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Bacteriemia , Clostridioides difficile , Infecciones por Clostridium , Colitis , Bacteriemia/complicaciones , Bacteriemia/tratamiento farmacológico , Clostridioides , Infecciones por Clostridium/complicaciones , Infecciones por Clostridium/tratamiento farmacológico , Colitis/complicaciones , Colitis/tratamiento farmacológico , HumanosAsunto(s)
Antibacterianos/farmacología , Infecciones Bacterianas/tratamiento farmacológico , Inhibidores de la Síntesis de la Proteína/farmacología , Resistencia a la Tetraciclina , Tetraciclina/farmacología , Tetraciclinas/farmacología , Antibacterianos/efectos adversos , Antibacterianos/farmacocinética , Antiportadores/genética , Proteínas Bacterianas/genética , Doxiciclina/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Humanos , Minociclina/análogos & derivados , Minociclina/farmacología , Inhibidores de la Síntesis de la Proteína/efectos adversos , Inhibidores de la Síntesis de la Proteína/farmacocinética , Tetraciclina/efectos adversos , Tetraciclina/farmacocinética , Tetraciclinas/efectos adversos , Tetraciclinas/farmacocinética , TigeciclinaRESUMEN
Adverse drug reactions causing the early discontinuation of therapy are common in patients with HIV infection. Hypersensitivity consisting mainly of a maculopapular rash on the face, extremities and trunk has been observed at a rate higher than expected in patients treated with tenofovir at our clinics. We therefore examined nine patients with suspected tenofovir hypersensitivity reactions in two indigent care HIV clinics. Type I and type IV hypersensitivity may be involved as immunological mechanisms.
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Adenina/análogos & derivados , Erupciones por Medicamentos/etiología , Infecciones por VIH/tratamiento farmacológico , Organofosfonatos/efectos adversos , Inhibidores de la Transcriptasa Inversa/efectos adversos , Piel/efectos de los fármacos , Adenina/efectos adversos , Adulto , Quimioterapia Combinada , Exantema/inducido químicamente , Femenino , Inhibidores de la Proteasa del VIH/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , TenofovirRESUMEN
BACKGROUND: To assess the sensitivity of biochemical, physiological, and pharmacological markers of peripheral norepinephrine (NE) transporter (NET) function, we chronically antagonized NET by a range of doses of duloxetine [(+)-N-methyl-3-(1-naphthalenyloxy)-2 thiophenepropanamine], which blocks the NE reuptake process. METHODS AND RESULTS: Duloxetine was administered in a randomized, placebo-controlled study in 15 healthy volunteers. Plasma from duloxetine-treated subjects (ex vivo effect) dose-dependently decreased radioligand binding to human NET (maximum inhibition was 60%) (P=0.02). The dose of intravenous tyramine required to raise systolic blood pressure by 30 mm Hg (PD30) increased dose-dependently with duloxetine and was significant at the end of the 120-mg/d dosage (P<0.001). The plasma dihydoxyphenylglycol to NE (DHPG/NE) ratio was reduced significantly at 2 weeks of treatment with 80 mg/d duloxetine (11.3 at baseline, 3.4 at 240 mg/d, P<0.001). Plasma NE was significantly increased starting at 120 mg/d duloxetine. Urine results (corrected for 24-hour creatinine excretion) showed a dose-dependent change from the baseline urinary excretion for NE, DHPG, and the DHPG/NE ratio. The most sensitive measure, the DHPG/NE ratio, was significant at the 80-mg dose. Urinary NE excretion was significantly raised after 2 weeks of treatment with 80 mg/d duloxetine (P<0.001), the lowest dose used in the study. CONCLUSIONS: These findings suggest that the degree of NET blockade can be assessed with the plasma or urine DHPG/NE ratio and the pressor effect of tyramine. Also, the DHPG/NE ratio is more sensitive at the lower end of NET inhibition, whereas tyramine exhibits a linear relation, with NET inhibition commencing at a higher dose.
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Inhibidores de Captación Adrenérgica/farmacología , Metoxihidroxifenilglicol/análogos & derivados , Simportadores/antagonistas & inhibidores , Tiofenos/farmacología , Adolescente , Inhibidores de Captación Adrenérgica/administración & dosificación , Adulto , Relación Dosis-Respuesta a Droga , Clorhidrato de Duloxetina , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Metoxihidroxifenilglicol/orina , Norepinefrina/sangre , Norepinefrina/orina , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática , Postura , Ensayo de Unión Radioligante , Sensibilidad y Especificidad , Sístole/efectos de los fármacos , Tiofenos/administración & dosificación , Tiramina/administración & dosificación , Tiramina/farmacologíaRESUMEN
Norepinephrine (NE) is a crucial neurotransmitter involved in autonomic regulation of blood pressure. Dopamine beta-hydroxylase (DBH), the norepinephrine transporter (NET), and the vesicular monoamine transporter subtype 2 catalyze intracellular NE biosynthesis, NE reuptake from the synapse, and vesicular transport, respectively. Genetic disorders in humans have been identified that render DBH, and the NET dysfunctional and result in cardiovascular and neurological abnormalities. Vesicular monoamine transporter subtype 2 (VMAT2) activity protects against neurotoxins, and reduced VMAT2 expression is implicated in drug addiction. Further investigation of the consequences of these genetic abnormalities has been achieved by the construction of mice strains deficient in the genes encoding DBH, NET, and VMAT2.
