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Chu P, Mioc J, O’Donovan P, Henry O. Clinical Efficacy and Safety of Treatments for Exocrine Pancreatic Insufficiency: A Systematic Literature Review. Digestion 2024; 106:45-61. [PMID: 39299226 PMCID: PMC11825132 DOI: 10.1159/000541326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 08/08/2024] [Indexed: 09/22/2024]
Abstract
INTRODUCTION Exocrine pancreatic insufficiency (EPI) is caused by multiple clinical conditions such as cystic fibrosis and chronic pancreatitis (CP). Standard management of EPI includes pancreatic enzyme replacement therapy (PERT) along with consultation with a dietitian. While PERTs have been on the market for several decades, newer publications on their clinical efficacy and safety raised the need for a comprehensive review of the literature. We aimed to identify the available evidence on the clinical efficacy and safety of treatments for EPI to understand the current treatment landscape and unmet need in patients with EPI. METHODS A systematic literature review (SLR) was conducted in Embase, Medline, and Evidence-Based Medicine databases from 2010 to 2022; conference proceedings from 2020 to 2022 were also searched. Articles were screened independently by two reviewers at abstract and full-text stage against predefined eligibility criteria. RESULTS We identified 26 journal publications and two conference abstracts, reporting on 22 randomized control trials, four observational studies, and two single-arm interventional studies. The most reported treatment was pancrelipase, specifically Creon® (n = 12). Fourteen studies reported coefficient of fat absorption (CFA) results. Across studies, patients experienced a considerable increase in CFA post-initiation of treatment regardless of intervention or timepoint. Mean change in CFA ranged from 7.5% in patients with CP who received placebo to 36% in patients with CP treated with Creon®. Ten studies reported coefficient of nitrogen absorption (CNA). Where reported, pancrelipase (including Creon®) increased CNA levels in EPI patients compared to placebo. Only one study compared PERT brands head-to-head: no significant differences were reported in the CNA-72 h values (Creon® 82.0% [SE: 1.2] vs. Zenpep® 80.9% [SE: 1.2]). Loss of body weight and low body mass index (BMI) are important features of EPI. Overall, treatment with PERT increased BMI and body weight, or limited their decline, with increases ranging from 0.1 to 6.1 kg. Based on the 18 studies that reported safety outcomes, PERT was considered safe and well tolerated. CONCLUSIONS This SLR confirmed that PERT is an effective and tolerable treatment option for patients with EPI. However, nutritional parameters and health-related quality of life data were sparsely reported, and future clinical trials should look to incorporate these data given their importance in clinical practice and patient outcomes. INTRODUCTION Exocrine pancreatic insufficiency (EPI) is caused by multiple clinical conditions such as cystic fibrosis and chronic pancreatitis (CP). Standard management of EPI includes pancreatic enzyme replacement therapy (PERT) along with consultation with a dietitian. While PERTs have been on the market for several decades, newer publications on their clinical efficacy and safety raised the need for a comprehensive review of the literature. We aimed to identify the available evidence on the clinical efficacy and safety of treatments for EPI to understand the current treatment landscape and unmet need in patients with EPI. METHODS A systematic literature review (SLR) was conducted in Embase, Medline, and Evidence-Based Medicine databases from 2010 to 2022; conference proceedings from 2020 to 2022 were also searched. Articles were screened independently by two reviewers at abstract and full-text stage against predefined eligibility criteria. RESULTS We identified 26 journal publications and two conference abstracts, reporting on 22 randomized control trials, four observational studies, and two single-arm interventional studies. The most reported treatment was pancrelipase, specifically Creon® (n = 12). Fourteen studies reported coefficient of fat absorption (CFA) results. Across studies, patients experienced a considerable increase in CFA post-initiation of treatment regardless of intervention or timepoint. Mean change in CFA ranged from 7.5% in patients with CP who received placebo to 36% in patients with CP treated with Creon®. Ten studies reported coefficient of nitrogen absorption (CNA). Where reported, pancrelipase (including Creon®) increased CNA levels in EPI patients compared to placebo. Only one study compared PERT brands head-to-head: no significant differences were reported in the CNA-72 h values (Creon® 82.0% [SE: 1.2] vs. Zenpep® 80.9% [SE: 1.2]). Loss of body weight and low body mass index (BMI) are important features of EPI. Overall, treatment with PERT increased BMI and body weight, or limited their decline, with increases ranging from 0.1 to 6.1 kg. Based on the 18 studies that reported safety outcomes, PERT was considered safe and well tolerated. CONCLUSIONS This SLR confirmed that PERT is an effective and tolerable treatment option for patients with EPI. However, nutritional parameters and health-related quality of life data were sparsely reported, and future clinical trials should look to incorporate these data given their importance in clinical practice and patient outcomes.
