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Biomedical subjects

W Bakker

Publications and source records attributed to W Bakker.

At least 19 recordsLinked to original sources
PubMed2000

OctreoTher: ongoing early clinical development of a somatostatin-receptor-targeted radionuclide antineoplastic therapy.

OctreoTher ((90)Y-DOTA-D-Phe(1)-Tyr(3)-octreotide, a.k.a. (90)Y-SMT 487) consists of a somatostatin peptide analogue (Tyr(3)-octreotide), coupled with a complexing moiety (DOTA), and labeled with a tightly bound beta-emitter (yttrium-90). By targeting somatostatin receptor-positive tumors (as imaged by OctreaScan it may deliver a tumoricidal dose of radiation. Phase I clinical trials, conducted in patients with neuroendocrine tumors, established the safety and tolerability of the dose selected for further study and demonstrated the capacity of OctreoTher to deliver radiation doses to tumors that resulted in significant neuroendocrine tumor shrinkage. Novartis-sponsored phase II studies will soon begin to test the efficacy of OctreoTher in breast and small cell lung cancer. A fixed-dose regimen of 120 mCi/cycle x 3 cycles administered with concomitant amino acid infusion has been chosen for the study. Phase I data and published literature support that this fixed dose regimen will be safely tolerated.

Animals↗
PubMed1999

Clinical and genetic studies on 12 preaxial polydactyly families and refinement of the localisation of the gene responsible to a 1.9 cM region on chromosome 7q36.

Polydactyly is the most frequently observed congenital hand malformation with a prevalence between 5 and 19 per 10000 live births. It can occur as an isolated disorder, in association with other hand/foot malformations, or as a part of a syndrome, and is usually inherited as an autosomal dominant trait. According to its anatomical location, polydactyly can be generally subdivided into pre- and postaxial forms. Recently, a gene responsible for preaxial polydactyly types II and III, as well as complex polysyndactyly, has been localised to chromosome 7q36. In order to facilitate the search for the underlying genetic defect, we ascertained 12 additional families of different ethnic origin affected with preaxial polydactyly. Eleven of the kindreds investigated could be linked to chromosome 7q36, enabling us to refine the critical region for the preaxial polydactyly gene to a region of 1.9 cM. Our findings also indicate that radial and tibial dysplasia/aplasia can be associated with preaxial polydactyly on chromosome 7q36. Combining our results with other studies suggests that all non-syndromic preaxial polydactylies associated with triphalangism of the thumb are caused by a single genetic locus, but that there is genetic heterogeneity for preaxial polydactyly associated with duplications of biphalangeal thumbs. Comparison of the phenotypic and genetic findings of different forms of preaxial polydactyly is an important step in analysing and understanding the aetiology and pathogenesis of these limb malformations.

Animals↗
PubMed1998

Effect of interleukin-8 and monocyte chemotactic protein-1 on adhesion of circulating granulocytes and monocytes from asthma patients to human venous endothelial cells.

The adhesive interactions between phagocytes and endothelial cells (EC) can be modulated by inflammatory cytokines and chemotactic proteins which are released during an inflammatory response. The aim of the present study was to investigate first whether the adhesive properties of granulocytes and monocytes from asthma patients for vascular endothelial cells differ from those of phagocytes from healthy individuals. Furthermore, we studied whether the chemokines interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1) can affect the binding of phagocytes to EC. No differences were observed in binding of phagocytes from asymptomatic or symptomatic asthma patients and from healthy individuals to non-stimulated or cytokine-stimulated EC. Incubation of granulocytes with IL-8 did not influence their adhesion to non-stimulated EC but inhibited the adhesion of granulocytes to IL-1-stimulated EC. Incubation of monocytes with MCP-1 did not affect their adhesion to non-stimulated or cytokine-stimulated EC. Our results indicate that adhesion of phagocytes to EC depends on the activation state of the endothelial cells but not on the origin of the phagocytes, since there were no differences in the adhesion of phagocytes from asthma patients and healthy individuals to non-stimulated or cytokine-stimulated EC.

Adolescent↗
PubMed1998

Expression of adhesion molecules on granulocytes and monocytes from patients with asthma stimulated in vitro with interleukin-8 and monocyte chemotactic protein-1.