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Enfermedades del Sistema Nervioso Autónomo/genética , Proteínas de Transporte de Membrana , Ratones Noqueados , Neuropéptidos , Fenotipo , Animales , Modelos Animales de Enfermedad , Dopamina beta-Hidroxilasa/genética , Dopamina beta-Hidroxilasa/metabolismo , Humanos , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Ratones , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática , Simportadores/genética , Simportadores/metabolismo , Proteínas de Transporte Vesicular de Aminas Biógenas , Proteínas de Transporte Vesicular de MonoaminasRESUMEN
OBJECTIVE: To determine whether a diet of high saturated fat and avoidance of starch (HSF-SA) results in weight loss without adverse effects on serum lipids in obese nondiabetic patients. PATIENTS AND METHODS: Twenty-three patients with atherosclerotic cardiovascular disease participated in a prospective 6-week trial at the Christiana Care Medical Center in Newark, Del, between August 2000 and September 2001. All patients were obese (mean +/- SD body mass index [BMI], 39.0+/-7.3 kg/m2) and had been treated with statins before entry in the trial. Fifteen obese patients with polycystic ovary syndrome (BMI, 36.1+/-9.7 kg/m2) and 8 obese patients with reactive hypoglycemia (BMI, 46.8+/-10 kg/m2) were monitored during an HSF-SA diet for 24 and 52 weeks, respectively, between 1997 and 2000. RESULTS: In patients with atherosclerotic cardiovascular disease, mean +/- SD total body weight (TBW) decreased 5.2%+/-2.5% (P<.001) as did body fat percentage (P=.02). Nuclear magnetic resonance spectroscopic analysis of lipids showed decreases in total triglycerides (P<.001), very low-density lipoprotein (VLDL) triglycerides (P<.001), VLDL size (P<.001), large VLDL concentration (P<.001), and medium VLDL concentration (P<.001). High-density lipoprotein (HDL) and LDL concentrations were unchanged, but HDL size (P=.01) and LDL size (P=.02) increased. Patients with polycystic ovary syndrome lost 14.3%+/-20.3% of TBW (P=.008) and patients with reactive hypoglycemia lost 19.9%+/-8.7% of TBW (P<.001) at 24 and 52 weeks, respectively, without adverse effects on serum lipids. CONCLUSION: An HSF-SA diet results in weight loss after 6 weeks without adverse effects on serum lipid levels verified by nuclear magnetic resonance, and further weight loss with a lipid-neutral effect may persist for up to 52 weeks.
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Enfermedades de las Arterias Carótidas/complicaciones , Carbohidratos de la Dieta/administración & dosificación , Grasas de la Dieta/administración & dosificación , Lípidos/sangre , Obesidad/dietoterapia , Adulto , Anciano , Índice de Masa Corporal , Femenino , Humanos , Hipoglucemia/complicaciones , Masculino , Persona de Mediana Edad , Obesidad/complicaciones , Cooperación del Paciente , Síndrome del Ovario Poliquístico/complicaciones , Estudios Prospectivos , Pérdida de PesoRESUMEN
BACKGROUND: Despite the widespread use of tyramine as a pharmacological tool to assess the effects of norepinephrine release from sympathetic nerve terminals, its vascular effects are not adequately characterized. In particular, previous results indicate that intravenous tyramine produces little if any systemic vasoconstriction, suggesting that tyramine does not cause significant norepinephrine release from sympathetic nerves innervating peripheral vascular beds. To test this hypothesis, we determined the effects of intravenous tyramine on local forearm norepinephrine spillover and vascular resistance. METHODS AND RESULTS: Seven healthy subjects were studied with systemic and local forearm norepinephrine spillover and forearm blood flow at baseline, during systemic tyramine infusion, and after sympathetic stimulation induced by the cold pressor test. Tyramine infusion caused a significant increase in systemic and forearm norepinephrine spillover. The amount of norepinephrine released into the forearm by tyramine was similar to that caused by cold pressor stimulation, 0.15+/-0.05 versus 0.18+/-0.05 ng x dL(-1) x min(-1). As expected, forearm vascular resistance increased during the cold pressor test, but tyramine produced forearm vasodilation (4.5+/-1 versus -5+/-1 mm Hg x dL(-1) x min(-1), P<0.03) despite the increase in local norepinephrine spillover. In 6 additional subjects, plasma dopamine increased significantly during tyramine administration, from 11+/-3 to 662+/-105 pg/mL. CONCLUSIONS: Thus, systemic tyramine infusion evokes a significant increase in peripheral norepinephrine spillover, and this, paradoxically, is associated with local vasodilatation rather than vasoconstriction.
