RESUMEN
We report an unusual case of a foreign body removed from the urinary bladder of a 63-year-old male which mimicked a parasitic worm. The foreign body was identified as an artificial fishing worm by morphological comparison to a similar commercially produced product and by infrared spectrum analysis.
Asunto(s)
Cuerpos Extraños/diagnóstico , Cuerpos Extraños/patología , Vejiga Urinaria/patología , Animales , Diagnóstico Diferencial , Cuerpos Extraños/cirugía , Humanos , Masculino , Persona de Mediana Edad , Análisis Espectral , Tomografía Computarizada por Rayos X , Vejiga Urinaria/cirugíaRESUMEN
OBJECTIVES: To test the hypothesis that heavy metal toxicity and consumption of thiaminase-containing foods predispose to symptomatic thiamine deficiency. STUDY DESIGN: In a case-control study, thiamine diphosphate (TDP) blood concentrations were measured in 27 infants diagnosed with beriberi at a rural clinic, as well as their mothers and healthy Cambodian and American controls. Blood and urine levels of lead, arsenic, cadmium, mercury, and thallium were measured. Local food samples were analyzed for thiaminase activity. RESULTS: Mean TDP level among cases and Cambodian controls was 48 and 56 nmol/L, respectively (P = .08) and was 132 nmol/L in American controls (P < .0001 compared with both Cambodian groups). Mean TDP level of mothers of cases and Cambodian controls was 57 and 57 nmol/L (P = .92), and was 126 nmol/L in American mothers (P < .0001 compared with both Cambodian groups). Cases (but not controls) had lower blood TDP levels than their mothers (P = .02). Infant TDP level decreased with infant age and was positively associated with maternal TDP level. Specific diagnostic criteria for beriberi did not correlate with TDP level. There was no correlation between heavy metal levels and either TDP level or case/control status. No thiaminase activity was observed in food samples. CONCLUSIONS: Thiamine deficiency is endemic among infants and nursing mothers in rural southeastern Cambodia and is often clinically inapparent. Neither heavy metal toxicity nor consumption of thiaminase-containing foods account for thiamine deficiency in this region.
Asunto(s)
Beriberi/diagnóstico , Deficiencia de Tiamina/diagnóstico , Deficiencia de Tiamina/etiología , Pueblo Asiatico , Beriberi/complicaciones , Cambodia , Estudios de Casos y Controles , Femenino , Hematócrito , Humanos , Hidrolasas/metabolismo , Lactante , Recién Nacido , Masculino , Metales Pesados/toxicidad , Población Rural , Tiamina , Deficiencia de Tiamina/complicaciones , Tiamina Pirofosfato/sangreRESUMEN
BACKGROUND: We describe a heart transplant patient with painful periostitis and exostoses who was receiving long-term therapy with voriconazole, which is a fluoride-containing medication. Elevated plasma and bone fluoride levels were identified. Discontinuation of voriconazole therapy led to improvement in pain and reduced fluoride and alkaline phosphatase levels. METHODS: To determine whether voriconazole is a cause of fluoride excess, we measured plasma fluoride levels in 10 adult post-transplant patients who had received voriconazole for at least 6 months and 10 post-transplant patients who did not receive voriconazole. To assess the effect of renal insufficiency on fluoride levels in subjects receiving voriconazole, half were recruited on the basis of a serum creatinine level of ≥1.4 mg/dL on their most recent measurement, whereas the other 5 subjects receiving voriconazole had serum creatinine levels <1.4 mg/dL. All control subjects had serum creatinine levels of ≥1.4 mg/dL. Patients were excluded from the study if they received a fluorinated pharmaceutical other than voriconazole. RESULTS: All subjects who received voriconazole had elevated plasma fluoride levels, and no subjects in the control group had elevated levels (14.32 µmol/L ± 6.41 vs 2.54 ± 0.67 µmol/L; P<.001). Renal function was not predictive of fluoride levels. Plasma fluoride levels remained significantly higher in the voriconazole group after adjusting for calcineurin inhibitor levels and doses. Half of the voriconazole group subjects had evidence of periostitis, including exostoses in 2 patients. Discontinuation of voriconazole therapy in patients with periostitis resulted in improvement of pain and a reduction in alkaline phosphatase and fluoride levels. CONCLUSIONS: Voriconazole is associated with painful periostitis, exostoses, and fluoride excess in post-transplant patients with long-term voriconazole use.
