RESUMEN
BACKGROUND: Health care is a major source of greenhouse gas emissions, leading to climate change and public health harms. Changes are needed to improve the environmental sustainability of health-care practices, but such changes should not sacrifice patient outcomes or financial sustainability. Alternative dosing strategies that reduce the frequency with which specialty drugs are administered, without sacrificing patient outcomes, are an attractive possibility for improving environmental sustainability. We sought to inform environmentally sustainable cancer care by estimating and comparing the environmental and financial effects of alternative, clinically equivalent strategies for pembrolizumab administration. METHODS: We conducted a retrospective analysis using a cohort of patients from the Veterans Health Administration (VHA) in the USA who received one or more pembrolizumab doses between May 1, 2020, and Sept 30, 2022. Using baseline, real-world administration of pembrolizumab, we generated simulated pembrolizumab use data under three near-equivalent counterfactual pembrolizumab administration strategies defined by combinations of weight-based dosing, pharmacy-level vial sharing and dose rounding, and extended-interval dosing (ie, every 6 weeks). For each counterfactual dosing strategy, we estimated greenhouse gas emissions related to pembrolizumab use across the VHA cohort using a deterministic environmental impact model that estimated greenhouse gas emissions due to patient travel, drug manufacture, and medical waste as the primary outcome measure. FINDINGS: We identified 7813 veterans who received at least one dose of pembrolizumab-containing therapy in the VHA during the study period. 59â140 pembrolizumab administrations occurred in the study period, of which 46â255 (78·2%) were dosed at 200 mg every 3 weeks, 12â885 (21·8%) at 400 mg every 6 weeks, and 14â955 (25·3%) were coadministered with infusional chemotherapies. Adoption of weight-based, extended-interval pembrolizumab dosing (4 mg/kg every 6 weeks) and pharmacy-level stewardship strategies (ie, dose rounding and vial sharing) for all pembrolizumab infusions would have resulted in 24·7% fewer administration events than baseline dosing (44â533 events vs 59â140 events) and an estimated 200 metric tons less CO2 emitted per year as a result of pembrolizumab use within the VHA (650 tons vs 850 tons of CO2, a relative reduction of 24%), largely due to reductions in distance travelled by patients to receive treatment. Similar results were observed when weight-based and extended-interval dosing were applied only to pembrolizumab monotherapy and pembrolizumab in combination with oral therapies. INTERPRETATION: Alternative pembrolizumab administration strategies might have environmental advantages over the current dosing and compounding paradigms. Specialty medication dosing can be optimised for health-care spending and environmental sustainability without sacrificing clinical outcomes. FUNDING: None.
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Anticuerpos Monoclonales Humanizados , Humanos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Estudios Retrospectivos , Estados Unidos , Masculino , Femenino , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Salud Pública , Persona de Mediana Edad , Anciano , Neoplasias/tratamiento farmacológico , Esquema de MedicaciónRESUMEN
BACKGROUND: Sustained elevated concentration of GHGs is predicted to increase global mortality. With the Australian health sector responsible for 7% of the nation's GHG emissions, the benefits and costs of various decarbonisation trajectories are currently being investigated. To assist with this effort, we model the impact earlier decarbonisation has on temperature-related mortality. DESIGN: We used DICE-EMR, an Integrated Assessment Model with an endogenous mortality response, to simulate Australian GHG trajectories and estimate the temperature-related mortality impact of early decarbonisation. We modelled a linear decline of the Australian health sector's and economy's GHG annual emissions to net-zero targets of 2040 and 2050. MAIN OUTCOME MEASURE: Deaths averted and monetary-equivalent welfare gain. RESULTS: Decarbonisation of the Australian health sector by 2050 and 2040 is projected to avert an estimated 69,000 and 77,000 global temperature-related deaths respectively in a Baseline global emissions scenario. Australian economy decarbonisation by 2050 and 2040 is projected to avert an estimated 988,000 and 1,101,000 global deaths respectively. Assuming a low discount rate and high global emissions trajectory, we estimate a monetary equivalent welfare gain of $151 billion if the Australian health sector decarbonises by 2040, only accounting for the benefits in reducing temperature-related mortality. CONCLUSIONS: Earlier decarbonisation has a significant impact on temperature-related mortality. Many uncertainties exist and health impacts other than temperature-related mortality are not captured by this analysis. Nevertheless, such models can help communicate the health risk of climate change and improve climate policy decision making.
