Small-intestinal abnormalities in cystic fibrosis patients

Eggermont, Ephrem; Boeck, K. De

doi:10.1007/bf01954999

Cited by 44 publications

(26 citation statements)

References 32 publications

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“…In contrast, CF patients were significantly more likely to have initial troughs of Յ1.5 g/ml by univariate analysis. A recently published voriconazole pharmacokinetics study among lung transplant recipients at our center identified CF as the most important patient variable associated with poor bioavailability (14, 15) likely due to intestinal mucosal dysfunction and other physiologic changes that accompany the disease (12,14,15). In another report, 50% to 70% of voriconazole troughs measured in CF patients were Յ1.5 g/ml during any given time period following lung transplantation (4).…”

Section: Discussionmentioning

confidence: 99%

Prospective, Observational Study of Voriconazole Therapeutic Drug Monitoring among Lung Transplant Recipients Receiving Prophylaxis: Factors Impacting Levels of and Associations between Serum Troughs, Efficacy, and Toxicity

Mitsani

Nguyen

Shields

et al. 2012

Antimicrob Agents Chemother

118

125

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ABSTRACTVoriconazole prophylaxis is common following lung transplantation, but the value of therapeutic drug monitoring is unknown. A prospective, observational study of lung transplant recipients (n= 93) receiving voriconazole prophylaxis was performed. Serum voriconazole troughs (n= 331) were measured by high-pressure liquid chromatography. The median initial and subsequent troughs were 1.91 and 1.46 μg/ml, respectively. The age of the patient directly correlated with initial troughs (P= 0.005). Patients that were ≥60 years old and cystic fibrosis patients were significantly more likely to have higher and lower initial troughs, respectively. In 95% (88/93) of patients, ≥2 troughs were measured. In 28% (25/88) and 32% (28/88) of these patients, all troughs were ≤1.5 μg/ml or >1.5 μg/ml, respectively. Ten percent (10/93) and 27% (25/93) of the patients developed invasive fungal infection (tracheobronchitis) and fungal colonization, respectively. The median troughs at the times of positive and negative fungal cultures were 0.92 and 1.72 μg/ml (P= 0.07). Invasive fungal infections or colonization were more likely with troughs of ≤1.5 μg/ml (P= 0.01) and among patients with no trough of >1.5 μg/ml (P= 0.007). Other cutoff troughs correlated less strongly with microbiologic outcomes. Troughs correlated directly with aspartate transferase levels (P= 0.003), but not with other liver enzymes. Voriconazole was discontinued due to suspected toxicity in 27% (25/93) of the patients. The troughs did not differ at the times of suspected drug-induced hepatotoxicity, central nervous system (CNS) toxicity, or nausea/vomiting and in the absence of toxicity. Voriconazole prophylaxis was most effective at troughs of >1.5 μg/ml. A cutoff for toxicity was not identified, but troughs of >4 μg/ml were rare. The data support a target range of >1.5 to 4 μg/ml.

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Section: Discussionmentioning

confidence: 99%

Prospective, Observational Study of Voriconazole Therapeutic Drug Monitoring among Lung Transplant Recipients Receiving Prophylaxis: Factors Impacting Levels of and Associations between Serum Troughs, Efficacy, and Toxicity

Mitsani

Nguyen

Shields

et al. 2012

Antimicrob Agents Chemother

118

125

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“…Due to its high lipophilicity and low water solubility, absorption of voriconazole is associated with digestion of fat and the subsequent formation of micelles. However, this process is severely impaired in CF patients for many reasons, including (i) pancreatic insufficiency, leading to decreased secretion of pancreatic enzymes (lipase), (ii) reduced activity of lipase due to low duodenal pH caused by decreased secretion of pancreatic bicarbonate (16) and gastric acid hypersecretion (6), (iii) precipitation of bile salts at low duodenal pH, leading to low duodenal bile salt concentration and a diminished bile salt pool (precipitated bile salts are not reabsorbed) (10), and (iv) intestinal mucosal dysfunction, alterations in the intestinal mucus layer, and accelerated intestinal transit time (8,30).…”

Section: Discussionmentioning

confidence: 99%

Bioavailability and Population Pharmacokinetics of Voriconazole in Lung Transplant Recipients

Han

Capitano

Bies

et al. 2010

Antimicrob Agents Chemother

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“…One hypothesized origin for the reduced growth of the CF mouse is the intestine. CF mice display impaired gastrointestinal physiology since they experience a high incidence of intestinal obstruction (9,21,39,48) similar to the less frequently occurring meconium ileus and distal intestinal obstruction syndrome observed in CF patients (15). The intestinal dysfunction in CF may include intestinal mucosal defects that interfere with normal nutrient absorption, leading to reduced growth (8,38).…”

mentioning

confidence: 97%

Cystic fibrosis growth retardation is not correlated with loss of Cftr in the intestinal epithelium

Hodges¹,

Grady²,

Mishra³

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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Maldigestion due to exocrine pancreatic insufficiency leads to intestinal malabsorption and consequent malnutrition, a mechanism proposed to cause growth retardation associated with cystic fibrosis (CF). However, although enzyme replacement therapy combined with increased caloric intake improves weight gain, the effect on stature is not significant, suggesting that growth retardation has a more complex etiology. Mouse models of CF support this, since these animals do not experience exocrine pancreatic insufficiency yet are growth impaired. Cftr absence from the intestinal epithelium has been suggested as a primary source of growth retardation in CF mice, a concept we directly tested by generating mouse models with Cftr selectively inactivated or restored in intestinal epithelium. The relationship between growth and functional characteristics of the intestines, including transepithelial electrophysiology, incidence of intestinal obstruction, and histopathology, were assessed. Absence of Cftr exclusively from intestinal epithelium resulted in loss of cAMP-stimulated short-circuit current, goblet cell hyperplasia, and occurrence of intestinal obstructions but only slight and transient impaired growth. In contrast, specifically restoring Cftr to the intestinal epithelium resulted in restoration of ion transport and completely protected against obstruction and histopathological anomalies, but growth was indistinguishable from CF mice. These results indicate that absence of Cftr in the intestinal epithelium is an important contributor to the intestinal obstruction phenotype in CF but does not correlate with the observed growth reduction in CF.

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Small-intestinal abnormalities in cystic fibrosis patients

Cited by 44 publications

References 32 publications

Prospective, Observational Study of Voriconazole Therapeutic Drug Monitoring among Lung Transplant Recipients Receiving Prophylaxis: Factors Impacting Levels of and Associations between Serum Troughs, Efficacy, and Toxicity

Prospective, Observational Study of Voriconazole Therapeutic Drug Monitoring among Lung Transplant Recipients Receiving Prophylaxis: Factors Impacting Levels of and Associations between Serum Troughs, Efficacy, and Toxicity

Bioavailability and Population Pharmacokinetics of Voriconazole in Lung Transplant Recipients

Cystic fibrosis growth retardation is not correlated with loss of Cftr in the intestinal epithelium

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