RESUMO
BACKGROUND: Having observed in recent years that the theophylline dose requirements needed to attain peak serum concentrations of 10 to 20 micrograms/ml infrequently reached previously described mean values, we hypothesized that a downward shift in the range of dose requirements had occurred among patients with asthma. STUDY DESIGN: We examined dosage requirements needed to attain peak serum concentrations of 10 to 20 micrograms/ml in all patients with chronic asthma treated with theophylline by the Pediatric Allergy and Pulmonary Clinic at the University of Iowa from 1990 to 1994 (n = 300) and at the Pediatric Pulmonary Clinic at the University of Florida from 1992 to 1995 (n = 93). We then compared these doses to previous dose requirements from 1978 to 1983 determined in the same manner. RESULTS: Despite similar mean peak serum concentrations during both time periods (14 micrograms/ml), mean theophylline dosage requirements during the period of this study were approximately 25% lower among all age groups than those previously observed (p < 0.001). There were no significant differences in mean dosage requirements between the Iowa and Florida patients in any age group examined. CONCLUSIONS: Theophylline dose requirements needed to attain serum concentrations of 10 to 20 micrograms/ml have decreased significantly from those on which current dosing recommendations are based. This suggests a decrease in mean clearance of the population.
Assuntos
Asma/sangue , Broncodilatadores/administração & dosagem , Broncodilatadores/farmacocinética , Teofilina/administração & dosagem , Teofilina/farmacocinética , Adolescente , Fatores Etários , Asma/tratamento farmacológico , Peso Corporal , Broncodilatadores/sangue , Criança , Pré-Escolar , Doença Crônica , Esquema de Medicação , Humanos , Lactente , Teofilina/sangueRESUMO
We have evaluated a method to simultaneously assess three major processes involved in hepatic drug clearance using three model substrates administered simultaneously as a 5-minute intravenous injection. Lorazepam, indocyanine green, and antipyrine are used to assess conjugation, liver blood flow, and microsomal oxidative metabolism, respectively. These substrates were administered individually and as a mixture to 10 healthy adult male volunteers to determine if clearances of any of the compounds were affected by simultaneous administration. Mean clearances of the substrates were not different when administered alone (9.97, 0.78, and 0.53 ml/min/kg) vs. together (11.5, 0.89, and 0.52 ml/min/kg), using a paired t test. Since we were using this method to assess hepatic drug clearance in children with leukemia, the effect of short-term allopurinol was assessed. The three model substrates were administered to the volunteers after 0, 1, 8, and 22 days of treatment with allopurinol, 200 mg t.i.d. There was no change in mean clearance of any of the three compounds at any point during allopurinol treatment (repeated-measures ANOVA). We conclude that this technique is a simple and valid method to simultaneously assess three major processes involved in hepatic drug clearance and is not affected by up to 22 days of oral allopurinol treatment. This simple technique, requiring a single set of blood samples, has potential applications in the assessment of developmental changes in hepatic drug clearance, as well as the effects of environmental, therapeutic, and pathophysiologic factors on three major processes involved in hepatic drug clearance.
Assuntos
Antipirina/metabolismo , Verde de Indocianina/metabolismo , Fígado/metabolismo , Lorazepam/metabolismo , Administração Oral , Adulto , Alopurinol/farmacologia , Antipirina/administração & dosagem , Interações Medicamentosas , Humanos , Verde de Indocianina/administração & dosagem , Infusões Intravenosas , Lorazepam/administração & dosagem , Masculino , Taxa de Depuração Metabólica/efeitos dos fármacosRESUMO
Interpatient pharmacokinetic variability normally observed in adults is often of even greater magnitude in paediatric patients because of age-related maturation of physiological processes responsible for drug disposition. Several antineoplastic agents have shown age-related changes, including alterations in volume of distribution, hepatic (doxorubicin, cyclophosphamide), and renal (bleomycin, methotrexate) clearances. These differences in pharmacokinetics as a function of age alter systemic exposure to chemotherapy, and may alter the efficacy and toxicity profile for standard doses of antineoplastic drugs. The relationship of systemic exposure to toxicity has been most clearly defined for methotrexate. Clinical monitoring of methotrexate serum concentrations, and adjustment of folinic acid dosages and duration of rescue based on methotrexate disposition is now routine. More recently, pharmacodynamic data have been published for high-dose methotrexate, epipodophyllotoxins, cisplatin, and cytarabine (cytosine arabinoside), indicating a relation between drug disposition and toxicity or efficacy. Collectively, these data suggest that the pharmacokinetics of many anticancer drugs in children is different from adults, and that variability in drug disposition may have an important influence on toxicity or efficacy.
