Plasma markers in pulmonary hypertension subgroups correlate with patient survival.

BACKGROUND: Recent studies have provided evidence for an important contribution of the immune system in the pathophysiology of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). In this report, we investigated whether the inflammatory profile of pulmonary hypertension patients changes over time and correlates with patient WHO subgroups or survival. METHODS: 50 PAH patients (16 idiopathic (I)PAH, 24 Connective Tissue Disease (CTD)-PAH and 10 Congenital Heart Disease (CHD)-PAH), 37 CTEPH patients and 18 healthy controls (HCs) were included in the study. Plasma inflammatory markers at baseline and after 1-year follow-up were measured using ELISAs. Subsequently, correlations with hemodynamic parameters and survival were explored and data sets were subjected to unbiased multivariate analyses. RESULTS: At diagnosis, we found that plasma levels of interleukin-6 (IL-6) and the chemokines (C-X3-C) motif legend CXCL9 and CXCL13 in CTD-PAH patients were significantly increased, compared with HCs. In idiopathic PAH patients the levels of tumor growth factor-ß (TGFß), IL-10 and CXCL9 were elevated, compared with HCs. The increased CXCL9 and IL-8 concentrations in CETPH patients correlated significantly with decreased survival, suggesting that CXCL9 and IL-8 may be prognostic markers. After one year of treatment, IL-10, CXCL13 and TGFß levels changed significantly in the PAH subgroups and CTEPH patients. Unbiased multivariate analysis revealed clustering of PH patients based on inflammatory mediators and clinical parameters, but did not separate the WHO subgroups. Importantly, these multivariate analyses separated patients with < 3 years and > 3 years survival, in particular when inflammatory mediators were combined with clinical parameters. DISCUSSION: Our study revealed elevated plasma levels of inflammatory mediators in different PAH subgroups and CTEPH at baseline and at 1-year follow-up, whereby CXCL9 and IL-8 may prove to be prognostic markers for CTEPH patients. While this study is exploratory and hypothesis generating, our data indicate an important role for IL-8 and CXCL9 in CHD and CTEPH patients considering the increased plasma levels and the observed correlation with survival. CONCLUSION: In conclusion, our studies identified an inflammatory signature that clustered PH patients into WHO classification-independent subgroups that correlated with patient survival.

Metastatic behavior and overall survival according to breast cancer subtypes in stage IV inflammatory breast cancer.

BACKGROUND: Distant metastatic disease is frequently observed in inflammatory breast cancer (IBC), with a poor prognosis as a consequence. The aim of this study was to analyze the association of hormone receptor (HR) and human epidermal growth factor receptor-2 (HER2) based breast cancer subtypes in stage IV inflammatory breast cancer (IBC) with preferential site of distant metastases and overall survival (OS). METHODS: For patients with stage IV IBC, diagnosed in the Netherlands between 2005 and 2016, tumors were classified into four breast cancer subtypes: HR+/HER2-, HR+/HER2+, HR-/HER2+, and HR-/HER2-. Patient, tumor, and treatment characteristics and sites of metastases were compared. OS of the subtypes was compared using Kaplan-Meier curves and the log-rank test. Association between subtype and OS was assessed in multivariable models using logistic regression. RESULTS: In total, 744 eligible patients were included: 340 (45.7%) tumors were HR+/HER2-, 148 (19.9%) HR-/HER2+, 131 (17.6%) HR+/HER2+, and 125 (16.8%) HR-/HER2-. Bone was the most common metastatic site in all subtypes. A significant predominance of bone metastases was found in HR+/HER2- IBC (71.5%), and liver and lung metastases in the HR-/HER2+ (41.2%) and HR-/HER2- (40.8%) subtypes, respectively. In multivariable analysis, the HR-/HER2- subtype was associated with significantly worse OS as compared to the other subtypes. CONCLUSION: Breast cancer subtypes in stage IV IBC are associated with distinct patterns of metastatic spread and display notable differences in OS. The use of breast cancer subtypes can guide a more patient-tailored staging directed to metastatic site and extend of disease.