Asunto(s)
Antifúngicos/efectos adversos , Antifúngicos/uso terapéutico , Fluoruros/sangre , Trasplante de Corazón/efectos adversos , Periostitis/inducido químicamente , Pirimidinas/efectos adversos , Pirimidinas/uso terapéutico , Triazoles/efectos adversos , Triazoles/uso terapéutico , Adulto , Anciano , Fosfatasa Alcalina/sangre , Exostosis/inducido químicamente , Femenino , Humanos , Masculino , Persona de Mediana Edad , Plasma/química , Trasplante , VoriconazolRESUMEN
This study examines the relationship between blood concentrations of venlafaxine and its active metabolite, O-desmethyl venlafaxine (ODV), and genetic variants of the cytochrome P450 enzymes CYP2D6 and CYP2C19 in human subjects. Trough blood concentrations were measured at steady state in patients treated with venlafaxine extended release in a clinical practice setting. CYP2D6 and CYP2C19 genotypes were converted to activity scores based on known activity levels of the two alleles comprising a genotype. After adjusting for drug dose and gender effects, higher CYP2D6 and CYP2C19 activity scores were significantly associated with lower venlafaxine concentrations (P < 0.001 for each). Only CYP2D6 was associated with the concentration of ODV (P < 0.001), in which genotypes with more active alleles were associated with higher ODV concentrations. The sum of venlafaxine plus ODV concentration showed the same pattern as venlafaxine concentrations with CYP2D6 and CYP2C19 genotypes with higher activity scores being associated with a lower venlafaxine plus ODV concentration (2D6 P = 0.01; 2C19 P < 0.001). Because allelic variants in both CYP2D6 and CYP2C19 influence the total concentration of the active compounds venlafaxine and ODV, both CYP2D6 and CYP2C19 genotypes should be considered when using pharmacogenomic information for venlafaxine dose alterations.
Asunto(s)
Ciclohexanoles/farmacocinética , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Polimorfismo Genético , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Hidrocarburo de Aril Hidroxilasas/genética , Hidrocarburo de Aril Hidroxilasas/metabolismo , Ciclohexanoles/administración & dosificación , Ciclohexanoles/sangre , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP2D6/farmacocinética , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/sangre , Clorhidrato de Venlafaxina , Adulto JovenRESUMEN
BACKGROUND: Nephrogenic systemic fibrosis (NSF) is a rare, potentially fatal fibrosing disorder associated with renal insufficiency and gadolinium (Gd)-based contrast exposure. The cause remains unknown. To date, all efforts to investigate skin Gd concentrations in patients with NSF have been performed on paraffin-embedded samples, and Gd deposition has not been correlated with disease activity by a statistically significant analysis. OBJECTIVE: We sought to: (1) quantify Gd concentration in fresh tissue skin biopsy specimens; (2) quantify and compare synchronous Gd concentration of affected skin and unaffected skin in patients with NSF (n = 13) with a control group (n = 13); and (3) quantify serum Gd. METHODS: We used inductively coupled plasma mass spectrometry. RESULTS: In patients with NSF, the mean ratio of paired Gd concentrations of affected skin to unaffected skin was 23.1, ranging from 1.2 to 88.9. Mean serum Gd concentrations in patients with NSF were 4.8 ng/mL, which is more than 10 times the level in control patients. A statistically significant correlation existed between serum and affected skin Gd concentrations (r(2) = .74, P < .0001). LIMITATIONS: Because of the feasibility of this study, the main limitation was the small sample size (n = 13 affected and 13 control). CONCLUSIONS: Determination of Gd concentrations in fresh skin samples and serum using inductively coupled plasma mass spectrometry demonstrates significant differences in the amounts of Gd in involved versus nonlesional skin of patients with NSF. This supports the role of differential free Gd deposition from Gd-based contrast in the pathogenesis of NSF.
