CF is a disease of exocrine gland function, involving multiple organ systems and chiefly resulting in chronic respiratory infections, pancreatic enzyme insufficiency, and associated complications in untreated patients. Pulmonary involvement occurs in 90% of patients surviving the neonatal period.End-stage lung disease (ESLD) is the principal cause of death.
Pathophysiology CF is caused by defects in the gene for CF trans- membrane conductance regulator (CFTR), which encodes to a protein that functions as a chloride channel and is regulated by cyclic adenosine monophosphate (cAMP). Mutations in the gene for CFTR result in abnormalities of cAMP-regulated chloride transport across epithelial cells on mucosal surfaces. The failure of epithelial cells to conduct chloride and the associated water transport abnor- malities result in viscid secretions in the respiratory tract, pancreas, gastrointestinal tract, sweat glands, and other exocrine tissues. Increased viscosity of these secretions makes them difficult to clear.
Pathophysiology of Lung Disease Most fatalities associated with CF result from progressive lung disease. For individuals with CF, the lungs are normal in utero, at birth, and after birth, before the onset of infection and inflammation (except, possibly, for the presence of dilated submucosal gland ducts in the airways). Shortly after birth, many patients with CF acquire a lung infection, which incites an inflammatory response.Infection becomes established with a distinctive bacterial flora. A repeating cycle of infection and neutrophilic inflammation develops.The neutrophils are the key players in the pathophysiology of lung disease.
Cleavage of complement receptors CR1 and C3bi and immunoglobulin G (IgG) by neutrophil elastase (NE) results in failure of opsonophagocytosis, leading to bacterial persistence. NE also causes production of the neutrophil chemoattractant interleukin (IL)-8 from epithelial cells and elastin degradation, and it acts as a secretogogue, thereby contributing to persistence of inflammation and infection,structural damage,impaired gas exchange, and, ultimately, ESLD and early death.
Pathophysiology of Gastrointestinal Disease Defects in CFTR lead to reduced chloride secretion with water following into the gut.This may result in meconium ileus at birth and distal intestinal obstruction syndrome (DIOS) later in life. In addition, other pathological disorders complicate the simple relationship between the apical chloride and water secretion and the disease.The pancreatic insufficiency (PI) decreases the absorption of intestinal contents.
Mechanical problems associated with inflammation, scarring, and strictures may predispose the patient to sludging of intestinal contents, leading to intestinal obstruction by fecal impaction or to intussusception.
Adhesions may form, leading to complete obstruction that may require resection, leading, in turn, to loss of absorptive epithelium of the distal ileum.
Pathophysiology of Pancreatic Disease As part of a normal digestion, stomach acid is neutralized by pancreatic bicarbonate, leading to the optimal pH for pancreatic enzyme action. Reduced bicarbonate secretion in response to secretin stimulation has been demonstrated in patients with CF; both those with PI and those with pancreatic sufficiency (PS). Reduced bicarbonate secretion affects the digestion so that neither endogenous nor exogenous pancreatic enzymes can work at their optimal pH.
Other factors, such as reduction in water content of secretions, precipitation of proteins, and plugging of ductules and acini, prevent the pancreatic enzymes from reaching the gut. Autodigestion of the pancreas occasionally leads to pancreatitis. Most patients with CF (90?95%) have pancreatic enzyme insufficiency and The Pathophysiology, Diagnosis, and Investigation of Cystic Fibrosis Girish Sharma, MD, FCCP, is Associate Professor of Pediatrics and Director of Pediatric Pulmonology and Rush Cystic Fibrosis Center at Rush University Medical Center. He is a member of the American Thoracic Society (ATS) and a fellow of the American College of Chest Physicians (ACCP). He is board-certified in pediatrics and pediatric pulmonology. Professor Sharma?s special interests include pulmonary problems in patients with neuromuscular disorders and patients with sickle cell disease, cystic fibrosis (CF), pediatric asthma, and novel techniques for lung function testing in children, including impulse oscillometry. He has written numerous book chapters and journal articles and has edited multiple chapters for eMedicine, the online textbook of pediatrics. He was trained at the Great Ormond Street Hospital for Children, London, UK, and at the Rainbow Babies and Children?s Hospital, Case Western Reserve University, Cleveland.
Sharma-Girish.qxp 19/12/05 9:18 am Page 64 Please see complete Prescribing Information on adjacent page REFERENCES: 1. Konstan M et al. ULTRASE MT12® in the treatment of exocrine pancreatic insufficiency in cystic fibrosis: safety and efficacy, Abstract #428, The 18th Annual North American Cystic Fibrosis Conference, St. Louis, MO, Oct. 14-17, 2004. 2. Data on file, Axcan PharmaTM, 2004 ULTRASE® and ULTRASE® MT are manufactured by Eurand International, Milan, Italy using its DIFFUCAPS® or EURAND MINITABS® technology for Axcan Scandipharm Inc. ® Registered trademarks and ? trademarks are used under license by Axcan Scandipharm Inc.
? Comprehensive patient support g87g03g33g55g52g59g48g51g03g46g4fg4cg51g4cg46g44g4fg03g48g49gc0g46g44g46g5cg03g44g51g47g03g56g44g49g48g57g5c1 g87g03g33g55g52g59g48g51g03g56g5cg50g53g57g52g50g44g57g4cg46g03g55g48g4fg4cg48g492 g87g03g31g52g03g44g53g53g55g52g59g48g47g03g4ag48g51g48g55g4cg46g03g48g54g58g4cg59g44g4fg48g51g57g562 g32g51g4fg5cg03g38g2fg37g35g24g36g28®g12g38g2fg37g35g24g36g28®g30g37 g29g4cg57g56 g26g52g50g53g55g48g4bg48g51g56g4cg59g48g03g33g44g57g4cg48g51g57 g36g58g53g53g52g55g57g03g5ag4cg57g4bg03 g33g55g52g59g48g51g03g28g49gc0g46g44g46g5c g44g51g47g03g36g44g49g48g57g5c1 Axcan_ad.qxp 19/12/05 10:39 am Page 5 ULTRASE® (?ul-tras) (pancrelipase) Capsules Enteric-Coated Microspheres Prescribing Information DESCRIPTION: ULTRASE® (pancrelipase) Capsules are orally administered and contain 250 mg of enteric-coated microspheres of porcine pancreatic enzyme concentrate, predominantly pancreatic lipase, amylase, and protease.
Each ULTRASE® Capsule contains: Lipase..................................................................................... 4,500 U.S.P. Units Amylase................................................................................. 20,000 U.S.P. Units Protease................................................................................. 25,000 U.S.P. Units Inactive ingredients: povidone, talc, sugar, methacrylic acid copolymer (Type C), triethyl citrate, simethi- cone emulsion.
CLINICAL PHARMACOLOGY: ULTRASE® (pancrelipase) Capsules are designed to prevent inactivation by gastric acid thereby resulting in the delivery of high levels of biologically active enzymes into the duodenum. The enzymes catalyze the hydrolysis of fats into glycerol and fatty acids, starch into dextrins and sugars, and protein into proteoses and derived substances.