Phase I and pharmacologie study of liposomal daunorubicin (DaunoXome)

Summary We have completed a phase I and pharmacology study of liposomally-encapsulated daunorubicin (DaunoXome). Of 32 patients entered, 30 were evaluable. No toxicity was encountered at the initial doseescalation steps from 10 to 60 mg/m². At 80 mg/m², two patients manifested grade 2 neutropenia. At least grade 3 neutropenia occurred in all patients receiving 120 mg/m². Alopecia and subjective intolerance were mild. Cardiotoxicity was not observed except for an episode of arrhythmia in a patient with lung cancer and prior radiation. Only one minor objective response was observed in this population of refractory solid tumors. Pharmacokinetics differed from those of the free drug with no detection of daunorubicinol. We recommend future phase II studies with a dose of 100 mg/m² in previously treated and 120 mg/m² of DaunoXome in previously untreated patients with solid tumors.EDW is supported in part by ACS award 92-14-1     

Carbohydrate metabolism in children receiving growth hormone for 5 years

Carbohydrate metabolism was evaluated by fasting and postprandial glucose, insulin, and hemoglobin (Hb)A_1c levels in children with chronic renal insufficiency and various other growth disorders treated with growth hormone. Mean fasting and postprandial glucose remained unchanged throughout the 5-year study period in all four study groups. Median fasting insulin levels rose from lownormal levels into the normal range after 5 years of growth hormone. Average fasting insulin level after 5 years was 10 mU/l. Median postprandial insulin values also rose, yet remained within the normal range at the 5-year mark. Mean Hb A_1c levels remained within low to middle end of the normal range in the patients with growth hormone deficiency, Turner syndrome, and idiopathic short stature. Mean Hb A_1c levels at the 5 years were slightly elevated to 6.3% for the patients with chronic renal insufficiency.     

How Frequent Are Asthma Exacerbations in a Pediatric Primary Care Setting and Do Written Asthma Action Plans Help in Their Management?

Purpose. In the National Heart, Lung, and Blood Institute Guidelines for the Diagnosis and Management of Asthma, the expert panel recommends that a written asthma action plan be provided for all patients with asthma. Studies evaluating the usefulness of the asthma action plan in children are limited. We aim to determine exacerbation frequency and usefulness of the asthma action plan in managing exacerbations that occur in a pediatric primary care setting. Methods. Caretakers of asthmatic children attending the general pediatric clinic in an inner-city hospital completed a one-page questionnaire covering topics such as asthma severity, frequency of exacerbations, and possession/usefulness of an asthma action plan. Although controversy exists over the definition of yellow and red zone exacerbations, we defined the yellow zone as symptoms that require albuterol more than three times a day or more than two nights in succession. The red zone was defined as symptoms requiring systemic corticosteroids and/or an urgent physician visit. Results. Seventy of 75 subjects completed the survey. Almost 80% of respondents carried the diagnosis of persistent asthma, whereas the remainder had intermittent asthma. Exacerbation frequency over a 3-month period was determined. Approximately 80% of children experienced at least one yellow zone episode: 42% had one or two yellow zone episodes, and 39.6% had between three and five episodes. Sixty-three percent of patients did not experience a single red zone exacerbation. Almost 75% (44 of 59) of subjects possessed an asthma action plan. Ninety percent (37 of 41) of respondents with action plans found the plan to be useful in managing exacerbations. Conclusion. Approximately four of every five asthmatic children seen in this primary care setting experienced a yellow zone exacerbation at least once during a 3-month period. One third experienced at least one red zone episode. Nine of every 10 caretakers with an action plan reported the asthma action plan to be of value in managing exacerbations.     

The myocardial performance index during low-dose dobutamine echocardiography in control subjects and patients with a recent myocardial infarction: a new index of left ventricular functional reserve?