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Biodiversidad , Modelos Teóricos , Australia , Cambio Climático , TemperaturaRESUMEN
Many studies project that climate change is expected to cause a significant number of excess deaths. Yet, in integrated assessment models that determine the social cost of carbon (SCC), human mortality impacts do not reflect the latest scientific understanding. We address this issue by estimating country-level mortality damage functions for temperature-related mortality with global spatial coverage. We rely on projections from the most comprehensive published study in the epidemiology literature of future temperature impacts on mortality (Gasparrini et al. in Lancet Planet Health 1:e360-e367, 2017), which estimated changes in heat- and cold-related mortality for 23 countries over the twenty-first century. We model variation in these mortality projections as a function of baseline climate, future temperature change, and income variables and then project future changes in mortality for every country. We find significant spatial heterogeneity in projected mortality impacts, with hotter and poorer places more adversely affected than colder and richer places. In the absence of income-based adaptation, the global mortality rate in 2080-2099 is expected to increase by 1.8% [95% CI 0.8-2.8%] under a lower-emissions RCP 4.5 scenario and by 6.2% [95% CI 2.5-10.0%] in the very high-emissions RCP 8.5 scenario relative to 2001-2020. When the reduced sensitivity to heat associated with rising incomes, such as greater ability to invest in air conditioning, is accounted for, the expected end-of-century increase in the global mortality rate is 1.1% [95% CI 0.4-1.9%] in RCP 4.5 and 4.2% [95% CI 1.8-6.7%] in RCP 8.5. In addition, we compare recent estimates of climate-change induced excess mortality from diarrheal disease, malaria and dengue fever in 2030 and 2050 with current estimates used in SCC calculations and show these are likely underestimated in current SCC estimates, but are also small compared to more direct temperature effects.
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Cambio Climático , Clima , Salud Global , Pobreza , Aclimatación , Aire Acondicionado , Dióxido de Carbono , Frío , Dengue/epidemiología , Diarrea/epidemiología , Predicción , Geografía , Calor , Humanos , Malaria/epidemiología , Medición de Riesgo , Factores de Riesgo , TemperaturaRESUMEN
Many studies project that climate change can cause a significant number of excess deaths. Yet, in integrated assessment models (IAMs) that determine the social cost of carbon (SCC) and prescribe optimal climate policy, human mortality impacts are limited and not updated to the latest scientific understanding. This study extends the DICE-2016 IAM to explicitly include temperature-related mortality impacts by estimating a climate-mortality damage function. We introduce a metric, the mortality cost of carbon (MCC), that estimates the number of deaths caused by the emissions of one additional metric ton of CO2. In the baseline emissions scenario, the 2020 MCC is 2.26 × 10â4 [low to high estimate -1.71× 10â4 to 6.78 × 10â4] excess deaths per metric ton of 2020 emissions. This implies that adding 4,434 metric tons of carbon dioxide in 2020-equivalent to the lifetime emissions of 3.5 average Americans-causes one excess death globally in expectation between 2020-2100. Incorporating mortality costs increases the 2020 SCC from $37 to $258 [-$69 to $545] per metric ton in the baseline emissions scenario. Optimal climate policy changes from gradual emissions reductions starting in 2050 to full decarbonization by 2050 when mortality is considered.