Inflammatory breast cancer in the Netherlands; improved survival over the last decades.

PURPOSE: Locally advanced breast cancer (LABC) includes inflammatory breast cancer (IBC) as well as non-inflammatory LABC (NI-LABC). The aim of this population-based study was to compare the tumour characteristics, treatment and relative survival of IBC and NI-LABC patients. METHODS: Patients with either IBC (cT4d) or NI-LABC (cT4a-c) were identified from the nationwide Netherlands Cancer Registry from the period 1989-2015. In each group, patients are divided into three time periods in order to perform a trend analysis: 1989-1997, 1998-2006, and 2007-2015. RESULTS: IBC comprised 1.1% and NI-LABC 4.6% of all diagnosed breast cancer patients. IBC patients showed more nodal metastases (77.8 vs. 69.7%, P < 0.001) and distant metastases (39.7 vs. 34.1%, P < 0.001). IBC tumours were more often triple negative (23.2 vs. 12.8%, P < 0.001) and poorly differentiated (69.8 vs. 53.8%, P < 0.001). Trimodality therapy (neoadjuvant chemotherapy, surgery and adjuvant radiotherapy) was more often applied over time in both groups (IBC: 23.7%-56.0%-68.6%; NI-LABC: 3.7%-25.9%-43.6%; P trend < 0.001). In IBC patients, relative 5-year survival was significantly shorter than in patients with NI-LABC (30.2 vs. 45.1%, P < 0.001). The relative survival significantly improved for IBC from 17.2% (1989-1997) to 30.0 and 38.9% for the last two time periods (1998-2006: P < 0.001; 2007-2015: P < 0.001). In contrast, survival did not significantly improve in NI-LABC breast cancer: from 44.7% (1989-1997) to 44.0 and 48.4% (1998-2006: P = 0.483; 2007-2015: P = 0.091). CONCLUSIONS: IBC has tumour characteristics that determine its aggressive biology compared to NI-LABC. Trimodality therapy was increasingly applied in both groups, but did not improve survival in NI-LABC. Although relative survival in IBC patients has improved during the last decades, it remains a disease with a dismal prognosis.

Development of eosinophilic inflammation is independent of B-T cell interaction in a chronic house dust mite-driven asthma model.

BACKGROUND: Chronic exposure to environmental triggers, such as house dust mite (HDM), drives T helper 2 (Th2) cell-mediated asthma. Recent evidence has shown that B-T cell interaction, and in particular germinal centre reactions and follicular T helper (Tfh) cells are required for the development of eosinophilic airway inflammation in HDM-driven models containing a sensitization and challenge phase. Whether B-T cell interactions are essential for pulmonary eosinophilic inflammation following chronic allergen provocation remains unknown. AIMS: In this study, we investigated the importance of B-T cell interaction in the development of eosinophilic airway inflammation and pulmonary remodelling in a chronic HDM-driven asthma model. METHODS: We exposed C57BL/6, Cd40l-/- , and Mb1-/- mice to HDM three times a week for five consecutive weeks. RESULTS: Chronic HDM exposure induced a pronounced eosinophilic allergic airway inflammation in broncho-alveolar lavage fluid (BALf) and lung tissue, associated with the formation of immunologically active inducible bronchus-associated lymphoid tissue (iBALT) in the lungs. The absence of B cells or lack of CD40L signalling did not hamper eosinophilic inflammation in the airways, although the number of Tfh and Th2 cells was substantially reduced in the lungs. Importantly, type 2 innate lymphoid cell (ILC2) numbers in BALf and lung were not affected by the absence of B cells or B-T cell interaction. Furthermore, eosinophilic airway inflammation is not sufficient to induce pulmonary remodelling and airway hyperresponsiveness. CONCLUSION AND CLINICAL RELEVANCE: From these findings, we conclude that B-T cell interaction is required for robust Tfh and Th2 cell induction, but not essential for eosinophilic airway inflammation during a chronic HDM-driven asthma model.

Outcomes that matter most to burn patients: A national multicentre survey study in the Netherlands.