Upregulation of adhesion molecule expression on endothelial cells (EC) and circulating leukocytes, by locally produced inflammatory mediators, may result in the enhanced infiltration of leukocytes into tissue, e.g. the airways of asthma patients. The present study investigates whether the expression of adhesion molecules on granulocytes and monocytes from asthma patients is affected by chemotactic factors, i.e. interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1). Flow cytometric analysis showed that the intrinsic expression of the various adhesion molecules on peripheral blood phagocytes from asthma patients was not different from that of healthy individuals. However, stimulation of monocytes with MCP-1 resulted only in upregulation of the expression of CD14 on monocytes from symptomatic asthma patients but not on monocytes from asymptomatic asthma patients and healthy individuals. Stimulation of granulocytes with IL-8 did not change the expression of the various beta 1- and beta 2-integrin molecules, such as VLA-4, LFA-1, CR3 and p150,95. Since earlier studies have shown that CD14 on monocytes mediates monocyte adhesion to activated vascular EC the present findings suggest that during the active phase of asthma upregulation of CD14 on monocytes by MCP-1 may lead to an increased adhesion of monocytes to vascular endothelium and their subsequent transendothelial migration into the tissue of the airways.

Adolescent↗
PubMed1997

Continuous infusion of ceftazidime in cystic fibrosis patients during home treatment: clinical outcome, microbiology and pharmacokinetics.

Acute exacerbations of Pseudomonas aeruginosa lung infections were treated with ceftazidime by continuous infusion in 17 adult patients with cystic fibrosis at home. Ceftazidime was delivered via an infusion pump and the effects of this 3 week home intravenous antibiotic treatment (HIVAT) were prospectively studied over a 2 year period. Patients with cystic fibrosis (eight male and nine female patients; mean age 26.9 +/- 7.6 years, range 15-52 years), received a total of 33 courses of continuous ceftazidime (100 mg/kg/24 h). Clinical data were collected at the start, the end and 4-6 weeks after the end of treatment in 12 patients. Ceftazidime pharmacokinetic data during continuous infusion were obtained from ten patients. The treatment was supervised by the clinician without home visits. All 25 clinically evaluable courses in 12 patients proved efficacious. The mean duration of the courses was 21 days. The entire antibiotic course was administered at home in 88% of the courses. The other 12% was started for 2-3 days as an inpatient. Objective clinical parameters significantly improved. Clinical improvement was noted in 91% of the patients, and lasted at least until 4-6 weeks after the end of the treatment in 70%. The number of cultures positive for P. aeruginosa decreased significantly during antibiotic treatment. Bacterial count returned to pretreatment values 4-6 weeks after treatment. Multiple courses of ceftazidime monotherapy did not result in a lasting increase of ceftazidime-resistant pseudomonas strains. Total body clearance was 9.1 +/- 1.3 L/h. The steady-state ceftazidime serum concentration during continuous infusion was 28.4 +/- 5.0 mg/L. Sputum concentrations were in the range of 0.5-13 mg/L (3.9 +/- 4.0 mg/L). In conclusion, HIVAT with ceftazidime administered by continuous infusion proved clinically effective and did not result in an increase in lasting resistance.

Adolescent↗
PubMed1997

Pharmacokinetics of aerosolized tobramycin in adult patients with cystic fibrosis.

This study was performed to determine the clinical pharmacokinetics of tobramycin in six patients with cystic fibrosis (CF) after inhalation of 600 mg. Tobramycin was administered with an ultrasonic nebulizer (WISTO SENIOR). Blood and urine were sampled until 24 h after inhalation. Maximum tobramycin levels in serum varied from 0.19 to 2.57 mg/liter (mean 1.27 mg/liter; standard deviation, 1.07 mg/liter). Systemic availability (calculated from urinary output) ranged from 6.0 to 27.4% (mean, 17.5%; standard deviation, 8.8%). The results illustrate that, provided that the systemic availability of tobramycin is a reflection of pulmonary deposition, inhalation studies with CF patients should have a concentration-controlled design. Furthermore, reliance on dose recommendations from the literature for a new patient starting on this treatment is not justified, but it is mandatory that deposition kinetics be studied for each patient and for each nebulizer. It may well be that, with higher levels of deposition, dosages lower than those recommended in the literature will suffice to obtain the desired clinical effect. In addition, the reverse may also be the case.