Assuntos
Antineoplásicos/metabolismo , Adulto , Criança , Pré-Escolar , Humanos , Lactente , CinéticaRESUMO
STUDY OBJECTIVE: To compare the in vitro performance of an ultrasonic nebulizer and a jet nebulizer in producing a respirable aerosol of tobramycin solution for injection. DESIGN: In vitro observational study DEVICES: Ultrasonic and jet nebulizers. INTERVENTION: Output was determined by measuring the difference in nebulizer weight before and after nebulizing 3 ml of tobramycin injection solution. Mass median aerodynamic diameter (MMAD) and respirable mass were determined by sampling tobramycin aerosol into a cascade impactor. MEASUREMENTS AND MAIN RESULTS: Mean (SD) output was 1.14 (0.09) ml/minute for the ultrasonic nebulizer and 0.64 (0.08) ml/minute (p<0.001) for the jet nebulizer. Mean MMAD for the jet nebulizer (2.31 [0.10] microm) was less than that of the ultrasonic nebulizer (2.81 [0.17] microm, p<0.001). The majority of tobramycin aerosol produced was in the respirable range for both the ultrasonic (65.1% [4.10%]) and jet (60.6% [0.73%], p=0.008) nebulizers. CONCLUSION: Despite small, clinically unimportant differences in aerosol size and respirable fraction, either device would be acceptable to administer tobramycin injection solution.
Assuntos
Antibacterianos/administração & dosagem , Sistemas de Liberação de Medicamentos/instrumentação , Nebulizadores e Vaporizadores , Tobramicina/administração & dosagem , Ultrassom , Aerossóis/administração & dosagem , Relação Dose-Resposta a Droga , Tamanho da PartículaRESUMO
STUDY OBJECTIVE: To compare the performance of a new point-of-care theophylline assay (AccuMeter) with that of a standard laboratory assay (TDx), and another point-of-care method (AccuLevel). DESIGN: Prospective evaluation of consecutive patients receiving theophylline. SETTING: University-based, ambulatory, allergy-pulmonary clinic. PATIENTS: Forty subjects receiving maintenance theophylline therapy for asthma. INTERVENTIONS: Theophylline concentrations obtained from AccuMeter, TDx, and AccuLevel were compared. MEASUREMENTS AND MAIN RESULTS: The error, or difference, between TDx and AccuMeter results in 40 subjects on maintenance theophylline described accuracy. Mean error, an estimate of bias, was 1.1 (95% CI 0.72-1.5), 0.67 (0.34-1.0), and 0.98 (0.79-1.2) microg/ml for AccuMeter capillary, serum, and heparinized blood samples. Square root of the mean squared error, an estimate of precision, was 1.6 (1.2-2.0), 1.22 (0.90-1.5), and 1.14 (0.96-1.3) microg/ml for AccuMeter capillary, serum, and heparinized samples. Difference between AccuMeter and AccuLevel ME, an estimate of relative bias, was 0.59 (0.04-1.1) microg/ml. The difference in mean squared errors, an estimate of relative precision, was 0.86 (-0.54-2.3) microg/ml. CONCLUSIONS: AccuMeter demonstrated good precision and minimal bias compared with TDx and AccuLevel . Method of sample collection had no effect on its accuracy.