BACKGROUND: The use of patient-reported outcomes to improve burn care increases. Little is known on burn patients' views on what outcomes are most important, and about preferences regarding online Patient Reported Outcome Measures (PROMs). Therefore, this study assessed what outcomes matter most to patients, and gained insights into patient preferences towards the use of online PROMs. METHODS: Adult patients (≥18 years old), 3-36 months after injury completed a survey measuring importance of outcomes, separately for three time periods: during admission, short-term (<6 months) and long-term (6-24 months) after burn injury. Both open and closed-ended questions were used. Furthermore, preferences regarding the use of patient-reported outcome measures in burn care were queried. RESULTS: A total of 140 patients were included (response rate: 27%). 'Not having pain' and 'good wound healing' were identified as very important outcomes. Also, 'physical functioning at pre-injury level', 'being independent' and 'taking care of yourself' were considered very important outcomes. The top-ten of most important outcomes largely overlapped in all three time periods. Most patients (84%) had no problems with online questionnaires, and many (67%) indicated that it should take up to 15 minutes. Patients' opinions differed widely on the preferred frequency of follow-up. CONCLUSIONS: Not having pain and good wound healing were considered very important during the whole recovery of burns; in addition, physical functioning at pre-injury level, being independent, and taking care of yourself were deemed very important in the short and long-term. These outcomes are recommended to be used in burn care and research, although careful selection of outcomes remains crucial as patients prefer online questionnaires up to 15 minutes.

Development of a value-based healthcare burns core set for adult burn care.

BACKGROUND: Value-based healthcare (VBHC) is increasingly implemented in healthcare worldwide. Transparent measurement of the outcomes most important and relevant to patients is essential in VBHC, which is supported by a core set of most important quality indicators and outcomes. Therefore, the aim of this study was to develop a VBHC-burns core set for adult burn patients. METHODS: A three-round modified national Delphi study, including 44 outcomes and 24 quality indicators, was conducted to reach consensus among Dutch patients, burn care professionals and researchers. Items were rated on a nine-point Likert scale and selected if ≥ 70% in each group considered an item 'important'. Subsequently, instruments quantifying selected outcomes were identified based on a literature review and were chosen in a consensus meeting using recommendations from the Dutch consensus-based standard set and the Dutch Centre of Expertise on Health Disparities. Time assessment points were chosen to reflect the burn care and patient recovery process. Finally, the initial core set was evaluated in practice, leading to the adapted VBHC-burns core set. RESULTS: Twenty-seven patients, 63 burn care professionals and 23 researchers participated. Ten outcomes and four quality indicators were selected in the Delphi study, including the outcomes pain, wound healing, physical activity, self-care, independence, return to work, depression, itching, scar flexibility and return to school. Quality indicators included shared decision-making (SDM), the number of patients receiving aftercare, determination of burn depth, and assessment of active range of motion. After evaluation of its use in clinical practice, the core set included all items except SDM, which are assessed by 9 patient-reported outcome instruments or measured in clinical care. Assessment time points included are at discharge, 2 weeks, 3 months, 12 months after discharge and annually afterwards. CONCLUSION: A VBHC-burns core set was developed, consisting of outcomes and quality indicators that are important to burn patients and burn care professionals. The VBHC-burns core set is now systemically monitored and analysed in Dutch burn care to improve care and patient relevant outcomes. As improving burn care and patient relevant outcomes is important worldwide, the developed VBHC-burns core set could be inspiring for other countries.

[18F]FDG PET/CT in the staging of inflammatory breast cancer: A systematic review.

Up to 78 % of patients with inflammatory breast cancer (IBC) present with axillary lymph node involvement and up to 40 % with distant metastases. Previous studies indicate that 2-deoxy-2-(18F)fluoro-d-glucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) might be used for initial staging in patients with inflammatory breast cancer (IBC). In other cancer types, [18F]FDG PET/CT has been demonstrated to be a sensitive technique, providing complementary information on locoregional and distant disease to conventional imaging modalities. This systematic review showed that 18F]FDG PET/CT detects additional locoregional lymph node metastases and distant metastases in 10.3 % of patients, that were not detected with standard staging imaging. Compared with conventional imaging procedures, [18F]FDG PET/CT had better diagnostic performance for detection of locoregional and distant metastases and should standardly be used in the diagnostic work-up of IBC patients.

