular single-unit recordings and controlled whisker stimuli were used to compare response properties of cells in the barreloids of the ventral posterior medial nucleus of the thalamus and the barrels in the rat primary somatosensory cortex. Whiskers were deflected alone or in combinations involving up to four immediately adjacent whiskers to assess their relative inhibitory and excitatory contributions to individual receptive fields. Quantitative data were obtained from 51 thalamocortical units (TCUs), 79 "regular-spiking" barrel neurons (RSUs), and 5 "fast-spiking" barrel neurons (FSUs) in 28 normal female adult rats. 2. A random-noise generator was used to produce small, continuously varying whisker movements that were applied to one to four adjacent whiskers while the principal (columnar) whisker was displaced with the use of a ramp-and-hold deflection. RSUs displayed adjacent whisker-evoked inhibition that increased as the number of adjacent whiskers stimulated was incremented. Asymptotic levels of inhibition were reached with the application of the noise stimulus to two or three adjacent whiskers depending on which particular combinations were deflected. By contrast, TCUs and FSUs showed weak, or no, surround inhibition. 3. As the number of adjacent whiskers stimulated increased, the background (prestimulus) activity in TCUs and FSUs increased, whereas displayed background activity in RSUs was relatively unaffected. The increase in background activity observed in the FSUs is hypothesized to mediate adjacent whisker-evoked inhibition in the RSUs. 4. A spatial gradient of adjacent whisker inhibition was observed in RSUs. The caudally adjacent whisker evoked more inhibition than the rostrally adjacent whisker, and the ventral more than the dorsal. A cortical origin for the gradient is suggested by the finding that TCUs did not show a spatial inhibitory gradient. 5. As the noise stimulus was applied to an increasing number of adjacent whiskers, RSUs became more sharply tuned for deflection angles. Neither TCUs nor FSUs showed increases in angular tuning. 6. Inhibition worked disproportionately in RSUs to inhibit those responses that were initially the least robust. For example, inhibition was most effective at reducing responses to nonpreferred versus preferred whisker deflection angles. 7. To assess the principal whisker's effect on adjacent whisker excitatory responses, the noise stimulus was applied to the principal whisker. In RSUs, principal whisker-evoked inhibition was more potent than adjacent whisker-evoked inhibition. FSUs were excited to a greater extent by the application of the noise stimulus to the principal whisker than to adjacent whiskers. TCUs did not display principal whisker-evoked inhibition. 8. Inhibition within the barrel serves as a contrast enhancement mechanism to differentiate small versus large magnitude responses. Less vigorous responses, such as those associated with perturbations of noncolumnar whiskers and inputs from nonoptimal deflection angles, are more strongly suppressed. During active touch, when many whiskers simultaneously palpate an object, these inhibitory interactions could effectively increase the "principal whiskerness" of the cortical column.
Assuntos
Percepção de Distância/fisiologia , Inibição Neural/fisiologia , Neurônios/fisiologia , Córtex Somatossensorial/fisiologia , Tálamo/fisiologia , Vibrissas/fisiologia , Animais , Potenciais Evocados/fisiologia , Feminino , Estimulação Física , Ratos , Ratos Sprague-Dawley , Córtex Somatossensorial/citologia , VibraçãoRESUMO
Controlled whisker stimulation and single-unit recordings were used to elucidate response transformations that occur during the processing of tactile information from ventral posterior medial thalamus (VPM) through cortical columns in the rat whisker/barrel cortex. Whiskers were either deflected alone, using punctate ramp-and-hold stimuli, or in combination with a random noise vibration applied simultaneously to two or more neighboring whiskers. Quantitative data were obtained from five anatomically defined groups of neurons based on their being located in: VPM, layer IV barrels, layer IV septa, supragranular laminae, and infragranular laminae. Neurons in each of these populations displayed characteristic properties related to their response latency and time course, relative magnitudes of responses evoked by stimulus onset versus offset, strength of excitatory responses evoked by the noise stimulus, and/or the degree to which the noise stimulus, when applied to neighboring whiskers, suppressed or facilitated responses evoked by the columnar whisker. Results indicate that within layer IV itself there are at least two anatomically distinct networks, barrel and septum, that independently process afferent information, transforming thalamic input in similar but quantitatively distinguishable ways. Transformed signals are passed on to circuits in supragranular and infragranular laminae. In the case of supragranular neurons, evidence suggests that circuits there function in a qualitatively different fashion from those in layer IV, diminishing response differentials between weak and strong inputs, rather than enhancing them. Compared to layer IV, the greater heterogeneity of receptive field properties in nongranular layers suggests the existence of multiple, operationally distinct local circuits in the output layers of the cortical column.