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Affiliation(s)
- Paula Chu
- Organon International GmbH, Lucerne, Switzerland
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Singh MP, Agrawal NR, Saurabh S, Krishna E, Singh JM. Exploring Therapeutic Digestive Enzyme Landscape in India: Current Evidence, Profit Motives, Regulations, and Future Perspectives. Cureus 2024; 16:e52891. [PMID: 38406012 PMCID: PMC10891418 DOI: 10.7759/cureus.52891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/24/2024] [Indexed: 02/27/2024] Open
Abstract
This analysis critically examines the profit-driven marketing of digestive enzymes as over-the-counter (OTC) supplements in the context of India, expressing ethical concerns regarding pharmaceutical companies prioritizing financial gain over genuine public health needs within the lucrative OTC supplement market. The review delves into various enzymes, their mechanisms of action, uses, adverse drug reactions, and provides evidence from various studies. The research method involves the exploration of profit-driven strategies employed by pharmaceutical companies, addressing regulatory challenges, investigating the gap between dietary supplements and pharmaceutical drugs, and emphasizing the impact of direct-to-consumer advertising on self-diagnosis and overuse. Additionally, the study reviews various e-pharmacy platforms in India, assessing formulations and pricing. Key findings highlight the diverse formulations on these platforms, exposing insights into cost variations and indicating a regulatory gap that necessitates a comprehensive re-evaluation by Indian and international authorities. The analysis emphasizes the influence of direct-to-consumer advertising on behavior and potential health risks, raising ethical concerns about oversimplified health claims that overlook the necessity for individualized treatment plans. In conclusion, the study underscores the ethical complexity of prioritizing profit over public health and advocates for regulatory re-evaluation, exploring broader implications such as cultural influences and alternative therapies. The evolving landscape, featuring plant-based and microbe-derived alternatives, is presented as transformative, particularly in conditions like celiac disease.
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Affiliation(s)
- Madhusudan P Singh
- Pharmacology and Therapeutics, All India Institute of Medical Sciences, Raipur, Raipur, IND
| | - Nikunj R Agrawal
- Pharmacology and Therapeutics, All India Institute of Medical Sciences, Raipur, Raipur, IND
| | | | - Ekta Krishna
- Community and Family Medicine, All India Institute of Medical Sciences Patna, Patna, IND
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Borowitz D, Brooks JF, Aliaj E, Gallotto D. Community Perspective on Pancreatic Enzyme Replacement Therapy in Cystic Fibrosis. J Pediatr Gastroenterol Nutr 2022; 75:e94-e97. [PMID: 36070542 DOI: 10.1097/mpg.0000000000003606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
People with cystic fibrosis (CF) and exocrine pancreatic insufficiency must take pancreatic enzyme replacement therapy (PERT) to prevent malnutrition and gastrointestinal (GI) symptoms. Finding better ways to manage GI complaints is a high priority for the CF community. We fielded a survey to assess the perspective of people affected by CF regarding symptoms attributed to and challenges associated with current PERT, to identify factors that affect participation in PERT studies, and to understand attitudes toward an outcome measure that could be an alternative to the coefficient of fat absorption test. Persistent GI symptoms are commonly ascribed to PERT. Minimizing time commitment and maximizing patient safety were factors affecting participation in research. We demonstrate 4 generalizable ways to incorporate patient experience early in the research process to aid in development of new medications and help improve study enrollment.