BACKGROUND: Wall-motion analysis during low-dose dobutamine echocardiography (LDDE) is a semiquantitative measure of left ventricular contractile reserve after myocardial infarction (MI). The Doppler echocardiographic myocardial performance index (MPI) is a quantitative measure of combined left ventricular systolic and diastolic function. We sought to characterize the changes in MPI during LDDE in control subjects and patients with MI, and to describe the relation of these changes to changes in regional systolic function. METHODS: MPI was obtained at rest and during LDDE (10 microg/kg/min) in 25 healthy volunteers (group 1) and 50 patients with a recent MI. Patients were divided into two subsets; those with (n = 23; group 2A) and those without (n = 27; group 2B) a contractile reserve defined as an improvement of wall motion in more than two contiguous infarct-zone segments during LDDE. DeltaMPI was defined as the change from rest to LDDE. RESULTS: MPI decreased significantly during LDDE in groups 1 and 2A, whereas MPI increased in group 2B (DeltaMPI = 0.12 +/- 0.04 and 0.10 +/- 0.08 vs -0.03 +/- 0.08, P <.0001). On multivariate analysis, Deltawall-motion score index predicted DeltaMPI (beta = 0.65, P <.0001) independently of age, sex, and the dobutamine-induced change in heart rate and systolic blood pressure. CONCLUSIONS: Data suggest that the change in MPI during LDDE may provide a simple and quantitative measure of overall left ventricular functional reserve in patients with a recent MI.     

The use of 19F spectroscopy and diffusion-weighted MRI to evaluate differences in gene-dependent enzyme prodrug therapies.

To evaluate noninvasive measures of gene expression and tumor response in a gene-dependent enzyme prodrug therapy (GDEPT), a bifunctional fusion gene between Saccharomyces cerevisiae cytosine deaminase (CD) and Haemophilus influenzae uracil phosphoribosyltransferase (UPRT) was constructed. CD deaminates 5-fluorocytosine (5FC) to 5-fluorouracil (5FU), and UPRT subsequently converts 5FU to fluorouridine monophosphate, and both of these reactions can be monitored noninvasively in vitro and in vivo using 19F magnetic resonance spectroscopy (MRS). Following transient transfection the CD-UPRT fusion protein exhibited both UPRT and CD enzymatic activities as documented by 19F MRS. In addition, an increase in CD activity and thermal stability was witnessed for the fusion protein compared to native CD. Stable expression of CD-UPRT in 9L glioma cells increased both 5FC and 5FU sensitivity in vitro compared to CD-expressing and wild-type 9L cells. Noninvasive 19F MRS of both CD and UPRT gene function in vivo demonstrated that in animals bearing CD-expressing tumors there was limited conversion of 5FC to 5FU with no measurable accumulation of cytotoxic fluorinated nucleotides (F-nucs). In contrast, CD-UPRT-expressing tumors had increased CD gene activity with a threefold higher intratumoral accumulation of 5FU and significant generation of F-nucs. Finally, CD-UPRT yielded increased efficacy in an orthotopic animal model of high-grade glioma. More importantly, early changes in cellular water mobility, which are felt to reflect cellular death, as measured by diffusion-weighted MRI, were predictive of both durable response and increased animal survival. These results demonstrate the increased efficacy of the CD-UPRT GDEPT compared to CD alone both biochemically and in a preclinical model and validate both 19F MRS and diffusion-weighted MRI as tools to assess gene function and therapeutic efficacy.     

Case report: Management of immediate post-car-diopulmonary bypass massive intra-cardiac thrombosis

PURPOSE: To describe the management of severe acute intracardiac thrombosis in a patient who underwent redo multiple valve replacement and valvular repair. The diagnostic features, associated risk factors, and anesthetic management are reviewed. CLINICAL FEATURES: A 67-yr-old woman undergoing redo mitral and aortic mechanical valve replacement and tricuspid annuloplasty under aprotinin prophylaxis exhibited severe refractory hypotension that began immediately after protamine reversal of intraoperative heparin anticoagulation following separation from cardiopulmonary bypass. Intraoperative transesophageal echocardiography revealed severe thrombosis in the right atrium, right ventricle and pulmonary artery. The patient was managed by immediate reheparinization and return to cardiopulmonary bypass (CPB), surgical thrombectomy, and intraoperative administration of recombinant tissue-plasminogen activator. After removal of the thrombi, and separation from CPB, no further protamine was given. One hundred units of blood products and two surgical re-explorations were required to manage subsequent massive postoperative bleeding. Acute heparin-induced thrombocytopenia (HIT) was ruled out using sensitive assays for HIT antibodies. After 16 days in the intensive care unit and 30 more days in hospital, the patient was subsequently transferred to a chronic care facility and succumbed several weeks later. CONCLUSION: Acute intraoperative thrombosis is a rare and potentially fatal complication of cardiac surgery. Intraoperative transesophageal echocardiography was essential for rapid diagnosis in this case. Multiple interacting prothrombotic factors (e.g., aprotinin use, acquired antithrombin deficiency, long pump time, post-protamine status, transfusion of blood components) were likely contributing factors related to this rare complication.