Assuntos
Neurônios/fisiologia , Córtex Somatossensorial/fisiologia , Tálamo/fisiologia , Vibrissas/inervação , Animais , Estimulação Elétrica , Potenciais Somatossensoriais Evocados/fisiologia , Feminino , Vias Neurais/fisiologia , Estimulação Física , Ratos , Ratos Sprague-Dawley , TatoRESUMO
DuP 654 (2-benzyl-1-naphthol) is a topically active anti-inflammatory agent that was evaluated in phase II clinical trials as an anti-psoriatic agent. The compound is a potent 5-lipoxygenase inhibitor and exhibits inhibitory activity against lipopolysaccharide-stimulated release of interleukin-1 from human monocytes. DuP 654 cannot be used as a systemic anti-inflammatory compound due to its rapid and extensive metabolism. Fifteen analogs were synthesized in an attempt to block the systemic route(s) of metabolism. The compounds were evaluated (IP and PO) in the rat carrageenan paw edema inflammation model with plasma samples taken at 1, 2, 3, and 4 hours post-dose. Substitutions at the 4- and/or 8-positions on the naphthol, and/or on the benzyl group of the DuP 654 molecule were unsuccessful in achieving an analog which displayed both oral activity in the inflammatory model and high plasma levels without manifesting toxicity. The low plasma levels of some analogs may indicate poor absorption, high volume of distribution, or that the substitution did not inhibit the high hepatic "first-pass" metabolism observed with DuP 654. Other compounds not studied but similar in structure to DuP 654 may exhibit rapid and extensive metabolism.
Assuntos
Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Naftóis/farmacologia , Administração Tópica , Animais , Anti-Inflamatórios/sangue , Anti-Inflamatórios/química , Carragenina , Avaliação Pré-Clínica de Medicamentos , Edema/sangue , Edema/tratamento farmacológico , Edema/etiologia , Inflamação/sangue , Masculino , Estrutura Molecular , Naftóis/sangue , Naftóis/química , Ratos , Ratos Endogâmicos , Relação Estrutura-AtividadeRESUMO
Neocortical networks of excitatory and inhibitory neurons can display alpha(a)-frequency rhythms when an animal is in a resting or unfocused state. Unlike some gamma- and beta-frequency rhythms, experimental observations in cats have shown that these alpha-frequency rhythms need not synchronize over long cortical distances. Here, we develop a network model of synaptically coupled excitatory and inhibitory cells to study this asynchrony. The cells of the local circuit are modeled on the neurons found in layer V of the neocortex where alpha-frequency rhythms are thought to originate. Cortical distance is represented by a pair of local circuits coupled with a delay in synaptic propagation. Mathematical analysis of this model reveals that the h and T currents present in layer V pyramidal (excitatory) cells not only produce and regulate the alpha-frequency rhythm but also lead to the occurrence of spatial asynchrony. In particular, these inward currents cause excitation and inhibition to have nonintuitive effects in the network, with excitation delaying and inhibition advancing the firing time of cells; these reversed effects create the asynchrony. Moreover, increased excitatory to excitatory connections can lead to further desynchronization. However, the local rhythms have the property that, in the absence of excitatory to excitatory connections, if the participating cells are brought close to synchrony (for example, by common input), they will remain close to synchrony for a substantial time.
Assuntos
Ritmo alfa , Sincronização Cortical , Modelos Neurológicos , Neocórtex/citologia , Neocórtex/fisiologia , Rede Nervosa/citologia , Rede Nervosa/fisiologia , Potenciais de Ação/fisiologia , Animais , Atenção/fisiologia , Interneurônios/citologia , Interneurônios/fisiologia , Canais Iônicos/fisiologia , Inibição Neural/fisiologia , Células Piramidais/citologia , Células Piramidais/fisiologia , Sinapses/fisiologiaRESUMO
Beginning from a biologically based integrate and fire model of a rat whisker barrel, we employ semirigorous techniques to reduce the system to a simple set of equations, similar to the Wilson-Cowan equations, while retaining the ability for both qualitative and quantitative comparisons with the biological system. This is made possible through the clarification of three distinct measures of population activity: voltage, firing rate, and a new term called synaptic drive. The model is activated by prerecorded neural activity obtained from thalamic "barreloid" neurons in response to whisker stimuli. Output is produced in the form of population PSTHs, one each corresponding to activity of spiny (excitatory) and smooth (inhibitory) barrel neurons, which is quantitatively comparable to PSTHs from electrophysiologically studied regular-spike and fast-spike neurons. Through further analysis, the model yields novel physiological predictions not readily apparent from the full model or from experimental studies.
Assuntos
Redes Neurais de Computação , Córtex Somatossensorial/fisiologia , Vibrissas/fisiologia , Animais , RatosRESUMO
The use of infusion cholecystography as an aid in the diagnosis of acute cholecystitis was investigated in 21 patients. Seventeen of 18 patients (94 per cent) with positive cholecyst-tomograms who underwent laparotomy had confirmation of acutely inflamed gallbladders both macroscopically and histologically. These findings suggest that infusion cholecystography can make a significant contribution in reducing the incidence of misdiagnosis in acute cholecystitis, and that the investigation should be part of the management of patients in whom early surgery is planned.