Administration, Inhalation↗
PubMed1996

Stability of aztreonam in a portable pump reservoir used for home intravenous antibiotic treatment (HIVAT).

The stability of the monocyclic beta-lactam antibiotic aztreonam in portable pump reservoirs was studied during storage at temperatures of -20 degrees C and +5 degrees C and during drug delivery at 37 degrees C. Three 100-ml drug reservoirs and three glass containers containing 60 mg/ml aztreonam were stored at -20 degrees C and 2-ml samples were analysed in the freshly prepared solution and after thawing at days 7, 21, 28, 70 and after 6 months of storage. A separate triplicate batch of 100-ml prefilled drug reservoirs and glass containers containing a similar aztreonam concentration (60 mg/ml) were refrigerated and tested immediately after preparation and daily for 8 days and after 70 days. Solutions of aztreonam in duplicate freshly prepared reservoirs were tested for stability when the solution was pumped at 37 degrees C over a 24-h period. All solutions were inspected for visual changes and tested for pH. Drug concentration was analysed by high-performance liquid chromatography. No colour changes or pH differences were observed in any of the solutions in the reservoirs of containers. No statistically significant decrease in aztreonam concentration could be detected after 6 months of storage at -20 degrees C. Aztreonam was stable at 5 degrees C for at least 8 days. A 24-h pumping period at 37 degrees C showed a 3.6% decrease in aztreonam concentration. Aztreonam at a concentration of 60 mg/ml in a pump reservoir is sufficiently stable to be used in home intravenous antibiotic treatment programmes.

Aztreonam↗
PubMed1996

In vitro dissolution profiles of enteric-coated microsphere/microtablet pancreatin preparations at different pH values.

OBJECTIVES: Enteric-coated microsphere/microtablet pancreatin should stay intact in the stomach and dissolve promptly on entering the duodenum. Postprandial intraluminal pH in the distal duodenum is 5.75 and is lower in exocrine pancreatic insufficiency. The aim of the study was to measure in vitro dissolution times in buffer solutions with pH 4.0-6.0 for five currently available enteric-coated microsphere/microtablet pancreatin preparations. METHODS: The following preparations were tested: Creon, Creon Forte, Pancrease, Pancrease HL and Panzytrat. Two capsules were placed in the buffer solution at 37 degrees C in a USP dissolution testing apparatus. Buffer solutions with pH between 4.0 and 6.0 were used. Solutions were stirred at 125 r.p.m. and the rate of dissolution was monitored by taking 2-mL samples at regular intervals and measuring extinction at 280 nm. Measurements were repeated six times. RESULTS: All preparations failed to dissolve at pH 4.0. At pH 5.0 Pancrease HL showed 43% dissolution within 30 min, all other preparations 15% or less. Panzytrat and Pancrease HL showed more than 50% dissolution within 30 min at pH 5.2. Panzytrat, Pancrease HL and Creon Forte had more than 90% dissolution within 30 min at pH 5.6, and all preparations more than 90% dissolution within 30 min at pH 5.8 and higher. CONCLUSIONS: For the treatment of exocrine pancreatic insufficiency conventional strength enteric-coated microsphere/microtablet pancreatin preparations do not have an optimal dissolution profile. The newer, high lipase preparations such as Pancrease HL perform better, although still not optimally, at pH 5.4 and lower.

Buffers↗
PubMed1996

Prospective evaluation of a dose prediction algorithm for intravenous tobramycin in adolescent and adult patients with cystic fibrosis.

