Pediatric phase I trial and pharmacokinetic study of the platelet-derived growth factor (PDGF) receptor pathway inhibitor SU101.

PURPOSE: To determine the maximum tolerated dose and the toxicity profile of the PDGF receptor pathway inhibitor SU101 in pediatric patients with refractory solid tumors, and to define the plasma pharmacokinetics of SU101 and its active metabolite SU0020 in children. EXPERIMENTAL DESIGN: Patients between 3 and 21 years of age with CNS malignancy, neuroblastoma, or sarcoma refractory to standard therapy were eligible. The starting dose of SU101 was 230 mg/m(2) per day administered as a 96-h continuous infusion every 21 days. Blood for pharmacokinetic analysis was obtained during the first cycle. RESULTS: Entered into the trial were 27 patients, and 24 were fully evaluable for toxicity. Dose-limiting central nervous system toxicity was observed in two patients at the 440 mg/m(2) per day dose level. Non-dose-limiting toxicities included nausea, vomiting, headache, fatigue, abdominal discomfort, diarrhea, pruritus, anorexia, constipation, and paresthesias. There were no complete or partial responses. One patient with rapidly progressive desmoplastic small round-cell tumor experienced symptomatic improvement and prolonged stable disease. Steady-state concentrations of SU101 were rapidly achieved and proportional to dose. The concentration of SU0020 was 100- to 1000-fold greater than that of SU101. The median clearance of SU0020 was 0.19 l/day per m(2) and its terminal elimination half-life was 14 days. CONCLUSIONS: SU101 administered on this schedule was generally well tolerated. The maximum tolerated dose of SU101 is 390 mg/m(2) per day for 4 days repeated every 3 weeks. The neurotoxicity observed at the 440 mg/m(2) per day dose level suggests that patients receiving repetitive cycles must be monitored closely, as SU0020 may accumulate over time.

Pharmacokinetics and interspecies scaling of a novel VEGF receptor inhibitor, SU5416.

The pharmacokinetics and allometric relationships of SU5416, a novel small anti-angiogenesis agent, were studied. The pharmacokinetics of SU5416 were examined in mice, rats, dogs, and cancer patients. The in-vitro intrinsic clearance (CLint) was estimated from the in-vitro metabolism study in mouse, rat, dog, monkey and human liver microsomes. The parameters of interest were correlated across species as a function of bodyweight using an allometric approach. The steady-state volume of distribution (Vd(ss)), plasma clearance (CLs), and CLint of SU5416 were well correlated across species. The exponent of the allometric relationship (b) of the corresponding parameters was 0.92, 0.80 and 0.66, respectively. The elimination half-life (t1/2) was consistent across species and independent of bodyweight. The prediction of CLs, Vd(ss), CLint, and t1/2 in humans using the data from mouse, rat, and dog, and monkey (for CLint) was reasonably good (within 4-fold of the observed values). However, an improved prediction (within 2-fold of the observed values) of the corresponding parameters in humans was obtained when extrapolation from only the rodent data was performed, suggesting that the rodent data are sufficient for the scale-up of SU5416 pharmacokinetic parameters in humans. Using allometry, it was possible to achieve reasonable predictions of the pharmacokinetic parameters of SU5416 in cancer patients with various solid tumours.

Phase I and pharmacologic study of the tyrosine kinase inhibitor SU101 in patients with advanced solid tumors.