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Contaminantes Atmosféricos/análisis , Dióxido de Carbono/análisis , Cambio Climático , Mortalidad/tendencias , Dióxido de Carbono/economía , Simulación por Computador , Humanos , Temperatura , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Neutrophil-induced cardiomyocyte injury requires the expression of myocyte intercellular adhesion molecule (ICAM)-1 and ICAM-1-CD11b/CD18 adhesion. We have previously demonstrated interleukin (IL)-6 activity in postischemic cardiac lymph; IL-6 is the primary stimulus for myocyte ICAM- 1 induction. Furthermore, we found that induction of IL-6 mRNA occurred very early on reperfusion of the infarcted myocardium. We hypothesized that the release of a preformed upstream cytokine induced IL-6 in leukocytes infiltrating on reperfusion. METHODS AND RESULTS: Constitutive expression of TNF-alpha and not IL-1beta was demonstrated in the normal canine myocardium and was localized predominantly in cardiac mast cells. Mast cell degranulation in the ischemic myocardium was documented by demonstration of a rapid release of histamine and TNF-alpha in the cardiac lymph after myocardial ischemia. Histochemical studies with FITC-labeled avidin demonstrated degranulating mast cells only in ischemic samples of canine myocardium. Immunohistochemistry suggested that degranulating mast cells were the primary source of TNF-alpha in the ischemic myocardium. In situ hybridization studies of reperfused myocardium localized IL-6 mRNA in infiltrating mononuclear cells and in mononuclear cells appearing in the postischemic cardiac lymph within the first 15 minutes of reperfusion. Furthermore, isolated canine mononuclear cells incubated with postischemic cardiac lymph demonstrated significant induction of IL-6 mRNA, which was partially blocked with a neutralizing antibody to TNF-alpha. CONCLUSIONS: Cardiac mast cells degranulate after myocardial ischemia, releasing preformed mediators, such as histamine and TNF-alpha. We suggest that mast cell-derived TNF-alpha may be a crucial factor in upregulating IL-6 in infiltrating leukocytes and initiating the cytokine cascade responsible for myocyte ICAM-1 induction and subsequent neutrophil-induced injury.
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Citocinas/biosíntesis , Gránulos Citoplasmáticos/patología , Mastocitos/patología , Isquemia Miocárdica/patología , Isquemia Miocárdica/fisiopatología , Reperfusión Miocárdica , Factor de Necrosis Tumoral alfa/biosíntesis , Animales , Gránulos Citoplasmáticos/ultraestructura , Perros , Endotelio Vascular/inmunología , Endotelio Vascular/fisiopatología , Liberación de Histamina , Interleucina-1/biosíntesis , Interleucina-6/biosíntesis , Linfa , Mastocitos/ultraestructura , Modelos Cardiovasculares , Isquemia Miocárdica/inmunología , Miocardio/inmunología , Miocardio/metabolismo , Miocardio/patología , ARN Mensajero/biosíntesis , Factores de Tiempo , Transcripción Genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: The late-phase allergic reaction is an eosinophilic inflammatory response that begins several hours after allergen exposure, may persist for 24 hours, and is an important pathogenic mechanism in allergic disease. OBJECTIVE: Cultured naive human mast cells were used to investigate whether mast cells are a direct source of the eosinophil-promoting cytokines IL-5, IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF). METHODS: Naive human mast cells were derived from bone marrow mononuclear cells cultured in the presence of stem-cell factor. Cytokine message and protein production in response to high-affinity IgE receptor ligation of cultured mast cells were measured by semiquantitative polymerase chain reaction and ELISA, respectively. RESULTS: IL-5, IL-3, and GM-CSF messenger RNA increased within 2 hours of mast cell activation, with IL-5 and GM-CSF message remaining elevated for 24 hours, whereas IL-3 mRNA rapidly declined. IL-5 and GM-CSF protein were measurable 4 to 6 hours after stimulation and peaked by 24 and 12 hours, respectively. IL-3 protein was not detectable. CONCLUSION: These findings demonstrate that naive mast cells do not constitutively produce IL-5 or GM-CSF protein but are a major source of these eosinophilotropic cytokines on high-affinity IgE receptor ligation.