Asunto(s)
Medios de Contraste/farmacocinética , Gadolinio/farmacocinética , Dermopatía Fibrosante Nefrogénica/sangre , Insuficiencia Renal Crónica/sangre , Piel/efectos de los fármacos , Anciano , Anciano de 80 o más Años , Biopsia con Aguja , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Espectrometría de Masas/métodos , Persona de Mediana Edad , Dermopatía Fibrosante Nefrogénica/diagnóstico por imagen , Dermopatía Fibrosante Nefrogénica/patología , Valor Predictivo de las Pruebas , Cintigrafía , Valores de Referencia , Insuficiencia Renal Crónica/diagnóstico por imagen , Insuficiencia Renal Crónica/patología , Muestreo , Sensibilidad y Especificidad , Índice de Severidad de la Enfermedad , Piel/metabolismo , Absorción Cutánea/efectos de los fármacosRESUMEN
To obtain preliminary evidence on the safety and efficacy of high dose nicotine patch therapy among smokeless tobacco (ST) users who consume > or =3 cans of ST per week, we conducted a randomized, placebo-controlled clinical trial with 42 ST users randomized to nicotine patch doses of 21, 42, and 63 mg/day or placebo. Serum nicotine concentrations were measured during ad libitum ST use and nicotine replacement therapy, and percentages of nicotine replacement were calculated. We observed substantial inter-subject variability in nicotine concentrations with ad lib ST use. The mean percentage replacement of ad lib ST use serum nicotine concentrations approximated 100% with the 42 mg/day patch dose (mean+/-S.D., 98.4%+/-45%). Dosing with the 21 mg/day nicotine patch was associated with mean "under-replacement" (53.2%+/-17.1%), and the 63 mg/day nicotine was associated with mean "over-replacement" (159.2%+/-121.9%). We observed symptoms of nausea consistent with nicotine toxicity in two subjects in the 63 mg/day group while no subjects in the 42 mg/day reported these symptoms. We conclude that the use of 42 mg/day nicotine patch therapy is safe and should be considered as initial therapy in the clinical setting among ST users who use > or =3 cans/week.
Asunto(s)
Nicotina/administración & dosificación , Tabaquismo/rehabilitación , Tabaco sin Humo , Administración Cutánea , Adulto , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Persona de Mediana Edad , Nicotina/efectos adversos , Nicotina/farmacocinética , Tabaquismo/sangre , Resultado del TratamientoRESUMEN
In patients with sickle cell disease or beta-thalassemia receiving RBC transfusions for a long period, a precise knowledge of the liver iron concentration (LIC) is essential for treatment. Patients underwent LIC and liver pathology assessment by duplicate biopsies in 2 passes from the same local liver site. Fresh tissue cores in trace element-free containers and tissues from dissolved paraffin-embedded cores were analyzed. LIC measurements in each of 2 paraffin-embedded cores did not differ significantly (median, 12,455 vs 12,153 microg/g dry weight; n = 29). A significant difference was observed when 1 fresh tissue sample and 1 paraffin-embedded core were analyzed (median, 11,716 vs 12,864 microg/g dry weight; n = 16; P < .001) with a median disagreement between LIC measurements of 23.0%. We found high agreement in LICs between liver biopsy specimens processed by the paraffin-embedding technique but overestimation of LICs in comparison with desiccated fresh tissue samples.
Asunto(s)
Transfusión de Eritrocitos/efectos adversos , Hemosiderosis/metabolismo , Hierro/metabolismo , Hígado/metabolismo , Biopsia con Aguja , Femenino , Hemosiderosis/patología , Humanos , Hígado/patología , Masculino , Adhesión en ParafinaRESUMEN
OBJECTIVE: To determine the concentration of nicotine and cotinine in maternal blood and neonatal cord blood among pregnant Alaska Native women and to assess the neonates for neurobehavioral effects. METHODS: In a nonrandomized, clinical observational pilot trial, 60 pregnant Alaska Native women were enrolled for assessment of Iqmik (a mixture of leaf tobacco and ash) and other tobacco use during pregnancy and at delivery. Neonatal cord blood, nicotine and cotinine concentrations were obtained, and neonatal neurobehavioral effects were assessed using the Lipsitz scale. RESULTS: At delivery, there were 22 subjects who reported using only Iqmik, and 10 who used other tobacco products. Subjects who reported using only Iqmik prior to delivery had higher concentrations of cotinine (167+/-116 vs. 81+/-100) in maternal blood (rank sum test, p=0.036) and higher concentrations of nicotine (8.4+/-7.3 vs. 4.4+/-5.1, p=0.048) and cotinine (153+/-115 vs. 70+/-95, p=0.048) in cord blood compared to subjects who reported using other tobacco products. Neurobehavioral signs as assessed by the Lipsitz score were increased in neonates born to mothers using only Iqmik (3.7+/-1.8, p=0.011), or to mothers using other tobacco products (3.4+/-1.4, p=0.034) compared to neonates born to women who reported no tobacco use (1.8+/-1.4). CONCLUSIONS: Mothers who use Iqmik and their neonates have higher cotinine concentrations compared to mothers who use cigarettes and/or other forms of tobacco. Neurobehavioral signs occur in neonates born to women who use Iqmik but also in neonates born to mothers who use other forms of tobacco during pregnancy.