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Antebrazo/irrigación sanguínea , Tiramina/administración & dosificación , Vasodilatación/efectos de los fármacos , Adulto , Presión Sanguínea/efectos de los fármacos , Arteria Braquial/efectos de los fármacos , Arteria Braquial/fisiología , Frío , Dopamina/sangre , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Infusiones Intravenosas , Norepinefrina/administración & dosificación , Norepinefrina/sangre , Norepinefrina/farmacocinética , Fenilefrina/administración & dosificación , Fenilefrina/sangre , Fenilefrina/farmacocinética , Estimulación Física , Valores de Referencia , Flujo Sanguíneo Regional/efectos de los fármacos , Flujo Sanguíneo Regional/fisiología , Vasoconstrictores/administración & dosificación , Vasoconstrictores/sangre , Vasoconstrictores/farmacocinética , Vasodilatación/fisiología , Venas/efectos de los fármacos , Venas/fisiologíaRESUMEN
Norepinephrine (NE), a vital neurotransmitter in both the central and peripheral nervous systems, is synthesized by dopamine beta-hydroxylase (DBH) through the oxidation of dopamine (DA) to NE. DBH deficiency is a congenital disorder characterized by severe orthostatic hypotension, ptosis, and retrograde ejaculation. Biochemical features of the syndrome include elevated levels of dopamine, undetectable levels of DBH, undetectable tissue and circulating levels of NE and epinephrine. Molecular genetic analysis studies suggested that DBH deficiency is a Mendelian recessive disorder attributable to heterogenous mutations at the DBH locus. DBH deficiency has been treated effectively with L-threo-3,4-dihydroxyphenylserine (DOPS). DOPS is converted directly to NE through decarboxylation by L-aromatic amino acid decarboxylase (AADC), thereby bypassing DBH. Orthostatic intolerance is a syndrome characterized by lightheadedness, fatigue, altered mentation, syncope, and postural tachycardia. Biochemical features may include plasma NE concentration that is disproportionately high in relation to sympathetic outflow, decreased NE clearance with standing, resistance to the NE-releasing effect of tyramine, and increased sensitivity to adrenergic agonists. A subset of OI patients has pathophysiologic features that have been associated with a genetic polymorphism. The coding mutation, A457P, occurs in one of the alleles of norepinephrine transporter gene of a proband with OI and her family. Alpha-methyl dopa, beta blockers and clonidine, a partial agonist of alpha2-adrenoceptor that acts centrally to reduce sympathetic outflow and lower blood pressure, have been effective in the treatment of this condition. The identification of the genetic polymorphisms involved in the synthesis, transport, storage, and metabolism of the catecholamines may provide new insights into the diagnosis and management of autonomic, cardiovascular, endocrine and psychiatric disorders.
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Catecolaminas/fisiología , Dopamina beta-Hidroxilasa/deficiencia , Simportadores/deficiencia , Mareo/genética , Dopamina beta-Hidroxilasa/genética , Humanos , Norepinefrina/deficiencia , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática , Simportadores/genéticaRESUMEN
Rheumatoid arthritis (RA) is an autoimmune disease associated with altered immunoregulation and resulting in a deforming polyarthritis. Methotrexate (MTX) is a commonly used second line agent for RA, and there have been several recent reports of Epstein-Barr virus (EBV)-associated polyclonal B cell lymphoproliferative disorder in MTX-treated RA patients. The patient in this report had long standing RA treated with MTX and had recently begun taking a cyclooxygenase-2 (COX-2) inhibitor. She developed a febrile illness associated with severe pancytopenia and leukocytoclastic vasculitic rash followed by diffuse adenopathy, with serologic and pathologic evidence of EBV infection. Previous studies have demonstrated the interaction of MTX and a variety of non-steroidal, anti-inflammatory drugs (NSAIDs) with various clinical manifestations including acute renal failure, pancytopenia, vomiting, diarrhea, elevated liver transaminases, jaundice, mucosal ulcerations, and pyrexia. However, we have not identified previous reports suggesting interaction between MTX and COX-2 inhibitors. We hypothesize that decreased renal elimination of MTX induced by the COX-2 inhibitor resulted in enhanced hematopoietic toxicity and immunosuppression causing the EBV-associated lymphoproliferative disease.