Asunto(s)
Factor Estimulante de Colonias de Granulocitos y Macrófagos/biosíntesis , Interleucina-5/biosíntesis , Mastocitos/metabolismo , Receptores de IgE/metabolismo , Secuencia de Bases , Células de la Médula Ósea , Células Cultivadas , Citocinas/análisis , Citocinas/biosíntesis , Citofotometría , Ensayo de Inmunoadsorción Enzimática , Factor Estimulante de Colonias de Granulocitos y Macrófagos/análisis , Liberación de Histamina , Humanos , Inmunohistoquímica , Interleucina-3/análisis , Interleucina-3/biosíntesis , Interleucina-5/análisis , Ligandos , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa/métodos , Regulación hacia ArribaRESUMEN
Non-insulin-dependent diabetes mellitus is a metabolic disease that is common and is characterized by insulin insufficiency and resistance. Measures such as body weight reduction and exercise improve the metabolic defects, but pharmacological therapy is the most frequently used and successful therapy. The sulphonylureas stimulate insulin secretion. Metformin and troglitazone increase disposal and decrease hepatic glucose output without causing hypoglycemia. Acarbose is a dietary aid that spreads the dietary carbohydrate challenge to endogenous insulin over time. These pharmacological agents, either alone or in combination, can improve blood glucose regulation in patients with non-insulin-dependent diabetes mellitus.
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Glucemia/efectos de los fármacos , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Tiazolidinedionas , Acarbosa , Cromanos/uso terapéutico , Quimioterapia Combinada , Humanos , Insulina/uso terapéutico , Metformina/uso terapéutico , Compuestos de Sulfonilurea/uso terapéutico , Tiazoles/uso terapéutico , Trisacáridos/uso terapéutico , TroglitazonaRESUMEN
Herein we report a patient with Behçet's like syndrome, idiopathic CD4+ T-lymphocytopenia, opportunistic infections, and a large polyclonal population of TCR alpha beta + CD4- CD8- T cells. Microfluorimetric analysis of peripheral blood mononuclear cells revealed CD4+ T-cell counts of 10 +/- 5/mm3. The CD3+ T cells were 99% TCR alpha beta +, of which 74 +/- 5% were CD4- CD8-. No clonal populations were detected by southern analysis for T-cell receptor V beta gene rearrangements. No evidence of human immunodeficiency virus infection was present, although nocardia, candida, pneumocystis, cytomegalovirus, and herpes infections were documented. The concomitant presence of opportunistic infections and a large population of TCR alpha beta + CD4- CD8- T cells suggests a pathogenic association and an intense immune response to microbial lipid or lipoglycan antigens presented in the context of CD1 molecules. This case demonstrates the potential for idiopathic CD4+ T-lymphocytopenia to occur in Behçet's-like syndrome with lethal consequences.
Asunto(s)
Síndrome de Behçet/complicaciones , Síndrome de Behçet/inmunología , Infecciones Oportunistas/complicaciones , Infecciones Oportunistas/inmunología , Linfocitopenia-T Idiopática CD4-Positiva/complicaciones , Linfocitopenia-T Idiopática CD4-Positiva/inmunología , Síndrome de Behçet/diagnóstico , Candidiasis/complicaciones , Candidiasis/inmunología , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/inmunología , Resultado Fatal , Seronegatividad para VIH , Infecciones por Herpesviridae/complicaciones , Infecciones por Herpesviridae/inmunología , Humanos , Masculino , Persona de Mediana Edad , Nocardiosis/complicaciones , Nocardiosis/inmunología , Nocardia asteroides , Neumonía por Pneumocystis/complicaciones , Neumonía por Pneumocystis/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Subgrupos de Linfocitos T/inmunologíaRESUMEN
The mechanism of inhibition of gluconeogenesis by phenylalkanoic acids was studied in vitro and in vivo. In vitro production of 14CO2 from labeled glucose or palmitate was not inhibited at 4 mM, a concentration of phenylacetic acid that inhibited gluconeogenesis from lactate/pyruvate. In vitro studies with isolated mitochondria showed that the CoA ester of phenylacetic acid was formed. The parent phenylalkanoic acid had no effect on purified pyruvate carboxylase activity, but phenylacetyl CoA ester decreased pyruvate carboxylation in a concentration-dependent manner. Phenylacetic acid inhibited gluconeogenesis in isolated rat liver cells from 10 mM lactate/1 mM pyruvate (decreased 39%, P < 0.05), but not 10 mM L-glutamine or [14C]aspartate, showing that the inhibition of gluconeogenesis occurred at the level of pyruvate carboxylase. A 20 mg bolus with infusion of 1 mg/min of phenylpropionic acid decreased blood glucose levels of normal [110 +/- 12 to 66 +/- 11 mg/dL, N = 7, P < 0.05 (unpaired Student's t-test vs control)] and streptozocin diabetic rats [295 +/- 14 to 225 +/- 12 mg/dL, N = 7, P < 0.01 (paired t-test vs basal)]. Hepatic glucose production in control and diabetic rats was suppressed under conditions where liver glycogen was depleted, indicating that gluconeogenesis had been inhibited in vivo. The results suggest the possibility that the inappropriate overproduction of glucose can be controlled by inhibitors of pyruvate carboxylase. This class of inhibitors may be useful in the treatment of non-insulin-dependent diabetes mellitus.