Asunto(s)
Enfermedades del Sistema Nervioso/etiología , Tabaquismo/complicaciones , Tabaco sin Humo/efectos adversos , Adulto , Alaska , Cotinina/sangre , Estudios de Factibilidad , Femenino , Sangre Fetal , Humanos , Recién Nacido , Enfermedades del Recién Nacido/etiología , Inuk , Nicotina/sangre , Proyectos Piloto , Embarazo , Resultado del Embarazo , Efectos Tardíos de la Exposición Prenatal/sangre , Fumar/efectos adversosRESUMEN
OBJECTIVES: To describe a homemade form of smokeless tobacco known as Iqmik used among Alaska Natives residing in western Alaska. METHODS: Individual and small-group interviews were conducted with 23 adult Alaska Natives. The major themes from the interview data were summarized. A chemical analysis was conducted of the alkalinity of a sample of fungus ash used to prepare Iqmik. RESULTS: Few adverse health effects of using Iqmik were reported. The alkalinity of the sample of fungus ash was high (pH=10.9). CONCLUSION: The high alkalinity of Iqmik may contribute to the higher rates of tobacco use in this population.
Asunto(s)
Inuk , Tabaco sin Humo/efectos adversos , Adolescente , Adulto , Alaska , Femenino , Hongos/química , Humanos , Entrevistas como Asunto , Masculino , Persona de Mediana Edad , Tabaco sin Humo/análisis , Tabaco sin Humo/químicaRESUMEN
OBJECTIVES: Cobalt (Co) exposure has been documented to result in increased erythropoiesis. To evaluate the potential for implant-derived Co toxicity, we examined the relationship between serum Co (sCo) and erythrocyte counts (ERY) in a metal-containing total-hip arthroplasty implant population. METHODS: Retrospective review of sCo concentrations identified 77 patients with concomitant ERY. Statistical analysis was performed to determine if there was a significant difference in ERY for patients divided into clinically relevant sCo ranges. A single detailed case review of a patient with a loose mal-positioned acetabular component and significantly elevated sCo was also performed for symptoms thought to arise from Co toxicity. RESULTS: Statistical difference in ERY was not observed between patients with significantly elevated (>10 ng/mL), elevated (4-10 ng/mL), modestly elevated (1.0-3.9 ng/mL), or normal (<1.0 ng/mL) sCo. While the detailed case report was unremarkable for any of the clinical symptoms previously reported to be associated with Co toxicity and no increase in ERY was observed, this patient's sCo was 84 ng/mL. CONCLUSIONS: Increased erythropoiesis was not observed in patients with implant-derived increased sCo. Even with a sCo 100 × the upper-limit of normal, the patient presented did not have increased ERY nor exhibit any symptoms ascribed with Co toxicity.
Asunto(s)
Cobalto/efectos adversos , Cobalto/sangre , Prótesis de Cadera/efectos adversos , Acetábulo/diagnóstico por imagen , Adulto , Anciano , Recuento de Eritrocitos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pelvis/diagnóstico por imagen , Radiografía , Estudios RetrospectivosRESUMEN
Unlike cigarette smokers, spit tobacco (ST) users absorb a significant amount of nicotine through the gastrointestinal tract while swallowing tobacco juice. The majority of the absorbed nicotine is rapidly converted to cotinine during first-pass hepatic metabolism. This process potentially compromises the utility of cotinine as a biomarker for systemic nicotine exposure in ST users. To investigate this question, we correlated nicotine and cotinine concentrations with clinical measures of ST use in 68 daily ST users enrolled in a non-nicotine pharmacologic intervention trial. We found that a higher frequency of swallowing tobacco juice (P=.007) was an independent predictor of higher serum cotinine concentrations. Serum nicotine concentrations, on the other hand, were not correlated with a higher frequency of swallowing. In the absence of a reliable way to measure frequency of swallowing, we conclude that cotinine should not be used for guiding clinical decisions that depend upon a precise quantification of systemic nicotine exposure, such as tailored nicotine replacement therapy.