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Affiliation(s)
- Drucy Borowitz
- From the University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY
| | | | - Enid Aliaj
- the Cystic Fibrosis Foundation, Bethesda, MD
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Abstract
BACKGROUND Most people with cystic fibrosis (CF) (80% to 90%) need pancreatic enzyme replacement therapy (PERT) to prevent malnutrition. Enzyme preparations need to be taken whenever food is taken, and the dose needs to be adjusted according to the food consumed. A systematic review on the efficacy and safety of PERT is needed to guide clinical practice, as there is variability between centres with respect to assessment of pancreatic function, time of commencing treatment, dose and choice of supplements. This is an updated version of a published review. OBJECTIVES To evaluate the efficacy and safety of PERT in children and adults with CF and to compare the efficacy and safety of different formulations of PERT and their appropriateness in different age groups. Also, to compare the effects of PERT in CF according to different diagnostic subgroups (e.g. different ages at introduction of therapy and different categories of pancreatic function). SEARCH METHODS We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Most recent search: 07 November 2019. We also searched an ongoing trials website and the websites of the pharmaceutical companies who manufacture pancreatic enzyme replacements for any additional trials. Most recent search: 26 December 2019. SELECTION CRITERIA Randomised and quasi-randomised controlled trials in people of any age, with CF and receiving PERT, at any dosage and in any formulation, for a period of not less than four weeks, compared to placebo or other PERT preparations. DATA COLLECTION AND ANALYSIS Two authors independently assessed trials and extracted outcome data. They also assessed the risk of bias and quality of the evidence (GRADE) of the trials included in the review. MAIN RESULTS 14 trials were included in the review (641 children and adults with CF), two of these were parallel trials and 12 were cross-over trials. Interventions included different enteric and non-enteric-coated preparations of varying formulations in comparison to each other. The number of participants in each trial varied between 14 and 129. 13 trials were for a duration of four weeks and one trial lasted seven weeks. The majority of the trials had an unclear risk of bias from the randomisation process as the details of this were not given; they also had a high risk of attrition bias and reporting bias. The quality of the evidence ranged from moderate to very low. We mostly could not combine data from the trials as they compared different formulations and the findings from individual trials provided insufficient evidence to determine the size and precision of the effects of different formulations. AUTHORS' CONCLUSIONS There is limited evidence of benefit from enteric-coated microspheres when compared to non-enteric coated pancreatic enzyme preparations up to one month. In the only comparison where we could combine any data, the fact that these were cross-over trials is likely to underestimate the level of inconsistency between the results of the trials due to over-inflation of CIs from the individual trials.There is no evidence on the long-term effectiveness and risks associated with PERT. There is also no evidence on the relative dosages of enzymes needed for people with different levels of severity of pancreatic insufficiency, optimum time to start treatment and variations based on differences in meals and meal sizes. There is a need for a properly designed trial that can answer these questions.
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Affiliation(s)
| | - Arturo Solis-Moya
- Servicio de Neumología, Hospital Nacional de Niños, San José, Costa Rica
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Altman K, McDonald CM, Michel SH, Maguiness K. Nutrition in cystic fibrosis: From the past to the present and into the future. Pediatr Pulmonol 2019; 54 Suppl 3:S56-S73. [PMID: 31715089 DOI: 10.1002/ppul.24521] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Accepted: 08/19/2019] [Indexed: 12/13/2022]
Abstract
Nutritional management is an integral part of multidisciplinary care for persons with cystic fibrosis. This review will look at how nutrition care has evolved over time. In addition, we will look at how some newer therapies impact nutrition care.