The predictive performance of a new algorithm to calculate the initial daily dose of tobramycin in patients with cystic fibrosis (CF) was prospectively evaluated. Twenty-six patients with CF (15 men, 11 women, 18-45 years of age) with an acute exacerbation of their chronic pulmonary infection were treated with intravenous tobramycin. The initial dose was calculated with a previously presented algorithm. This algorithm was derived from correlation analysis performed on the adjusted daily dose guided by the determination of serum concentrations: dose (mg three times daily) = 90 + 2.13 x LBM (kg), where LBM (male) = (1.1 x body weight [BW]) - (128 x BW2/height2) and LBM (female) = (1.07 x BW) - (148 x BW2/height2). The predictive performance of this algorithm was evaluated comparing the calculated initial daily dose with the adjusted daily dose for peak and trough levels of 9-11 mg/L and 1.0 mg/L, respectively. Mean squared error and mean error were determined as reflections of precision and bias. The predictive performance of the algorithm was compared with historical data on the predictive performance of the standard equation to dose of 3.3 mg/kg body weight three times daily. The dose calculated with the algorithm proved to give peak serum concentrations in a narrower range and to have a greater precision, but bias was equal. Applying the algorithm, more patients had initial peak serum concentrations in the pre-determined range of 9-11 mg/L than when using the standard equation, so fewer dose adjustments had to be made.

Adolescent↗
PubMed1996

Creatinine clearance as predictor of tobramycin elimination in adult patients with cystic fibrosis.

Assessment of renal function and relating this parameter to amino-glycoside clearance is important for an appropriate individualization of dosage regimens in patients with impaired renal function. However, it has been suggested that in cystic fibrosis (CF), creatinine clearance (CrCl) is not a good predictor of tobramycin clearance because of a lack of correlation. The aim of this study was to investigate the correlation between the tobramycin clearance and the measured CrCl. In addition, because most pharmacokinetic computer models use an a priori relationship between CrCl and tobramycin elimination rate constant [k(el)], regression analysis of k(el) on CrCl was performed. Eighteen CF patients (12 men, 6 women, ages 21-55 years) were treated with intravenous tobramycin. Blood and urine samples were collected for tobramycin analysis and determination of the CrCl. For each patient, CrCl was also estimated using the formulas of Cockcroft and Gault (C/G), Jelliffe I (J I), and Jelliffe II (J II). Predictive performance of these formulas was evaluated using mean error and mean squared error as reflections of bias and precision. Tobramycin total body clearance as well as renal clearance correlated significantly with CrCl (r = 0.52; p = 0.02 and r = 0.78; p = 0.02, respectively). Regression of the tobramycin k(el) versus CrCl gave the following equation: k(el) = 0.135 + 0.00134*CrCl/1.73 m2 (r = 0.64; p = 0.004). The 95% confidence interval of intercept and slope of the regression line were 0.019-0.251 and 0.00049-0.00219, respectively. The formulas of C/G, J I, and J II all overpredicted CrCl. Bias was 19, 24, and 8 ml/min, and precision was 37, 42, and 33 ml/min, respectively, for the C/G, J I, and J II formulas. In our CF population the J II formula gave the best estimation of the CrCl but calculated estimates deviated -25(-)+62% from measured values.

Adult↗
PubMed1996

Population pharmacokinetics of ceftazidime in cystic fibrosis patients analyzed by using a nonparametric algorithm and optimal sampling strategy.

Postinfusion data obtained from 17 patients with cystic fibrosis participating in two clinical trials were used to develop population models for ceftazidime pharmacokinetics during continuous infusion. Determinant (D)-optimal sampling strategy (OSS) was used to evaluate the benefits of merging four maximally informative sampling times with population modeling. Full and sparse D-optimal sampling data sets were analyzed with the nonparametric expectation maximization (NPEM) algorithm and compared with the model obtained by the traditional standard two-stage approach. Individual pharmacokinetic parameter estimates were calculated by weighted nonlinear least-squares regression and by maximum a posteriori probability Bayesian estimator. Individual parameter estimates obtained with four D-optimally timed serum samples (OSS4) showed excellent correlation with parameter estimates obtained by using full data sets. The parameters of interest, clearance and volume of distribution, showed excellent agreement (R2 = 0.89 and R2 = 0.86). The ceftazidime population models were described as two-compartment kslope models, relating elimination constants to renal function. The NPEM-OSS4 model was described by the equations kel = 0.06516+ (0.00708.CLCR) and V1 = 0.1773 +/- 0.0406 liter/kg where CLCR is creatinine clearance in milliliters per minute per 1.73 m2, V1 is the volume of distribution of the central compartment, and kel is the elimination rate constant. Predictive performance evaluation for 31 patients with data which were not part of the model data sets showed that the NPEM-ALL model performed best, with significantly better precision than that of the standard two-stage model (P < 0.001). Predictions with the NPEM-OSS4 model were as precise as those with the NPEM-ALL model but slightly biased (-2.2 mg/liter; P < 0.01). D-optimal monitoring strategies coupled with population modeling results in useful and cost-effective population models and will be of advantage in clinical practice, as it allows pharmacokinetic-pharmacodynamic modeling with sparse data, thus describing the relationship between ceftazidime exposure and response in the treatment of acute exacerbations in patients with cystic fibrosis.