Asunto(s)
Cotinina/sangre , Tabaquismo/diagnóstico , Tabaco sin Humo/farmacocinética , Adulto , Anciano , Biomarcadores/sangre , Deglución , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nicotina/administración & dosificación , Nicotina/sangre , Estudios Prospectivos , Tabaquismo/sangreRESUMEN
BACKGROUND AND OBJECTIVES: Kidney stones are heterogeneous but often grouped together. The potential effects of patient demographics and calendar month (season) on stone composition are not widely appreciated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The first stone submitted by patients for analysis to the Mayo Clinic Metals Laboratory during 2010 was studied (n=43,545). Stones were classified in the following order: any struvite, any cystine, any uric acid, any brushite, majority (≥50%) calcium oxalate, or majority (≥50%) hydroxyapatite. RESULTS: Calcium oxalate (67%) was the most common followed by hydroxyapatite (16%), uric acid (8%), struvite (3%), brushite (0.9%), and cystine (0.35%). Men accounted for more stone submissions (58%) than women. However, women submitted more stones than men between the ages of 10-19 (63%) and 20-29 (62%) years. Women submitted the majority of hydroxyapatite (65%) and struvite (65%) stones, whereas men submitted the majority of calcium oxalate (64%) and uric acid (72%) stones (P<0.001). Although calcium oxalate stones were the most common type of stone overall, hydroxyapatite stones were the second most common before age 55 years, whereas uric acid stones were the second most common after age 55 years. More calcium oxalate and uric acid stones were submitted in the summer months (July and August; P<0.001), whereas the season did not influence other stone types. CONCLUSIONS: It is well known that calcium oxalate stones are the most common stone type. However, age and sex have a marked influence on the type of stone formed. The higher number of stones submitted by women compared with men between the ages of 10 and 29 years old and the change in composition among the elderly favoring uric acid have not been widely appreciated. These data also suggest increases in stone risk during the summer, although this is restricted to calcium oxalate and uric acid stones.
Asunto(s)
Cálculos Renales/química , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Oxalato de Calcio/análisis , Fosfatos de Calcio/análisis , Niño , Preescolar , Cistina/análisis , Durapatita/análisis , Femenino , Humanos , Lactante , Recién Nacido , Compuestos de Magnesio/análisis , Masculino , Persona de Mediana Edad , Fosfatos/análisis , Estaciones del Año , Factores Sexuales , Estruvita , Estados Unidos , Ácido Úrico/análisis , Adulto JovenRESUMEN
The condition of hereditary hemochromatosis (HH) is caused by gene-dependent protein abnormalities involved in iron absorption, storage, or modulation of iron; these abnormalities result in iron overload. The clinical laboratory plays a significant role in case finding, diagnostic validation, and monitoring HH therapy. Elevated serum iron, transferrin saturation, and ferritin suggest HH, but results can also indicate other forms of hepatocyte injury such as alcoholic or viral hepatitis, or other inflammatory disorders involving the liver. In the context of elevated serum iron, transferrin saturation, and ferritin, and after ruling out secondary causes of iron overload, HFE gene evaluation is the preferred test to confirm the diagnosis of HH. However, 5% to 15% of patients with phenotypic HH do not have HFE gene mutations. In these cases, MRI evaluation or liver biopsy with iron quantification is indicated. The clinical role of hepcidin, the iron modulating protein, is undetermined at this time. Because hepcidin also plays a key role in antimicrobial and inflammatory activities, interpretation of hepcidin serum or urine concentration will require thorough understanding of its complex role in iron regulation.