Better survival after surgery of the primary tumor in stage IV inflammatory breast cancer.

INTRODUCTION: Information regarding the effects of resection of the primary tumor in stage IV inflammatory breast cancer (IBC) is scarce. We analyzed the impact of resection of the primary tumor on overall survival (OS) in a large stage IV IBC population. MATERIALS AND METHODS: Patients diagnosed with stage IV IBC between 2005 and 2016 were selected from the Netherlands Cancer Registry, excluding patients without any treatment. To correct for immortal time bias, we performed a landmark analysis including patients alive at least six months after diagnosis. With propensity score matching, patients undergoing surgery of the primary tumor were matched to patients not receiving surgery. Multivariable Cox proportional hazard analyses were performed to determine the association between treatment strategy and OS in the non-matched and matched cohort. RESULTS: Of the 580 included patients after landmark analysis, 441 patients (76%) received only non-surgical treatments and 139 (24%) underwent surgery (96% mastectomy). Median follow-up was 28.8 and 20.0 months in the surgery and no surgery group, respectively. Surgery in the non-matched cohort was independently associated with better survival (HR0.56[95%CI:0.42-0.75]). In the matched cohort (n = 202), surgically treated patients had improved survival over nonsurgically treated patients (p < 0.005). Multivariable analysis of the matched cohort revealed that surgery was still associated with better survival (HR0.62[95%CI:0.44-0.87]). CONCLUSION: Although residual confounding and confounding by severity cannot be ruled out, this study suggests that surgery of the primary tumor is associated with improved OS and should be considered as part of the treatment strategy in stage IV IBC.

Inflammatory breast cancer: an overview.

Inflammatory breast cancer (IBC) is the most aggressive entity of breast cancer. Management involves coordination of multidisciplinary management and usually includes neoadjuvant chemotherapy, ablative surgery if a tumor-free resection margin is expected and locoregional radiotherapy. This multimodal therapeutic approach has significantly improved patient survival. However, the median overall survival among women with IBC is still poor. By elucidating the biologic characteristics of IBC, new treatment options may become available. We performed a comprehensive review of the English-language literature on IBC through computerized literature searches. The objective of the current review is to present an overview of the literature related to the biology, imaging and multidisciplinary treatment of inflammatory breast cancer.

Inactivation of heparin during extracorporeal circulation in infants.

Heparin anticoagulation is necessary to prevent clotting during procedures involving the extracorporeal circulation of blood. Our preliminary observations suggested that heparin was inactivated in the extracorporeal circuit during extracorporeal membrane oxygenation. We tested this hypothesis by comparing heparin pharmacokinetics in five infants during extracorporeal circulation with kinetics, respectively determined in each patient and in the isolated circuit immediately after discontinuation of the procedure. Heparin clearance was 1.6 +/- 0.5 ml/kg/min in the patient and 2.1 +/- 0.8 ml/kg/min in the separated circuit. In each patient, the total of heparin clearances in the patient and circuit, 3.7 +/- 1.0 ml/kg/min, was virtually identical with the heparin clearance during the procedure, 3.8 +/- 1.9 ml/kg/min (r = 0.94, p less than 0.01). We conclude that more than one half of the heparin administered to infants during extracorporeal membrane oxygenation is eliminated by the extracorporeal circuit itself or by blood components in the circuit. These data explain the relatively large heparin doses needed to maintain anticoagulation in infants during extracorporeal circulation. In light of these findings, a reexamination of the normal mechanisms of elimination of heparin activity appears to be warranted.

Intravenous glycerol and mannitol therapy in children with intracranial hypertension.