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Affiliation(s)
- Kimberly Altman
- Gunnar Esiason Adult Cystic Fibrosis and Lung Center, New York Presbyterian/Columbia University Medical Center, New York, New York, United States
| | | | - Suzanne H Michel
- Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, United States
| | - Karen Maguiness
- Section of Pediatric Pulmonology, Allergy, and Sleep Medicine, Riley Hospital for Children at Indiana University Health, Indianapolis, Indiana, United States
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Layer P, Kashirskaya N, Gubergrits N. Contribution of pancreatic enzyme replacement therapy to survival and quality of life in patients with pancreatic exocrine insufficiency. World J Gastroenterol 2019; 25:2430-2441. [PMID: 31171887 PMCID: PMC6543241 DOI: 10.3748/wjg.v25.i20.2430] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 04/02/2019] [Accepted: 04/20/2019] [Indexed: 02/06/2023] Open
Abstract
The objective of this study was to analyze the current evidence for the use of pancreatic enzyme replacement therapy (PERT) in affecting survival and quality of life in patients with pancreatic exocrine insufficiency (PEI). Systematic searches of the literature were performed using the PubMed database. Articles were selected for inclusion if they reported findings from trials assessing the effects of PERT on quality of life, survival, malabsorption, growth parameters (such as height, body weight and body mass index), or gastrointestinal symptoms (such as abdominal pain, stool consistency and flatulence). PERT improved PEI-related malabsorption and weight maintenance in patients with cystic fibrosis, chronic pancreatitis, pancreatic cancer, and post-surgical states. In patients with chronic pancreatitis, PERT improved PEI-related symptoms and quality of life measures. Several small retrospective studies have also suggested that PERT may have a positive impact on survival, but long-term studies assessing this effect were not identified. PERT is effective for treating malnutrition and supporting weight maintenance, and it is associated with improved quality of life and possibly with enhanced survival in patients with PEI. However, there is evidence that not all patients with PEI receive adequate PERT. Future work should aim to assess the long-term effects of PERT on the survival of patients with PEI.
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Affiliation(s)
- Peter Layer
- Department of Internal Medicine, Israelitic Hospital, Hamburg 22297, Germany
| | - Nataliya Kashirskaya
- Department of Genetic Epidemiology (Cystic Fibrosis group), Federal State Budgetary Institution “Research Centre for Medical Genetics”, Moscow 115522, Russia
| | - Natalya Gubergrits
- Department of Internal Medicine, Donetsk National Medical University, Lyman 83001, Ukraine
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Colombo C, Nobili RM, Alicandro G. Challenges with optimizing nutrition in cystic fibrosis. Expert Rev Respir Med 2019; 13:533-544. [PMID: 31094240 DOI: 10.1080/17476348.2019.1614917] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Introduction. Optimizing nutrition remains the cornerstone of therapy for patients with cystic fibrosis (CF) since it is associated with better pulmonary function and survival. However, a significant proportion of patients still fail to achieve normal growth and nutritional status. Areas covered. This review describes the current challenges in providing effective nutritional therapy in CF with a focus on the current issues related to energy imbalance, dietary composition, adherence to nutritional recommendations, pancreatic enzyme replacement therapy, and the effects of modulators of the CF transmembrane conductance regulator. Expert opinion. CF is a multisystemic disease that requires a personalized nutritional approach with accurate evaluation of energy balance. There is an urgent need for evidence-based recommendations on the dietary composition, in consideration of the increasing prevalence of overweight, diabetes and the potential effects of fatty acids on inflammation and immune response. More research into new pancreatic enzyme formulations is also required.