PURPOSE: To evaluate the clinical feasibility and pharmacologic behavior of the platelet-derived growth factor (PDGF) tyrosine kinase inhibitor SU101, administered on a prolonged, intermittent dosing schedule to patients with advanced solid malignancies. PATIENTS AND METHODS: Twenty-six patients were treated with SU101 doses ranging from 15 to 443 mg/m(2) as a 24-hour continuous intravenous (IV) infusion weekly for 4 weeks, repeated every 6 weeks. Pharmacokinetic studies were performed to characterize the disposition of SU101 and its major active metabolite, SU0020. Immunohistochemical staining of PDGF-alpha and -beta receptors was performed on malignant tumor specimens obtained at diagnosis. RESULTS: Twenty-six patients were treated with 52 courses (187 infusions) of SU101. The most common toxicities were mild to moderate nausea, vomiting, and fever. Two patients experienced one episode each of grade 3 neutropenia at the 333 and 443 mg/m(2) dose levels. Dose escalation of SU101 above 443 mg/m(2)/wk was precluded by the total volume of infusate required, 2.5 to 3.0 L. Individual plasma SU101 and SU0020 concentrations were described by a one-compartment model that incorporates both first-order formation and elimination of SU0020. SU101 was rapidly converted to SU0020, which exhibited a long elimination half-life averaging 19 +/- 12 days. At the 443 mg/m(2)/wk dose level, trough plasma SU0020 concentrations during weeks 2 and 4 ranged from 54 to 522 micromol/L. Immunohistochemical studies revealed PDGF-alpha and -beta receptor staining in the majority (15 of 19) of malignant neoplasms. CONCLUSION: SU101 was well tolerated as a 24-hour continuous IV infusion at doses of up to 443 mg/m(2)/wk for 4 consecutive weeks every 6 weeks. Although further dose escalation was precluded by infusate volume constraints, this SU101 dose schedule resulted in the achievement and maintenance of substantial plasma concentrations of the major metabolite, SU0020, for the entire treatment period.

Clinical characteristics and genotype analysis of patients with cystic fibrosis and nasal polyposis requiring surgery.

OBJECTIVE: To analyze the clinical characteristics and genotypes of patients with cystic fibrosis (CF) and nasal polyposis who require surgery. DESIGN: Cross-sectional analysis of a large patient database. SETTING: Data obtained from the National CF Patient Registry of the Cystic Fibrosis Foundation, Bethesda, Md. PATIENTS: Clinical and genotype data on 20198 patients with CF who were registered in 1992 and 1993 were analyzed. The study group (n = 815) consisted of patients with CF who had undergone surgical procedures for the treatment of nasal polyposis. The comparison group (n = 19383) comprised the remainder of the patients in the database. RESULTS: Statistical analysis revealed that patients with CF and nasal polyposis who required surgery had better pulmonary function (higher percent-predicted forced expiratory volume in 1 second and forced vital capacity), better nutritional status, a higher rate of Pseudomonas aeruginosa colonization, more office visits, more hospitalizations, and a higher rate of acute exacerbations per year (P < .001 for each) than did the comparison group. Among the patients who had mutation analysis performed, patients with nasal polyposis who required surgery were significantly associated with 2 specific genotypes: the delta-F508/delta-F508 (57.5% vs 49.9%, P = .01) and the delta-F508/G551D (12% vs 8%, P = .05) genotypes. CONCLUSIONS: Patients with CF and nasal polyposis who require surgery may constitute a clinical subgroup within the spectrum of the disease. These patients appear to have slightly better pulmonary function and nutritional status; yet, they seem to have a higher degree of health care utilization. The higher rate of P aeruginosa respiratory infection in this patient group suggests an association with the presence of nasal polyposis. Genotype analysis showed a higher prevalence of the delta-F508/delta-F508 and the delta-F508/G551D genotypes in this patient group.

Effectiveness of bronchodilators in cystic fibrosis.