Acute intracranial hypertension may respond to intravenous mannitol, but frequent administration can cause cerebral edema or renal problems. We evaluated the use of 20% glycerol administered intravenously as an alternative to mannitol. Intravenous glycerol and mannitol were equally effective in lowering acute elevations of intracranial pressure. The duration of effect was similar for both agents. Side effects of intravenous glycerol were related to concentration, rate, and frequency of administration. In severe encephalopathies, such as Reye syndrome, we recommend infusions of 20% glycerol or 20% mannitol at a dose of 0.5-1.0 gm per kilogram. Glycerol should be administered in 0.45% or 0.9% saline, no faster than 1.5 ml (3.3 mOsm) per minute.

Self-regulation of salivary immunoglobulin A by children.

In a prospective randomized controlled study, the possibility that children could regulate their own salivary immunoglobulins was investigated using cyberphysiologic techniques. Fifty-seven children were randomly assigned to one of three groups. Group A subjects learned self-hypnosis with permission to increase immune substances in saliva as they chose; group B subjects learned self-hypnosis with specific suggestions for control of saliva immunoglobulins; group C subjects were given no instructions but received equal attention time. At the first visit, saliva samples (baseline) were collected, and each child looked at a videotape concerning the immune system and was tested with the Stanford Children's Hypnotic Susceptibility Scale. At the second visit, an initial saliva sample was collected prior to 30 minutes of self-hypnosis practice or conversation. At the conclusion of the experiment, a third saliva sample was obtained. Salivary IgA and IgG levels for all groups were stable from the first to the second sampling. Children in group B demonstrated a significant increase in IgA (P less than .01) during the experimental period. There were no significant changes in IgG. Stanford Children's Hypnotic Susceptibility Scale scores were stable across groups and did not relate to immunoglobulin changes.

Comparison of self-hypnosis and propranolol in the treatment of juvenile classic migraine.

In a prospective study we compared propranolol, placebo, and self-hypnosis in the treatment of juvenile classic migraine. Children aged 6 to 12 years with classic migraine who had no previous specific treatment were randomized into propranolol (at 3 mg/kg/d) or placebo groups for a 3-month period and then crossed over for 3 months. After this 6-month period, each child was taught self-hypnosis and used it for 3 months. Twenty-eight patients completed the entire study. The mean number of headaches per child for 3 months during the placebo period was 13.3 compared with 14.9 during the propranolol period and 5.8 during the self-hypnosis period. Statistical analysis showed a significant association between decrease in headache frequency and self-hypnosis training (P = .045). There was no significant change in subjective or objective measures of headache severity with either therapy.

Cefpodoxime proxetil vs. penicillin V in pediatric streptococcal pharyngitis/tonsillitis.

This multicenter, randomized, parallel treatment, observer-blinded study was designed to evaluate the safety and efficacy of cefpodoxime proxetil (5 mg/kg twice daily for 10 days) compared with penicillin V (13.4 mg/kg three times daily for 10 days) for treatment of Group A streptococcal pharyngitis and tonsillitis in pediatric patients. Clinical and microbiologic results were evaluated before therapy, during therapy (Study Days 3 to 5), at the end of therapy (Study Days 14 to 18) and at long term follow-up (Study Days 30 to 32). Both drugs were well-tolerated in 578 patients evaluable for safety. Mild gastrointestinal complaints were noted in 6.7% of 386 cefpodoxime-treated patients and in 5.2% of 192 penicillin-treated patients. In 413 patients evaluable for efficacy, both treatment regimens resulted in comparably favorable clinical outcome; cure rates were 83.8% for 275 cefpodoxime-treated patients and 77.5% for 138 penicillin-treated patients. However, eradication of S. pyogenes at end of therapy was significantly higher with cefpodoxime (93.1%) than with penicillin (81.2%) (P < 0.01). Cefpodoxime proxetil provides an effective alternative to penicillin V for the treatment of streptococcal pharyngitis and tonsillitis.

Aortic valve replacement in adult patients with small aortic annuli.