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Affiliation(s)
- Carla Colombo
- a Department of Pathophysiology and Transplantation , Università degli Studi di Milano , Milan , Italy.,b Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Cystic Fibrosis Centre , Milan , Italy
| | - Rita Maria Nobili
- b Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Cystic Fibrosis Centre , Milan , Italy
| | - Gianfranco Alicandro
- c Department of Clinical Sciences and Community Health , Università degli Studi di Milano , Milano , Italy
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Abstract
INTRODUCTION Cystic fibrosis (CF) outcomes and survival have improved over the last century primarily due to advancements in antibiotics, nutritional, and pulmonary therapies. Reviewed here are the significant unmet needs that exist for individuals with CF. Areas covered: With the recent development of medications that address the underlying defect in the CF protein, there is hope that there will be continued improvement in CF outcomes. However, there remains a need to prevent or stop progression of CF-related complications, as the CF protein is important to several body systems. As end stage lung disease is the primary cause of mortality in CF, a need exists for advancements in pulmonary therapies to reduce time burden, identification of best practices for the treatment of pulmonary exacerbations, further development of anti-infective and anti-inflammatory therapies, and appropriately timed referral for lung transplantation at end-stage lung disease. Extra-pulmonary complications are increasingly recognized and better understanding of such problems as CF related liver disease is needed. Expert commentary: While CFTR modulators are available for the majority of CF patients, there remains a need for effective therapies to address infection, inflammation, irreversible lung disease, and extrapulmonary complications of CF.
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Affiliation(s)
- Natalie E West
- a Department of Medicine, Division of Pulmonary and Critical Care Medicine , Johns Hopkins University , Baltimore , USA
| | - Patrick A Flume
- b Departments of Medicine and Pediatrics , Medical University of South Carolina , Charleston , SC , USA
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Pierzynowska K, Valverde-Piedra J, Szymanczyk S, Prykhod’ko O, Pieszka M, Kardas M, Grochowska-Niedworok E, Grabowski T, Winiarczyk M, Pierzynowski S. Pancreatic-like enzymes of microbial origin restore growth and normalize lipid absorption in a pig model with exocrine pancreatic insufficiency. Arch Med Sci 2018; 14:407-414. [PMID: 29593816 PMCID: PMC5868679 DOI: 10.5114/aoms.2018.73471] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Accepted: 08/12/2015] [Indexed: 11/23/2022] Open
Abstract
INTRODUCTION The standard therapy for exocrine pancreatic insufficiency (EPI) is porcine-derived pancreatic enzyme replacement therapy (PERT). In the present study we tested a new approach with a mixture of pancreatic-like enzymes of microbial origin (PLEM) in a 1-week efficacy study in EPI pigs. In addition to the conventionally used coefficient of fat and nitrogen absorption (CFA and CNA), parameters that more accurately reflect the nutritional and health status, such as changes in the lipemic index (LI), plasma triglyceride (TG) and non-esterified fatty acid (NEFA) levels, and somatic growth, were determined. MATERIAL AND METHODS A PLEM dose containing 120 000 active lipase units, 80 000 active protease units and 12 000 active amylase units (all from Sigma, St. Louis, MO) was given as a powder, twice daily with a meal (40 g fat/meal) to 8 EPI pigs for 7 days. Ten healthy pigs were used as a comparator. RESULTS The PLEM enhanced fat and protein digestion, and reversed growth impairment in EPI pigs. With treatment, CFA and CNA increased by 59% and 43% (p < 0.05), respectively. Although fat and protein absorption were lower than in the comparator, the postprandial blood lipid profile was normal as in healthy pigs. The mucosal thickness significantly increased by 27%, 50% and 26%, in the proximal, middle, and distal jejunum (p < 0.05) with treatment and resembled that of healthy animals. CONCLUSIONS Pancreatic-like enzymes of microbial origin supported somatic growth and normalized the postprandial lipid profile. As a measure of efficacy, postprandial LI, TG and NEFA are viable endpoints to be explored in human trials.