Assuntos
Antiasmáticos/sangue , Monitoramento de Medicamentos/métodos , Teofilina/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antiasmáticos/uso terapêutico , Asma/sangue , Asma/tratamento farmacológico , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Teofilina/uso terapêuticoAssuntos
Antineoplásicos/uso terapêutico , Interferon-alfa/uso terapêutico , Transtornos Mieloproliferativos/tratamento farmacológico , Adulto , Idoso , Doença Crônica , Feminino , Humanos , Interferon alfa-2 , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/sangue , Agregação Plaquetária/efeitos dos fármacos , Mielofibrose Primária/tratamento farmacológico , Proteínas Recombinantes , Trombocitemia Essencial/tratamento farmacológico , Resultado do TratamentoAssuntos
Adjuvantes Imunológicos/uso terapêutico , Timopentina/uso terapêutico , Uremia/tratamento farmacológico , Ensaios Clínicos Controlados como Assunto , Humanos , Contagem de Leucócitos , Valores de Referência , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Uremia/imunologiaAssuntos
Antineoplásicos/uso terapêutico , Interferon-alfa/uso terapêutico , Leucemia de Células Pilosas/tratamento farmacológico , Idoso , Transfusão de Sangue , Medula Óssea/efeitos dos fármacos , Medula Óssea/patologia , Feminino , Humanos , Leucemia de Células Pilosas/sangue , Leucemia de Células Pilosas/patologia , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
OBJECTIVE: To evaluate the attitudes of healthcare providers on drug-nutrient interaction (DNI) counseling. DESIGN: A mail survey. SETTING: Random sample of healthcare providers with interest in nutrition, practicing in Iowa or Nebraska. METHODS: A 48-item questionnaire was constructed on the basis of a review of DNI literature. The survey was sent to 100 pharmacists, 50 registered dietitians, 25 registered nurses, and 25 physicians identified from culled mailing lists of the American Society of Parenteral and Enteral Nutrition and the Iowa Nebraska Society of Parenteral and Enteral Nutrition. Assessed variables included the amount of DNI counseling provided, who is in the best position to provide DNI counseling, and what information should be included in instructional materials on DNIs for patients. Data were entered into a relational database for evaluation and comparison. RESULTS: The usable response rate was 49.5 percent (n = 99): 49 pharmacists, 29 dietitians, 18 nurses, and 3 physicians. Only 12 respondents provided DNI counseling in > 50 percent of patient interactions. Seventy-one respondents (72 percent) felt pharmacists were in the best position to discuss DNIs with patients. More than half of the respondents felt a new DNI pamphlet should be developed to replace an existing Food and Drug Administration-sponsored pamphlet. Although 70 percent felt the new pamphlet should be organized according to specific drugs, many felt the format should also include specific populations and disease states. Eighty-six percent indicated that a chart on DNIs geared toward healthcare professionals would be useful. CONCLUSIONS: Patient-oriented resources should be developed to enhance DNI counseling. Pharmacists are in a uniquely advantageous position to provide DNI counseling.
Assuntos
Atitude do Pessoal de Saúde , Aconselhamento , Interações Medicamentosas , Alimentos , Educação de Pacientes como Assunto , Humanos , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Pigmented banding of the nails and hyperpigmentation of hands and feet may occur during cyclophosphamide therapy. Ifosfamide, an analogue of cyclophosphamide, might be expected to cause similar pigmentary changes, but, to the knowledge of the authors, there are no reports of this. METHODS: The authors describe skin pigment changes in a 5-year-old patient receiving ifosfamide, MESNA, and etoposide for the treatment of relapsed Wilms tumor. RESULTS: A review of the literature concerning cyclophosphamide-induced pigmentary changes is presented, along with a discussion of the possible correlation of renal dysfunction with pigmentary changes. CONCLUSIONS: This case should alert health care providers to this uncommon adverse effect of ifosfamide.