Bronchodilators (xanthines, adrenergics, and parasympatholytics) have been used for years in the treatment of airway obstruction associated with cystic fibrosis. Their effectiveness in bringing about consistent and significant reversal of airway obstruction remains a topic for debate. A review of the literature suggests that the majority of patients with cystic fibrosis have hyperresponsive and hyperactive airways and will respond favorably to bronchodilators, at least some of the time. Bronchial hyperresponsiveness tends to be greater in patients with advanced disease than in mildly affected ones. Responses to bronchodilators appear to be greatest when airway disease is mild-to-moderate, when there is a documented excessive bronchial hyperresponsiveness to nonspecific bronchoconstrictors (methacholine, histamine), and when the patients are young. The response to intravenous xanthine and terbutaline is best when patients experience an acute pulmonary exacerbation and when aerosolized bronchodilators are relatively ineffective. Patients with advanced airway destruction and obstruction have a high degree of airway wall instability, which may be worsened by inhaled bronchodilators. Adrenergic and parasympatholytic aerosols are equally effective; combining them in optimal doses may be more beneficial than using either alone. Atropine and ipratropium bromide may be more effective in adults than children, but this remains to be further evaluated. Some of the apparently poor responses to inhaled bronchodilators are likely due to inadequate dosing. In conclusion, most patients with cystic fibrosis are likely to benefit from bronchodilator therapy when given in adequate doses, appropriate combinations, and by the appropriate route.

Resting oxygen consumption and ventilation in cystic fibrosis.

Resting oxygen consumption (VO2) and minute ventilation (VE) were measured on nine control subjects and 13 patients with cystic fibrosis (CF). In patients with CF, VO2 was 20% higher (P less than 0.01) when expressed per m2 and 47% higher (P less than 0.001) when expressed per kg body weight, and VE was 58% higher when expressed per m2 and 94% higher when expressed per kg body weight (P less than 0.001) than in control subjects. Repeated measures of VO2 and VE were highly reproducible over 2 hours (within-subject coefficients of variation: in controls, VO2 = 5.5%, VE = 7.4%; in CF, VO2 = 3.1%, VE = 5.1%). Since the increases in VE were greater than those in VO2, the ventilatory equivalent (VE/VO2) was 32% higher in CF than in controls. We conclude that size-corrected total energy expenditures and VE at rest are higher in patients with CF than in control subjects. Ventilation appears mechanically inefficient but necessary to keep arterial PCO2 from rising and oxygen saturation from falling at rest. Our results are consistent with observations that these patients have an abnormally large physiological dead space (Featherby et al.: Ann Rev Respir Dis 1969; 102:737).

Special features of asthma in children.

Asthma in children has many special features which deserve consideration. This disease is probably underdiagnosed and is often undertreated. Vague, persistent respiratory symptoms, especially chronic cough, may often be due to asthma. Chronic bronchitis is extremely rare in the pediatric patient and is a manifestation of reactive airway disease or cystic fibrosis. The absolute severity, the extent of the disease, responses to treatment, and long-term course should be evaluated by repeated pulmonary function tests. Fortunately, asthma responds well to pharmacologic and supportive therapy, and it is important to approach its management as that of a chronic rather than episodic illness. Therapy should include comprehensive, closely supervised drug therapy, health education, and a program of self-management. Asthma usually starts before youngsters enter school, and the majority get better as they get older. Nevertheless, many children with moderate or severe asthma will continue to be troubled by intermittent or chronic airway obstruction into adulthood, and they require long-term, anticipatory treatment programs. Comprehensive care will optimize the quality of life for the affected children and their families, and it will minimize the discomfort and restrictions to which some of them have been subjected unnecessarily. Asthma in childhood, especially when not well controlled, may constitute a risk factor for the development of chronic obstructive pulmonary disease in adulthood; however, this is as yet only suspected and not proved.

Evaluation of a family asthma program.

This article presents the results of an evaluation of a 12-hour patient education program for children with asthma and their parents. Ninety-two of 147 participants (63%) completed the 1-year follow-up. The effectiveness of the family asthma program (FAP) was measured by a "knowledge of asthma" questionnaire administered before and at the last session; it demonstrated a significant improvement for parents (p less than 0.001) and children (p less than 0.01). The "multidimensional health locus of control scales" (administered to a subgroup of 42 adults and 29 children before and 3 mo after the FAP) demonstrated a significant change in attitude toward asthma for both parents (p less than 0.05) and children (p less than 0.005), indicating an interest to assume more responsibility for self-management. In addition, eight variables were measured in the children before the FAP was started and longitudinally on a monthly basis for 1 yr after completion of the FAP. Three of these variables demonstrated a significant change: total activities were increased (p less than 0.001), unscheduled health-care visits were decreased (p less than 0.005), and school absences were decreased (p less than 0.005). Four variables did not reach statistical significance but did change in the expected direction: medication score, 10% decrease; emergency treatments, 24% decrease; hospital admissions, 44% decrease; school activities, 5% increase. These results demonstrate that this FAP effectively complemented medical care and provided a useful preparation for self-management.