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Affiliation(s)
| | - Jose Valverde-Piedra
- SGPlus, Malmo, Sweden
- Department of Animal Biochemistry and Physiology, Life Science University, Lublin, Poland
- Department of Toxicology and Environmental Protection, University of Live Sciences, Lublin, Poland
| | - Sylwia Szymanczyk
- SGPlus, Malmo, Sweden
- Department of Toxicology and Environmental Protection, University of Live Sciences, Lublin, Poland
| | | | - Marek Pieszka
- Department of Animal Nutrition and Feed Science, National Research Institute of Animal Production, Balice, Poland
| | - Marek Kardas
- Department of Food Technology and Quality Evaluation, School of Public Health in Bytom, Medical University of Silesia, Katowice, Poland
| | | | | | | | - Stefan Pierzynowski
- Department of Biology, Lund University, Lund, Sweden
- SGPlus, Malmo, Sweden
- Department of Medical Biology, Institute of Rural Medicine, Lublin, Poland
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Gan C, Chen YH, Liu L, Gao JH, Tong H, Tang CW, Liu R. Efficacy and safety of pancreatic enzyme replacement therapy on exocrine pancreatic insufficiency: a meta-analysis. Oncotarget 2017; 8:94920-94931. [PMID: 29212278 PMCID: PMC5706924 DOI: 10.18632/oncotarget.21659] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Accepted: 09/21/2017] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Pancreatic enzyme replacement therapy (PERT) is widely applied to patients with exocrine pancreatic insufficiency (EPI), but its effect and safety has not been quantified. Therefore we performed a meta-analysis to determine the efficacy and tolerance of PERT on patients with EPI. MATERIALS AND METHODS PubMed, Medline, Cochrane library database, Evidence-based medicine/clinical trials published before December 2016 were searched by two independent reviewers to identify prospective randomized controlled trials (RCTs). RESULTS Seven RCTs, randomizing a total of 282 patients, were filtrated and assessed qualitatively (Jadad score). PERT increased CFA (WMD: 26.56, 20.35 to 32.76, I2= 79.6%, P < 0.001) compared with baseline, and CFA (WMD: 17.97, 12.61 to 23.34, I2 = 76.7%, P < 0.001) vs. placebo. Meanwhile, CNA, SFE, SNE and SW were significantly improved in PERT compared with baseline and placebo, with no statistical differences in adverse events. Subgroup analysis indicated that standard forms of PERT displayed more effectiveness with significantly decreased heterogeneity, and large sample size also reduced the heterogeneity to some degree. CONCLUSIONS PERT is demonstrated to be effective and tolerable in patients with EPI, especially using standard administration of PERT. Larger and higher quality studies on EPI are demanded to long-term effect of standard PERT treatment.
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Affiliation(s)
- Can Gan
- Division of Peptides Related with Human Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Yan-Hua Chen
- Division of Peptides Related with Human Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Ling Liu
- Division of Peptides Related with Human Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Jin-Hang Gao
- Division of Peptides Related with Human Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Huan Tong
- Division of Peptides Related with Human Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Cheng-Wei Tang
- Division of Peptides Related with Human Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Rui Liu
- Division of Peptides Related with Human Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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Chin M, Aaron SD, Bell SC. The treatment of the pulmonary and extrapulmonary manifestations of cystic fibrosis. Presse Med 2017; 46:e139-e164. [PMID: 28576636 DOI: 10.1016/j.lpm.2016.11.030] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Revised: 10/12/2016] [Accepted: 11/06/2016] [Indexed: 12/26/2022] Open
Abstract
Cystic fibrosis (CF) is a complex multisystem disease with considerable between patient variability in its manifestations and severity. In the past several decades, the range of treatments and the evidence to support their use for the pulmonary and extrapulmonary manifestations of CF have increased dramatically, contributing to the improved median survival of patients. As therapy for CF has evolved, new challenges including treatment adherence, medication intolerance and allergy, medical complications and coping with the burden of disease in the context of having a family and managing employment have arisen. While the majority of current therapy focuses primarily on improving symptoms, new therapies (CFTR modulators) target the underlying genetic defect.