Assuntos
Ifosfamida/efeitos adversos , Neoplasias Renais/tratamento farmacológico , Neoplasias Pulmonares/secundário , Transtornos da Pigmentação/induzido quimicamente , Tumor de Wilms/tratamento farmacológico , Pré-Escolar , Etoposídeo/administração & dosagem , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Mesna/administração & dosagemRESUMO
This article documents that hydroxyurea (HUR) is excreted into human breast milk, and it reviews the literature describing similar evaluations for other antineoplastic agents.
Assuntos
Hidroxiureia/farmacocinética , Leite Humano/metabolismo , Adulto , Feminino , Humanos , Hidroxiureia/uso terapêutico , Leucemia Mieloide/tratamento farmacológico , Leucemia Mieloide/metabolismo , EspectrofotometriaRESUMO
Although methotrexate is one of the most commonly used drugs for maintenance therapy in childhood acute lymphocytic leukemia (ALL), its oral absorption is highly variable and its intramuscular bioavailability at dosages used for ALL therapy has not been assessed in children. We therefore determined the absolute bioavailability of orally and intramuscularly administered methotrexate in 12 pediatric patients receiving 13 to 120 mg/m2 methotrexate every week as maintenance therapy for ALL. Mean bioavailability, as determined by comparing the area under the concentration-time curve after oral or intramuscular administration with that produced by the same dosage given intravenously, was 33% (range 13% to 76%) for oral (n = 11) and 76% (54% to 112%) for intramuscular (n = 7) administration (P less than 0.01). Median bioavailability (with orally administered dosages less than or equal to 40 mg/m2 (range 13 to 40 mg/m2) was 42% (19% to 76%); at dosages greater than 40 mg/m2 (43 to 76 mg/m2), bioavailability was significantly lower, 17.5% (12.7% to 22.3%, p less than 0.02). Conversely, there was no significant relationship between dosage and bioavailability with intramuscularly administered drug. The substantially higher bioavailability for intramuscularly injected methotrexate may warrant its consideration as an alternative to oral administration, especially for dosages greater than 40 mg/m2.
Assuntos
Leucemia Linfoide/tratamento farmacológico , Metotrexato/metabolismo , Administração Oral , Disponibilidade Biológica , Criança , Feminino , Humanos , Injeções Intramusculares , Cinética , Metotrexato/administração & dosagemRESUMO
The myotomy performed for achalasia of the esophagus should divide all of the constricting, diseased muscular elements that obstruct the esophagogastric junction (EGJ). Whether the disease process includes proximal gastric as well as esophageal components is as yet unclear, but anatomic evidence complemented by clinical data suggest that the disease process does not end at the evanescent and poorly defined EGJ. Clinical reports from enthusiastic proponents of a particular operative approach for achalasia have not been illuminating in this regard, because all patients are improved to some degree post-operatively, and there are no objective parametric standards for the evaluation of swallowing function. This study reports a series of patients in whom endoscopic viewing was used to judge the adequacy of myotomy after 'esophageal' myotomy. The question posed by this study was, 'Does esophageal myotomy remove all constricting elements at the gastroesophageal junction?' Laparoscopic myotomy was performed in 48 patients with a diagnosis of achalasia; these patients are the most recent in a total cohort of 72 patients operated upon for achalasia during the past 20 years. Myotomy was begun on the esophagus, and extended to the esophagogastric junction; anatomic landmarks, including the appearance of submucosal veins, guided the initial dissection. Intraoperative endoscopy was then performed to determine whether there was residual constriction of the channel between the esophagus and stomach; if so, myotomy was extended onto the gastric cardia until visual evidence of obstruction had disappeared. All patients had either Toupet fundoplication or Dor fundoplication after myotomy. There were obvious constricting elements distal to the gastroesophageal junction in 90% of the patients. These patients required extension of the myotomy onto the stomach for an average of 15 mm. All but one patient had improved swallowing post-operatively. Eight patients required 'stretch' of the distal esophagus/cardia within the first year post-operatively; one patient was reoperated for fibrous scar obstruction of the distal esophagus. Esophageal myotomy limited to the esophageal muscle does not remove all constricting elements at the gastroesophageal junction; as a result, the extended myotomy must be complemented by an antireflux procedure during operations for achalasia.