Asunto(s)
Hemocromatosis/diagnóstico , Péptidos Catiónicos Antimicrobianos/metabolismo , Cobre/metabolismo , Ferritinas/metabolismo , Hemocromatosis/genética , Hemocromatosis/metabolismo , Hemocromatosis/terapia , Hepcidinas , Humanos , Hierro/metabolismo , Hígado/metabolismo , Flebotomía , Transferrina/metabolismoRESUMEN
OBJECTIVES: This study was designed to determine whether genotype testing for patients initiating warfarin treatment will reduce the incidence of hospitalizations, including those due to bleeding or thromboembolism. BACKGROUND: Genotypic variations in CYP2C9 and VKORC1 have been shown to predict warfarin dosing, but no large-scale studies have prospectively evaluated the clinical effectiveness of genotyping in naturalistic settings across the U.S. METHODS: This national, prospective, comparative effectiveness study compared the 6-month incidence of hospitalization in patients receiving warfarin genotyping (n = 896) versus a matched historical control group (n = 2,688). To evaluate for temporal changes in the outcomes of warfarin treatment, a secondary analysis compared outcomes for 2 external control groups drawn from the same 2 time periods. RESULTS: Compared with the historical control group, the genotyped cohort had 31% fewer hospitalizations overall (adjusted hazard ratio [HR]: 0.69, 95% confidence interval [CI]: 0.58 to 0.82, p < 0.001) and 28% fewer hospitalizations for bleeding or thromboembolism (HR: 0.72, 95% CI: 0.53 to 0.97, p = 0.029) during the 6-month follow-up period. Findings from a per-protocol analysis were even stronger: 33% lower risk of all-cause hospitalization (HR: 0.67, 95% CI: 0.55 to 0.81, p < 0.001) and 43% lower risk of hospitalization for bleeding or thromboembolism (HR: 0.57, 95% CI: 0.39 to 0.83, p = 0.003) in patients who were genotyped. During the same period, there was no difference in outcomes between the 2 external control groups. CONCLUSIONS: Warfarin genotyping reduced the risk of hospitalization in outpatients initiating warfarin. (The Clinical and Economic Impact of Pharmacogenomic Testing of Warfarin Therapy in Typical Community Practice Settings [MHSMayoWarf1]; NCT00830570).
Asunto(s)
Anticoagulantes/efectos adversos , Hemorragia/genética , Hospitalización/estadística & datos numéricos , Farmacogenética , Tromboembolia/genética , Warfarina/efectos adversos , Anciano , Anticoagulantes/uso terapéutico , Hidrocarburo de Aril Hidroxilasas/genética , Estudios de Casos y Controles , Intervalos de Confianza , Citocromo P-450 CYP2C9 , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Genotipo , Hemorragia/inducido químicamente , Hemorragia/mortalidad , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Oxigenasas de Función Mixta/genética , Probabilidad , Modelos de Riesgos Proporcionales , Medición de Riesgo , Análisis de Supervivencia , Tromboembolia/inducido químicamente , Tromboembolia/mortalidad , Resultado del Tratamiento , Vitamina K Epóxido Reductasas , Warfarina/uso terapéuticoRESUMEN
A 65-year-old female with biopsy-confirmed nephrogenic systemic fibrosis (NSF) received a kidney transplantation. Despite good kidney function, her symptoms continued to progress. Deferoxamine was administered intramuscularly at 500 mg/day and later 1000 mg/day after 1 week with no adverse effects. Urine excretion of gadolinium increased from 6.0 µg/day to 11.6 µg/day and subsequently to 13.0 µg/day with 500 mg/day and 1000 mg/day of deferoxamine, respectively. Serum levels, however, remain unchanged from 1.7 ng/ml to 1.4 ng/ml. Although chelation therapy may have a role in the treatment of NSF, deferoxamine is too weak and a stronger chelator is needed.