Adult↗
PubMed1996

Cost of care of patients with cystic fibrosis in The Netherlands in 1990-1.

BACKGROUND: Research on the cost of care of patients with cystic fibrosis is scarce. The aim of this study was to estimate the costs using age-specific medical consumption from real patient data. METHODS: The age-specific medical consumption of patients with cystic fibrosis in The Netherlands in 1991 was estimated from a survey of medical records and a patient questionnaire. A distinction was made between costs of hospital care, hospital and non-hospital medication, and home care. Costs per year were obtained by multiplying the yearly amount of care and the costs per unit. RESULTS: On average the annual cost of a patient with cystic fibrosis in 1991 was 10,908 pounds (hospital care 42%, medication 37%, home care 20%). The cost of care of cystic fibrosis in The Netherlands, with approximately 1000 patients, is estimated at 10.9 million pounds per year, which is 0.07% of the total health care budget. The cost of care of a patient up to the age of 35 is estimated at 614,587 pounds. When year-to-year survival is taken into account and future costs are discounted to the year of birth with a yearly discount rate of 5%, the cost of care of a patient with cystic fibrosis is estimated at 164,365 pounds for 1991. This estimate will be used in a prospective evaluation of screening for cystic fibrosis carriers. CONCLUSIONS: The cost of care of patients with cystic fibrosis estimated by age-specific medical consumption of real patients is higher than that estimated by non-age-specific medical consumption and/or expert opinions.

Adolescent↗
PubMed1996

The nonhospital costs of care of patients with CF in The Netherlands: results of a questionnaire.

Cystic fibrosis (CF) causes a relatively high medical consumption. A large part of the treatment takes place at home. Because data regarding nonhospital care are lacking, we wished to determine the costs of care of patients with CF outside the hospital. A questionnaire was sent to 73 patients with CF from two Dutch hospitals (response rate 64%, 14 children and 33 adults). Average consumption and average costs per patient per year were calculated for children and adults for six categories: nonhospital medical care; domestic help; diet; travelling because of CF; medication; and devices and special facilities at home, work or school. The average nonhospital costs of care amounted to Pounds 4,641 per child per year (range Pounds 712-13,269) and Pounds 10,242 per adult (range Pounds 1,653-26,571). Nonhospital medical care for children and adults accounted for, respectively, 8 and 5% of these costs, domestic help for 15 and 9%, diet for 10 and 7%, travelling because of CF for 4 and 8%, medication for 63 and 67%, and devices and special facilities at home, work or school for 1 and 4%. Nonhospital costs of care of cystic fibrosis are very high and amount to 50% of the total (medical and nonmedical) lifetime costs of cystic fibrosis.

Absenteeism↗
PubMed1995

A cystic fibrosis mutation associated with mild lung disease.