Fifty-five patients with small aortic annuli underwent valve replacement either isolated or combined with other procedures. Patch enlargement of the aortic annulus in the area of the noncoronary sinus was used in 32 patients. The width of the patch was calculated by multiplying the desired increase in diameter by pi and adding 8 mm for suturing. The remaining 23 patients had aortic valve replacement with a prosthesis larger than the aortic annulus. The prosthesis was sutured in a supraannular position in the area corresponding to the noncoronary sinus. This slightly tilted position does not compromise function of Carpentier-Edwards or Björk-Shiley prostheses. Prosthetic gradients ranged from 0 to 18 mm Hg (9.2 +/- 3.9 mm Hg) in patients with patch enlargement of the aortic annulus and from 0 to 22 mm Hg (7.2 +/- 5.8 mm Hg) in patients with supraannular aortic prostheses. Although these techniques allow for insertion of prosthetic valves only one and two sizes larger than the aortic annulus, they appear to be satisfactory in most adult patients with a small aortic annulus.

The effect of paraldehyde on intravenous tubing sets.

Paraldehyde is used in the treatment of status epilepticus, alcohol withdrawal, and delirium tremens. Because it is a solvent, concerns have been raised about infusing it through plastic intravenous tubing sets. In a three-phase study, 4% paraldehyde in 5% dextrose solution was analyzed over 24 hours for photodegradation, adsorption to polyvinylchloride- (PVC) and polyethylene- (PE) lined intravenous tubing, and the presence of di(2-ethylhexyl) phthalate (DEHP). Paraldehyde and DEHP samples were quantified by gas chromatography, and DEHP was confirmed by mass spectral analysis. On exposure to light for 24 hours, the concentration of paraldehyde decreased from 100 to 97%. This decrease is statistically significant but clinically insignificant. A 24-hour continuous infusion of paraldehyde through the two types of tubing revealed a decrease in concentration attributable to adsorption of 4% with PE and 13% with PVC tubing at 2 hours. In addition, there was no appreciable leaching of DEHP over 24 hours with either type of tubing. Concerns about paraldehyde's light instability and effects on tubing integrity appear to be unwarranted with commercially available intravenous administration sets.

Determination of theophylline bioavailability using saliva theophylline concentrations.

Substantial error occurs when individual saliva theophylline concentrations are used to predict serum theophylline concentrations. However, the use of saliva theophylline concentrations to determine product bioavailability has never been evaluated. Subjects in this study were 18 stable patients (20-51 yr) with a history of chronic obstructive pulmonary disease. Three preparations--a capsule (Elixophyllin 400 mg), elixir (Elixophyllin 373 mg), and tablet (Theolair 375 mg)--were administered in a randomized crossover design. Serum and saliva samples were obtained pre-dose and 0.25, 0.5, 1, 2, 4, 6, and 8 hours after theophylline administration. The saliva AUC0-infinity and serum AUC0-infinity were highly associated for the elixir (r = 0.84) tablet (r = 0.89), and capsule (r = 0.89). The bioavailability of the tablet and capsule calculated from elixir saliva and elixir serum AUC0-infinity were not significantly different (p = 0.2). The bioavailability of the tablet calculated from saliva and serum was 93% and 102%, respectively. The bioavailability of the capsule calculated from saliva and serum was 113% and 102% respectively. Our data suggests that theophylline bioavailability can be reliably estimated from saliva theophylline concentrations. However, study designs that include larger sample sizes and more frequent sampling may be necessary when determining bioavailability from saliva.

Evaluation of a rapid monitoring system to study heparin pharmacokinetics and pharmacodynamics.