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Gluconeogénesis/efectos de los fármacos , Fenilpropionatos/farmacología , Piruvato Carboxilasa/antagonistas & inhibidores , Animales , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucosa/metabolismo , Hipoglucemiantes/farmacología , Hígado/metabolismo , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Non-insulin-dependent diabetes mellitus (NIDDM) is a metabolic disease that is common in the elderly, and is characterised by insulin insufficiency and resistance. Measures such as bodyweight reduction and exercise improve the metabolic defects, but pharmacological therapy is the most frequently used and successful therapy. The sulphonylureas stimulate insulin secretion. Metformin and troglitazone increase glucose disposal and decrease hepatic glucose output without causing hypoglycaemia. Acarbose is a dietary aid that spreads the dietary carbohydrate challenge to endogenous insulin over time. These pharmacological agents, either alone or in combination, should improve blood glucose regulation in patients with NIDDM.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Administración Oral , Anciano , Diabetes Mellitus Tipo 2/etiología , Interacciones Farmacológicas , Quimioterapia Combinada , Humanos , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/farmacologíaRESUMEN
STUDY OBJECTIVE: To investigate the magnitude of serum cholinesterase reduction following repeated therapeutic plasma exchange in patients with neuromuscular disease. DESIGN: Serum cholinesterase activity was measured immediately before and after each plasma exchange in open-label fashion and then analyzed using an analysis of variance model. SETTING: Inpatient neurology and allergy and immunology clinics at a university-affiliated hospital. PATIENTS: 50 consecutive patients with neuromuscular disease. INTERVENTIONS: All patients underwent repeated therapeutic plasma exchange, with each subject receiving up to a maximum of six plasma exchanges. MEASUREMENTS AND MAIN RESULTS: Serum cholinesterase activity was determined spectrophotometrically. Analysis of variance revealed a significant reduction in serum cholinesterase following each therapeutic plasma exchange (p < 0.0001), a significant and consistent reduction across the six treatments (p < 0.0001), and a significant interaction between (before versus after exchange) and treatment number (p < 0.0001). Mean serum cholinesterase before repeated therapeutic plasma exchange was 4817 U/L, but it decreased to a mean of 929 U/L following six plasma exchanges. CONCLUSIONS: There is a significant reduction in serum cholinesterase following repeated therapeutic plasma exchange. It is suggested that drugs metabolized by serum cholinesterase (e.g., succinylcholine, mivacurium) be used with caution in the period immediately following repeated therapeutic plasma exchange.