Assuntos
Cárdia/cirurgia , Acalasia Esofágica/cirurgia , Laparoscopia , Fundoplicatura , Hérnia Hiatal/cirurgia , Humanos , Técnicas de Sutura , Fatores de TempoRESUMO
Clinical studies comparing the potency of inhaled corticosteroids require steep dose-response slopes (b) and minimal response variability (s), as statistical power is inversely related to the s/b ratio. To evaluate a new study model, we performed a randomized, crossover study of 12 adult asthmatics who required 800 to 2,000 microg of inhaled corticosteroids daily, and calculated s/b for 21 raw clinical outcomes and 36 mathematically derived variables based on these raw outcomes. Each of two 21-d treatment periods was preceded by 4 to 7 d of oral prednisone to maximize asthma control and minimize carry-over of previous inhaled treatment. Treatments were 100 and 800 micron/d of an HFA-134a beclomethasone dipropionate formulation. Assessments included daily home spirometry, histamine challenge, inhaled albuterol use, and asthma symptom scores. Efficacy variables with the greatest power (lowest s/b values) were A.M.FEF25-75, A.M.FEV1, and A.M.PEF, (s/b = 0.46, 0.48, and 0.59). Carry-over between treatment periods was not significant. Crossover study sample size calculations using these ratios yielded samples of 23, 25, and 37 patients, respectively. Otherwise identical parallel studies would require sample sizes of 657, 1,438, and 2,261 patients. These results support the use of a crossover asthma stability model after a short course of oral prednisone as a clinical study model for comparing topical potency of inhaled corticosteroids.
Assuntos
Antiasmáticos/administração & dosagem , Asma/tratamento farmacológico , Beclometasona/administração & dosagem , Glucocorticoides/administração & dosagem , Prednisona/administração & dosagem , Administração por Inalação , Administração Oral , Adulto , Asma/fisiopatologia , Estudos Cross-Over , Relação Dose-Resposta a Droga , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Hidrocarbonetos Fluorados , Masculino , Pico do Fluxo Expiratório/efeitos dos fármacosRESUMO
OBJECTIVE: To compare the bioequivalence of a generic methotrexate (MTX) tablet (Mylan) with that of a brand-name (Lederle) product. DESIGN: A single-dose, randomized, crossover study. SETTING: Clinical Research Center (CRC) at a university hospital. PATIENTS: Men and women who had a diagnosis of malignancy or psoriasis who were at least 21 years old. METHODOLOGY: Two overnight study periods were scheduled at the CRC at least one week, but not more than two weeks apart. Each period consisted of a 10-hour fast prior to and 4 hours following oral MTX 15 mg administered as six 2.5-mg tablets. Blood samples were collected over 48 hours. Plasma MTX concentrations were determined using an HPLC assay. Area under the curve from zero to infinity (AUC0-infinity) was calculated by the log-trapezoidal method. RESULTS: Twenty-two patients (21 psoriasis, 1 colon cancer) aged 23-61 years completed both study periods. Mean values for peak concentration, time to peak concentration, and AUC0-infinity were 0.80 mumol/L, 1.2 hours, and 3.0 mumol.h/L, respectively, for Mylan's MTX tablets and 0.81 mumol/L, 1.4 hours, 3.0 mumol.h/L, respectively, for Lederle's MTX. Normalization for weight or body surface area did not affect interpatient variability. Relative bioavailability of generic MTX was 99.2 percent. Rate and extent of absorption were not significantly different and the confidence intervals were within the range of 80-120 percent required by the Food and Drug Administration. CONCLUSIONS: Mylan's MTX tablet is bioequivalent to Lederle's product.