The pharmacokinetic and pharmacodynamic characteristics of heparin were studied in 10 healthy volunteers using the Hepcon/System B-10. This coagulation-monitoring system uses each patient's body weight, height, baseline activated clotting time (ACT), and heparin dose response values to determine initial heparin doses. We administered a calculated mean +/- SD heparin doses of 85 +/- 14 U/kg to 10 subjects to achieve a mean +/- SD target ACT of 364 +/- 29 seconds. This dose produced a mean +/- SD measured peak ACT of 337 +/- 53 seconds from a mean +/- SD baseline of 121 +/- 10 seconds. The measured peak ACT values resulting from the individualized heparin doses were within 20% of the desired peak in 9 (90%) of the subjects. Using the ACT values, the average mean residence time for heparin effect was 1.2 hours and half-life was 0.8 +/- 0.2 hours, with all the subjects' values returning to within 10% of baseline by 4 hours after the dose. Using the protamine-derived heparin concentrations, heparin total-body clearance ranged from 43 to 99 ml/hr/kg (mean +/- SD 73.3 +/- 14.5 ml/hr/kg). A linear relationship was found between heparin concentration and change in ACT that was described by delta ACT = 16.85 + 136.7.(heparin concentration). We conclude that this method is easy to perform and accurate for determining initial heparin dosage requirements, and could be an important improvement over existing approaches. In addition, it is a valuable research tool for studying heparin pharmacodynamics and pharmacokinetics.

Pharmacokinetics of fluconazole in immune-compromised children with leukemia or other hematologic diseases.

STUDY OBJECTIVE: To describe the pharmacokinetics of fluconazole in immune-compromised children with leukemia or other hematologic disease. DESIGN: Prospective. SETTING: Children's Health Care-Minneapolis hematology/oncology inpatient ward and outpatient clinic. PATIENTS: Ten immune-compromised children (mean +/- SD age 7.4 +/- 4.0 yrs, weight 31.6 +/- 25.9 kg) with leukemia or other hematologic disease. INTERVENTIONS: Serum was sampled before and after a single 6-mg/kg intravenous dose and after seven oral 3-mg/kg doses of fluconazole. MEASUREMENTS AND MAIN RESULTS: Mean (SD) pharmacokinetics were distribution half-life 1.67 (1.25) hours, elimination half-life 15.62 (3.21) hours, total body clearance 0.63 (0.19) ml/min/kg, volume of distribution for the central compartment 0.56 (0.10) L/kg, volume of distribution at steady state 0.77 (0.12) L/kg, absorption half-life 0.41 (0.26) hour, and oral bioavailability 0.92 (0.09). Volume of distribution for the central compartment was highly correlated with body surface area (r2 = 0.891) and weight (r2 = 0.949). Volume of distribution at steady state correlated with body surface area (r2 = 0.986), and total body clearance correlated with body surface area (r2 = 0.867). CONCLUSIONS: Fluconazole elimination was well described using a two-compartment model. Oral absorption was rapid and nearly complete. Children have a larger volume of distribution for the central compartment and faster elimination rate than adults. Body surface area and weight are important factors in determining pharmacokinetics in these patients.

Bronchodilation from intravenous theophylline in patients with cystic fibrosis: results of a blinded placebo-controlled crossover clinical trial.

Most patients with cystic fibrosis (CF) eventually develop chronic obstructive pulmonary disease and theoretically could benefit from theophylline therapy. The purpose of this study was to investigate the pharmacologic response to intravenous theophylline by pulmonary function tests (PFT) and the theophylline pharmacokinetics in patients with CF. A randomized, double-blind, placebo-controlled, crossover trial was conducted in 10 ambulant patients with CF (5 females, 5 males), aged 11 to 21 years. Each patient received an intravenous dose of theophylline and normal saline over 1/2 hour on consecutive days. Spirometry and whole-body plethysmography were performed at baseline, 1, 3, 5, and 7 h after the theophylline dose, and 10 blood samples were collected over 9 h on both study days. The percent change of PFT from the baseline was recorded. Analysis of variance for balanced two-period crossover design was used to evaluate the effectiveness of theophylline therapy. The serum concentration (Conc.) vs. time data were fitted using nonlinear least-squares regression analysis. The theophylline dose administered was 7.9 +/- 0.4 (mean +/- SD) mg/kg, which produced a maximal Conc. (Cmax) of 14.6 +/- 2.7 microgram/ml. The half-life (T1/2), volume of distribution (Vd), and total body clearance (TBC) were 4.9 +/- 1.9 h, 537 +/- 124 mL/kg, and 80 +/- 16 ml/h/kg, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)