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Colinesterasas/sangre , Enfermedades Neuromusculares/terapia , Intercambio Plasmático/efectos adversos , Anestesia , Humanos , Isoquinolinas , Mivacurio , Fármacos Neuromusculares Despolarizantes , Fármacos Neuromusculares no Despolarizantes , Factores de Riesgo , SuccinilcolinaRESUMEN
A total of 107, 636 subjects of both sexes who were drafted into the Israeli Defense Forces during 1986 to 1988 were analyzed for the presence of asthma based on questionnaire responses and the results of pulmonary function tests. Most patients (79%) had either mild or inactive disease. Lifetime prevalence increased by 21.7% from 5.3% in 1986 to 6.5% in 1988. The results of a follow-up carried out over 5 to 7 years showed no major change in severity in most patients. The incidence rate remained stable throughout 1987 to 1989 (275, 245, and 243 per 100,000, respectively), without there being any major change in the severity of the asthma during the subsequent 3 to 5 years. It was also revealed that the more physically demanding jobs were associated with a higher prevalence of job transfer. The results of this study suggest that the factors causally associated with asthma are relatively more active during early childhood.
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Asma/epidemiología , Personal Militar , Adulto , Asma/fisiopatología , Femenino , Volumen Espiratorio Forzado , Humanos , Incidencia , Israel/epidemiología , Masculino , PrevalenciaRESUMEN
Following a myocardial infarction the patient with a dilated heart is at greater risk for arrhythmias, congestive failure and sudden death. Studies of myocardial infarction in experimental animals have shown that, with infarcts involving up to 20% of the left ventricle, hypertrophy of surviving myocytes occurs and there are minimal hemodynamic changes. Infarctions greater than 20% induce little additional hypertrophy, and develop increased left ventricular filling pressures and cardiac dilatation. It has been suggested that inadequate hypertrophy of residual myocardium may be a reason for the progressive left ventricular dilatation which occurs after large myocardial infarcts. There are data in humans and animals suggesting that the mass of the left ventricle following a myocardial infarction correlates with improvement in systolic function. Studies from our laboratories have previously shown that 2-tetradecylglycidic acid, an inhibitor of carnitine palmitoyl transferase I, inhibits mitochondrial long-chain fatty acid oxidation and causes myocardial hypertrophy when given to rats by mouth for 7-28 days. We carried out studies to see whether induction of additional myocardial hypertrophy by means of feeding tetradecylglycidic acid might prevent pathologic dilation following a large (50%) infarct in rats. Treatment of control and infarcted rats with tetradecylglycidic acid for 10 days resulted in myocardial hypertrophy in both groups. The rats with myocardial infarction treated with tetradecylglycidic acid had an increase in peak developed left ventricular pressure during abrupt aortic occlusion and lower left ventricular end-diastolic volumes, when compared to untreated rats with myocardial infarction, while the stroke volume was maintained. Thus induction of myocardial hypertrophy with an inhibitor of long-chain fatty acid oxidation retarded the process of left ventricular dilatation and had beneficial effects on systolic function following a large myocardial infarction.
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Cardiomegalia/metabolismo , Compuestos Epoxi/farmacología , Ácidos Grasos/metabolismo , Ácidos Grasos/farmacología , Miocardio/metabolismo , Animales , Cardiomegalia/inducido químicamente , Glucosa/metabolismo , Hemodinámica/efectos de los fármacos , Humanos , Hígado/metabolismo , Masculino , Ratones , Infarto del Miocardio/complicaciones , Infarto del Miocardio/tratamiento farmacológico , Oxidación-Reducción , Ratas , Ratas Sprague-DawleyRESUMEN
Depression is a common problem in elderly patients. The identification and treatment of depression may be more complex in older than in younger patients because of co-existing illnesses and concurrent drug therapy. In addition, a variety of medical conditions and drugs can cause depression. The pharmacology and pharmacokinetics of the cyclic antidepressants have been extensively studied. These agents are hepatically metabolised, often to an active agent. The clearance of the parent compound and the active metabolite(s) may be reduced in elderly patients, causing drug accumulation and increased toxicity. The cyclic antidepressants interact with a variety of neurotransmitters and their receptors. While these effects explain many of the adverse effects of the cyclic antidepressants, it is not clear whether the noradrenergic and serotoninergic effects of such drugs explain their antidepressant effects. Cyclic antidepressant therapy is associated with a variety of adverse effects, including sedation, anticholinergic effects and effects caused by alpha-adrenergic blockade. The cyclic antidepressants differ in their relative ability to cause these adverse effects. The newer cyclic antidepressants such as the selective serotonin reuptake inhibitors are relatively free of sedative and anticholinergic effects, but cause insomnia, nausea and possibly cardiac arrhythmias. All cyclic antidepressants appear to be equally effective. Therefore, the choice of a cyclic antidepressant for a specific patient must be based on several factors, including the risk of adverse effects. In elderly patients, the initial dose of cyclic antidepressants should be lower than the usual dose recommended for younger adults, and titrated slowly. All antidepressants require at least 2 to 3 weeks for their antidepressant effects to be seen. Because depression is a relapsing disease, maintenance antidepressant therapy may be indicated to reduce the risk of recurrent depression. The monoamine oxidase (MAO) inhibitors are effective antidepressants, especially in atypical depression. However, the adverse effects and risk of potentially lethal drug interactions of the older agents preclude their routine use. However, the new reversible MAO inhibitors may prove to be a well tolerated alternative in older patients. Antidepressant therapy should not be avoided simply because of a patient's age. However, the clinician must be conservative in the use of cyclic antidepressants in elderly patients and monitor closely for adverse drug reactions.