BACKGROUND: Cystic fibrosis is the most common lethal autosomal recessive disorder among whites. Among Dutch patients with cystic fibrosis, delta F508 is the most common mutation and A455E the second most common mutation of the cystic fibrosis transmembrane conductance regulator gene on chromosome 7. A455E is associated with preserved pancreatic function and residual secretion of chloride across membranes. We investigated whether it is also associated with less severe pulmonary disease in patients with cystic fibrosis. METHODS: A total of 33 patients with compound heterozygosity for the A455E mutation were matched according to age and sex with patients who were homozygous for the delta F508 mutation. The pairs were analyzed with respect to the following outcome variables: age at diagnosis, pulmonary-function values, and the frequency of pseudomonas colonization, pancreatic sufficiency, and diabetes mellitus. RESULTS: Cystic fibrosis was diagnosed at a later age in the patients with the A455E mutation than in the delta F508 homozygotes (mean age at diagnosis, 15.0 vs. 3.1 years; P < 0.001). Fewer patients with the A455E mutation had pancreatic insufficiency (21.2 percent vs. 93.9 percent, P < 0.001), and none had diabetes mellitus (0 percent vs. 27.3 percent, P = 0.004). Forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were significantly higher in the patients with the A455E mutation (mean FEV1, 73.9 percent of the predicted value vs. 54.3 percent of the predicted value; P = 0.002; mean FVC, 88.7 percent of the predicted value vs. 76.3 percent of the predicted value; P = 0.04). Fewer patients with the A455E mutation were colonized with Pseudomonas aeruginosa (33.3 percent vs. 60.6 percent, P = 0.02). CONCLUSIONS: A455E is a common mutation causing cystic fibrosis in the Netherlands. Although several mutations are known to be associated with less severe pancreatic disease, our findings demonstrate a correlation between the A455E mutation and mild pulmonary disease. Because mortality in this disease depends primarily on the progression of pulmonary disease, patients with the A455E mutation have a better prognosis than patients who are homozygous for the delta F508 mutation.

Adolescent↗
PubMed1995

Effect of rhDNase on lung function and quality of life in adult cystic fibrosis patients.

Accumulation of viscous sputum enhances lung damage in patients with cystic fibrosis. High contents of DNA, released by leucocytes, are the major cause of the high viscosity of this sputum. Recombinant human DNase I (rhDNase) decreases viscoelastic properties of sputum in cystic fibrosis and improves lung function. We have investigated the effect of rhDNase over a period of 6 weeks, 2.5 mg once daily, on lung function and quality of life in 12 adult patients with cystic fibrosis. Significant improvements in FEV1, IVC and daily peak flow values were measured. Airway resistance and FVC did not improve significantly. The cause of the improvements found is probably due to recruitment of previously, due to mucus plugging, unventilated lung areas. In addition, the awareness of symptoms related to sputum retention improved, although subjective parameters on general well-being and physical condition remained unchanged.

Adolescent↗
PubMed1995

Genetic and clinical features of patients with cystic fibrosis diagnosed after the age of 16 years.

BACKGROUND: Cystic fibrosis is usually diagnosed in childhood, but a number of patients are not diagnosed until adulthood. The aim of this study was to investigate whether patients diagnosed at an older age had a different genetic constitution, manifestations of disease, and prognosis from those diagnosed at an early age. METHODS: Clinical data and results of lung function tests and DNA analysis of 143 adult patients with cystic fibrosis were entered into a computerised database. Patients diagnosed before their 16th birthday (early diagnosis, ED) were compared with those diagnosed at 16 years of age or older (late diagnosis, LD). RESULTS: Mean age of diagnosis of the ED group was 4.6 years compared with 27.7 years for the LD group. Mean (SD) percentage predicted pulmonary function was better for the LD group than for the ED group: forced expiratory volume in one second (FEV1) 72.5 (31.1)% and 52.0 (24.8)%, and forced vital capacity (FVC) 89.8 (25.7)% and 71.9 (23.0)%, respectively. Colonisation with Pseudomonas aeruginosa was present in 70% of the ED group and 24% of the LD group. In the ED group 81% had pancreatic insufficiency compared with only 12% of the LD group. None of the LD group was homozygous for delta F508 compared with 58% of the ED group. In the LD group 72% were compound AF508 heterozygotes and 28% had two non-delta F508 mutations. CONCLUSIONS: Among this group of 143 adult patients with cystic fibrosis late diagnosis is caused mainly by delayed expression and mild progression of clinical symptoms. Late diagnosis is associated with milder pulmonary disease, less pancreatic insufficiency, and different cystic fibrosis mutations. Since mortality in cystic fibrosis depends on the progression of pulmonary disease, patients with a late diagnosis have a better prognosis than those diagnosed early.

Adolescent↗