RESUMEN
The antithrombotic benefits of warfarin are countered by a narrow therapeutic index that contributes to excessive bleeding or cerebrovascular clotting and stroke in some patients. This article reviews the current literature describing warfarin sensitivity genotyping and compares the results of that review to the findings of our study in 189 patients at Mayo Clinic conducted between June 2001 and April 2003. For the review of the literature, we identified relevant peer-reviewed articles by searching the Web of Knowledge using key word warfarin-related adverse event. For the 189 Mayo Clinic patients initiating warfarin therapy to achieve a target international normalized ratio (INR) in the range of 2.0 to 3.5, we analyzed the CYP2C9 (cytochrome P450 2C9) and VKORC1 (vitamin K epoxide reductase complex, subunit 1) genetic loci to study the relationship among the initial warfarin dose, steady-state dose, time to achieve steady-state dose, variations in INR, and allelic variance. Results were compared with those previously reported in the literature for 637 patients. The relationships between allelic variants and warfarin sensitivity found in our study of Mayo Clinic patients are fundamentally the same as in those reported by others. The Mayo Clinic population is predominantly white and shows considerable allelic variability in CYP2C9 and VKORC1. Certain of these alleles are associated with increased sensitivity to warfarin. Polymorphisms in CYP2C9 and VKORC1 have a considerable effect on warfarin dose in white people. A correlation between steady-state warfarin dose and allelic variants of CYP2C9 and VKORC1 has been demonstrated by many previous reports and is reconfirmed in this report. The allelic variants found to most affect warfarin sensitivity are CYP2C9*1*1-VKORC1BB (less warfarin sensitivity than typical); CYP2C9*1*1-VKORC1AA (considerable variance in INR throughout initiation); CYP2C9*1*2-VKORC1AB (more sensitivity to warfarin than typical); CYP2C9*1*3-VKORC1AB (much more sensitivity to warfarin than typical); CYP2C9*1*2-VKORC1AB (much more sensitivity to warfarin than typical); CYP2C9*1*3-VKORC1AA (much more sensitivity to warfarin than typical); and CYP2C9*2*2-VKORC1AB (much more sensitivity to warfarin than typical). Although we were unable to show an association between allelic variants and initial warfarin dose or dose escalation, an association was seen between allelic variant and steady-state warfarin dose. White people show considerable variance in CYP2C9 allele types, whereas people of Asian or African descent infrequently carry CYP2C9 allelic variants. The VKORC1AA allele associated with high warfarin sensitivity predominates in those of Asian descent, whereas white people and those of African descent show diversity, carrying either the VKORC1BB, an allele associated with low warfarin sensitivity, or VKORC1AB or VKORC1AA, alleles associated with moderate and high warfarin sensitivity, respectively.
Asunto(s)
Anticoagulantes/efectos adversos , Hidrocarburo de Aril Hidroxilasas/genética , Monitoreo de Drogas , Oxigenasas de Función Mixta/genética , Polimorfismo Genético , Warfarina/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Anticoagulantes/administración & dosificación , Anticoagulantes/farmacocinética , Biomarcadores Farmacológicos , Citocromo P-450 CYP2C9 , Femenino , Hemorragia/inducido químicamente , Hemorragia/epidemiología , Hemorragia/prevención & control , Humanos , Masculino , Persona de Mediana Edad , Estados Unidos , Vitamina K Epóxido Reductasas , Warfarina/administración & dosificación , Warfarina/farmacocinéticaRESUMEN
The ganglionic blocking agent trimethaphan (TMP) is no longer produced. Therefore, a need exists for alternative pharmacological approaches to investigate baroreflex control of the circulation. The aim of the present study was to examine baroreflex-mediated cardiovascular responses during the administration of a muscarinic receptor antagonist (glycopyrrolate; GLY: ) and a selective alpha-2 receptor agonist (dexmedetomidine; DEX: ) and to compare responses to ganglionic blockade with TMP. We hypothesized that combined GLY-: DEX: would inhibit the baroreflex similar to TMP. Ten volunteers participated in two study days and were instrumented with pulse oximeter, nasal cannula, ECG, continuous blood pressure monitoring (Finapres), and I.V. catheter for drug infusions. Each study day consisted of a control condition followed by either combined GLY: -DEX: or TMP on alternating days. A Valsalva maneuver was performed under each condition with every subject and six subjects received bolus phenylephrine (25 mug) during GLY: -DEX: and TMP. Combined GLY: -DEX: increased (P < 0.05) blood pressure (99 +/- 4 mmHg) and heart rate (99 +/- 3 bpm) relative to control condition (BP: 90 +/- 2 mmHg; HR: 64 +/- 3 bpm) and TMP infusion decreased (P < 0.05) blood pressure (79 +/- 3 mmHg) while increasing heart rate (88 +/- 3 bpm). Valsalva maneuver elicited a persistent drop in arterial pressure (no phase IIb recovery) with the absence of a phase IV overshoot during both GLY: -DEX: and TMP conditions. Phenylephrine increased systolic pressure 34 +/- 4 mmHg under GLY: -DEX: and 23 +/- 3 mmHg with TMP (P < 0.05). Heart rate only decreased 1 +/- 2 bpm during GLY: -DEX: and 1 +/- 1 bpm with TMP. Taken together, our results suggest that GLY: -DEX: is a reasonable alternative to TMP for baroreflex inhibition.