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Antidepresivos/farmacología , Depresión/tratamiento farmacológico , Anciano , Antidepresivos/farmacocinética , Antidepresivos/uso terapéutico , Antidepresivos Tricíclicos/farmacocinética , Antidepresivos Tricíclicos/farmacología , Antidepresivos Tricíclicos/uso terapéutico , HumanosRESUMEN
Urticaria and angioedema are usually the clinical consequence of vasoactive mediators derived from mast cells in the skin or mucosal tissues. Efforts to classify mast cell-mediated causes of urticaria and angioedema have generally been frustrated by their diverse pathogenesis and clinical course. The term acute is typically used to describe fleeting lesions whose recurrence does not extend beyond 6 weeks. Chronic is the term used to describe lesions that persist for more than a few hours but usually less than a day, and recurrences extend for more than 6 weeks. These definitions do not take histology into account. Skin biopsies of fleeting lesions demonstrate a paucity of inflammatory cells, whereas more persistent lesions display a spectrum of perivascular cuffing by predominantly T cells and monocytes. The presence of leukocytoclastic vasculitis in persistent lesions indicates an underlying immune complex disease. Many of the physical urticarias have fleeting lesions that can be induced with the appropriate stimulus for years. This review article has emphasized the clinical course and histology of urticaria and angioedema lesions in an effort to provide a more complete understanding of the pathogenesis and appropriate treatment. Clearly, avoidance of an identifiable inciting stimulus is optimum management, although most patients have no etiology defined or the cause is not realistically avoidable. At present, treatment options for these patients rely on antihistamines to control the immediate consequence of mast cell degranulation. Corticosteroids are reserved for the treatment of patients whose urticaria or angioedema lesions persist, reflecting the increasing involvement of mononuclear cells in the disease process. For leukocytoclastic vasculitis, corticosteroids are indicated, and cytotoxic drugs may be required for adequate treatment. Future treatments of urticaria and angioedema will evolve based on elucidation of the relevant cells and soluble mediators and will include counterregulatory or antagonistic peptides and drugs. C1 esterase inhibitor deficiency is a relatively uncommon cause of angioedema but is important to understand because of its ability to clinically mimic mast cell-mediated angioedemas and its unique pathogenesis and treatment. HAE can be divided into two serologic subtypes that simply reflect the location of the defect in one of the codominantly expressed C1-INH genes on chromosome 11. AAE can be divided into two serologic subtypes. AAE type I is due to massive consumption of C1-INH, presumably by tumor-related immune complexes. AAE type II is due to an anti-C1-INH autoantibody.(ABSTRACT TRUNCATED AT 400 WORDS)
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Angioedema , Urticaria , Enfermedad Aguda , Angioedema/diagnóstico , Angioedema/inmunología , Angioedema/terapia , Antifibrinolíticos/uso terapéutico , Enfermedad Crónica , Protocolos Clínicos/normas , Proteínas Inactivadoras del Complemento 1/deficiencia , Proteínas Inactivadoras del Complemento 1/inmunología , Proteínas Inactivadoras del Complemento 1/uso terapéutico , Danazol/uso terapéutico , Diagnóstico Diferencial , Antagonistas de los Receptores Histamínicos/administración & dosificación , Antagonistas de los Receptores Histamínicos/farmacología , Antagonistas de los Receptores Histamínicos/uso terapéutico , Humanos , Inmunidad Celular , Mastocitos/inmunología , Plasma , Recurrencia , Urticaria/diagnóstico , Urticaria/inmunología , Urticaria/terapiaRESUMEN