Hospital therapy improves exercise tolerance and lung function in cystic fibrosis.

We studied the benefits of in-hospital therapy on exercise capacity and related these changes to improvements in lung function in 17 patients with cystic fibrosis (CF) of moderate to extreme severity, as defined by results of pulmonary function tests performed at admission and discharge. Tolerance and adaptations to exercise were assessed from measures of peak work capacity (PWC), peak heart rate (PHR), and peak ventilation (PVE) obtained during an incremental exercise test. Treatment lasted from nine to 18 days. All measures of lung function improved; there also were significant increases in PWC, PHR, PVE, and PHR/PWC. Exercise-induced arterial desaturation was less at discharge than at admission. The PWC of the most severely affected patients remained abnormally low, and their adaptations to exercise were abnormal at discharge. We concluded that intensive in-hospital therapy will significantly improve exercise tolerance and lung function in patients with CF with moderate to severe pulmonary dysfunction.

Pulmonary function and bronchial challenge testing in office and hospital practice.

Pulmonary function and provocation testing in the office or the small hospital is now justifiable, cost-effective and necessary for the optimal management of patients with pulmonary disease. These tests provide the only way to assess lung function objectively, they are helpful in the development of an optimal and rational plan of therapy, and they offer an effective means to evaluate the adequacy of treatment and follow-up. It is fortunate that the relatively simple and cheap test of spirometry can provide most of the information needed for the evaluation of patients with lung disease, and it is also the test which can indicate whether airway obstruction develops during bronchial provocations or in the work environment.

Exercise tolerance and cardiorespiratory adjustments at peak work capacity in cystic fibrosis.

Exercise tolerance and cardiorespiratory adjustments at peak work capacity (PWC) were determined in 20 patients with cystic fibrosis (CF) during progressive cycle ergometry. The results were related to resting lung function tests, expressed by a pulmonary function score (PFS) that ranged from 0 (no pulmonary dysfunction) to 18 (extreme dysfunction). Patients with CF with no (PFS less than 3), mild (PFS 3-7), or moderate (PFS 8-12) pulmonary dysfunction exercised as well as normal subjects. When the PFS exceeded 12, PWC was reduced on the average by 51%, peak heart rate (PHR) was reduced by 15%, and peak ventilation (PVE) was reduced by 39%. Severely affected patients developed arterial desaturation at PWC (-7.3%), CO2 retention (end-tidal PCO2 + 5 mmHg), and an increase in the PHR/PWC ratio. In most patients with CF the PVE/PWC ratio was elevated, suggestion wasted VE and a probable increase in dead space ventilation. The results indicate that whenever pulmonary disease in CF is advanced, there are decreases in exercise tolerance and cardiorespiratory reserves, exercise-induced ventilation-perfusion abnormalities, arterial desaturation, and alveolar hypoventilation. In view of the abnormal physiological adaptations to exercise in patients with CF with advanced lung disease (PFS greater than 12), they should engage in exercise training programs and strenuous physical activity with caution and only after their cardiorespiratory reserves and adjustments to exercise have been objectively evaluated.

Cardiorespiratory adaptations to exercise in cystic fibrosis.

We compared the cardiorespiratory adaptations to exercise of 21 patients with cystic fibrosis (CF) with those of 17 age-, height-, and weight-matched subjects without lung disease. To assess differences in adaptations to exercise in patients with varying severities of pulmonary disease, we grouped them on the basis of their lung function tests results. Exercise consisted of a progressive, incremental cycle ergometer work test. Work load increased every 2 min until the subject could not continue. During exercise, heart rate, and end-tidal and mixed expired O2 and CO2 tensions, minute ventilation (VE), arterial oxygen saturation, and blood pressure were monitored. The patients breathed significantly larger volumes than normal subjects at work loads greater than 0.8 W/kg. Patients with mild, moderate, or seven disease ventilated more per unit of oxygen consumption than did patients with normal pulmonary functions or control subjects. Despite this high total VE, alveolar hypoventilation was observed in the severe groups, as evidenced by elevated end-tidal PCO2, and contributed to aterial desaturation. Resting heart rate was higher in the severe group. The rate of changes in heart rate with increasing work load was the same in all groups. We conclude that the increased VE during exercise was an attempt to maintain alveolar ventilation in the face of increased dead space. The elevated VE was adequate to preserve normal gas exchange in all patients except those with severe lung disease, where CO2 retention and arterial desaturation were observed.

Ventilatory response and drive of asthmatic children to alveolar hypoxia.

Hypoxic ventilatory responses and 100-msec inspiratory occlusion pressures (P100s) were measured at constant alveolar PCO2 (normocapnia) in 13 asthmatic [12.5 +/- 1.0 (S.E.) years] and in 12 normal children (13.3 +/- 0.6 years) to determine the appropriateness of the asthmatics' minute ventilation and ventilatory (inspiratory) drive, respectively. Most asthmatics were well controlled with continuous drug therapy and exhibited only mild pulmonary abnormalities at the time of testing. Hypoxia-induced increases in minute ventilation were quantitated in terms of A-values per m2 body surface area. An A-value describes, in numerical terms, the slope of the hyperbolic ventilatory response to progressive alveolar hypoxia. Larger A-values denote greater increases in ventilation. The A-values were not significantly different between the asthmatic (105 +/- 14) and normal children (123 +/- 24). The occlusion pressures were significantly different, however, and were 2.3 +/- 0.2 cm H2O (sub-atmospheric) for the asthmatics and 1.5 +/- 0.1 cm H2O for the normal children at an alveolar PO2 = 80 mm Hg, and 7.7 +/- 0.9 and 5.2 +/- 0.8 cm H2O for the respective groups at an alveolar PO2 = 40 mm Hg (P less than 0.05). These findings indicate that asthmatic children with minimal pulmonary abnormalities maintain a normal ventilatory response to alveolar hypoxia by increasing their ventilatory drive, whereas adult asthmatics have been reported to have less than normal increase in ventilatory drive and hence a diminished ventilatory response during hypoxic exposure.

Theophylline therapy in bronchiolitis. A retrospective study.

Since bronchiolitis has clinical and pathophysiologic similarities to asthma, the use of bronchodilator drugs has been suggested; however, their effectiveness remains unproven. We reviewed the outcome of treatment in 64 children less than 18 months of age hospitalized for the first time with a diagnosis of bronchiolitis or wheezing. Thirty one of the patients received theophylline therapy and sometimes steroids and/or inhaled sympathomimetic drugs, and 34 received no such therapy. Although the theophylline-treated children were older (9.4 vs 4.9 months of age), there were no other differences in the histories, clinical findings, laboratory assessments, or outcome between theophylline-treated and untreated groups. The results suggest that theophylline and steroid therapies had not beneficial effects on the resolution of acute bronchiolitis or wheezing in the majority of infants and small children.

Community and family programs for children with asthma.

Asthma programs have been developed to improve knowledge about this disease, to reduce morbidity and anxiety and to improve coping skills in families of children with asthma. These programs' goals are (1) to increase knowledge about the disease and its treatment, (2) to reduce morbidity, (3) to increase participation in recreational activities, (4) to improve family harmony, (5) to alleviate anxiety and promote the ability to relax and (6) to develop some self-management ability. Short-term evaluation has shown a significant increase in knowledge about asthma in parents and children. Long-term evaluation is in process and looks promising.