Currently available pharmacological agents have not been completely successful in restoring euglycemia in the non-insulin-dependent diabetes mellitus (NIDDM) patient. Several new approaches to the therapy of NIDDM have been formulated in recent years and are in various stages of laboratory or pharmaceutical development. Several of these agents are discussed in this article under categories relating to their mechanisms of lowering blood glucose: 1) inhibition of the release or action of counterregulatory hormones; 2) inhibition of postprandial glucose rise; 3) sensitization of tissues to insulin's actions; and 4) inhibition of gluconeogenesis, including inhibition of the long-chain acyl-CoA-carnitine acyltransferase I, the long-chain acylcarnitine translocase, and pyruvate carboxylase.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Hipoglucemiantes/uso terapéutico , Animales , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/sangre , Retroalimentación , Glucagón/análogos & derivados , Glucagón/uso terapéutico , Gluconeogénesis/efectos de los fármacos , Humanos , Insulina/metabolismo , Secreción de InsulinaRESUMEN
BACKGROUND: Previous studies have shown that hypertrophy of surviving myocytes after myocardial infarction (MI) is limited. Progressive ventricular dilatation after MI may occur when compensatory hypertrophy cannot restore left ventricular (LV) wall stress to normal. METHODS AND RESULTS: To test whether induction of additional myocyte hypertrophy might prevent pathological LV remodeling after large MI, we administered 2-tetradecylglycidic acid (TDGA) 20 mg/kg/day to sham-operated (n = 12) and MI (n = 10) rats for 10 days, beginning the third day after infarction. We have previously shown that chronic inhibition of long-chain fatty acid oxidation with TDGA in rats results in myocardial hypertrophy without any apparent impairment of LV systolic function. When compared with untreated MI rats (n = 9), we found that TDGA-treated MI rats had increases in LV weight/body wt, myocyte cross-sectional area, and peak developed LV pressure during abrupt aortic occlusion. MI rats treated with TDGA had lower LV end-diastolic pressures and smaller end-diastolic volumes, whereas stroke volume was maintained. The ex vivo passive LV pressure-volume relation was shifted toward the pressure axis compared with untreated infarct rats. In sham-operated rats, TDGA caused increases in LV weight/body wt, myocyte size, peak developed LV pressure, cardiac index, and stroke volume index, and a shift of the passive LV pressure-volume relation toward the pressure axis. CONCLUSIONS: Induction of myocardial hypertrophy with an inhibitor of long-chain fatty acid oxidation retarded the process of LV dilatation and produced beneficial effects on systolic function after large myocardial infarction. These data support the hypothesis that inadequate hypertrophy of residual myocardium after infarction may contribute to LV dilatation and the development of congestive heart failure.
Asunto(s)
Cardiomegalia/fisiopatología , Compuestos Epoxi/uso terapéutico , Ácidos Grasos/uso terapéutico , Infarto del Miocardio/fisiopatología , Función Ventricular Izquierda/fisiología , Animales , Cardiomegalia/inducido químicamente , Vasos Coronarios/cirugía , Hemodinámica/efectos de los fármacos , Masculino , Microscopía Electrónica , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/patología , Miocardio/ultraestructura , Ratas , Ratas EndogámicasRESUMEN
The authors provide a brief review of the structure of the skin in general and the specializations of the plantar skin and superficial fascia. This review is intended to provide a basis from which the reader can interpret any relevant data in other papers on anatomy and to direct the reader to a variety of more detailed references.