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Affiliation(s)
- Melanie Chin
- Adult Cystic Fibrosis Centre, The Prince Charles Hospital, Rode Road, Chermside, Brisbane, QLD 4032, Australia
| | - Shawn D Aaron
- The Ottawa Hospital Research Institute, University of Ottawa, 501, Smyth Road, K1H 8L6 Ottawa, Canada
| | - Scott C Bell
- Adult Cystic Fibrosis Centre, The Prince Charles Hospital, Rode Road, Chermside, Brisbane, QLD 4032, Australia; QIMR Berghofer Medical Research Institute, 300, Herston Road, Herston, QLD 4006, Australia; School of Medicine, The University of Queensland, Brisbane, QLD 4006, Australia.
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Abstract
BACKGROUND Most people with cystic fibrosis (80% to 90%) need pancreatic enzyme replacement therapy to prevent malnutrition. Enzyme preparations need to be taken whenever food is taken, and the dose needs to be adjusted according to the food consumed. A systematic review on the efficacy and safety of pancreatic enzyme replacement therapy is needed to guide clinical practice, as there is variability between centres with respect to assessment of pancreatic function, time of commencing treatment, dose and choice of supplements. This is an updated version of a published review. OBJECTIVES To evaluate the efficacy and safety of pancreatic enzyme replacement therapy in children and adults with cystic fibrosis and to compare the efficacy and safety of different formulations of this therapy and their appropriateness in different age groups. Also, to compare the effects of pancreatic enzyme replacement therapy in cystic fibrosis according to different diagnostic subgroups (e.g. different ages at introduction of therapy and different categories of pancreatic function). SEARCH METHODS We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Most recent search: 15 July 2016.We also searched an ongoing trials website and the websites of the pharmaceutical companies who manufacture pancreatic enzyme replacements for any additional trials. Most recent search: 22 July 2016. SELECTION CRITERIA Randomised and quasi-randomised controlled trials in people of any age, with cystic fibrosis and receiving pancreatic enzyme replacement therapy, at any dosage and in any formulation, for a period of not less than four weeks, compared to placebo or other pancreatic enzyme replacement therapy preparations. DATA COLLECTION AND ANALYSIS Two authors independently assessed trials and extracted outcome data. They also assessed the risk of bias of the trials included in the review. MAIN RESULTS One parallel trial and 12 cross-over trials of children and adults with cystic fibrosis were included in the review. The number of participants in each trial varied between 14 and 129 with a total of 512 participants included in the review. All the included trials were for a duration of four weeks. The included trials had mostly an unclear risk of bias from the randomisation process as the details of this were not given; they also mostly had a high risk of attrition bias and reporting bias.We could not combine data from all the trials as they compared different formulations. Findings from individual studies provided insufficient evidence to determine the size and precision of the effects of different formulations. Ten studies reported information on the review's primary outcome (nutritional status); however, we were only able to combine data from two small cross-over studies (n = 41). The estimated gain in body weight was imprecise, 0.32 kg (95% confidence interval -0.03 to 0.67; P = 0.07). Combined data from the same studies gave statistically significant results favouring enteric-coated microspheres over enteric-coated tablets for our secondary outcomes stool frequency, mean difference -0.58 (95% confidence interval -0.85 to -0.30; P < 0.0001); proportion of days with abdominal pain, mean difference -7.96% (95% confidence interval -12.97 to -2.94; P = 0.002); and fecal fat excretion, mean difference -11.79 g (95% confidence interval -17.42 to -6.15; P < 0.0001). Data from another single small cross-over study also favoured enteric-coated microspheres over non-enteric-coated tablets with adjuvant cimetidine in terms of stool frequency, mean difference -0.70 (95% confidence interval -0.90 to -0.50; P < 0.00001). AUTHORS' CONCLUSIONS There is limited evidence of benefit from enteric-coated microspheres when compared to non-enteric coated pancreatic enzyme preparations up to one month. In the only comparison where we could combine any data, the fact that these were cross-over studies is likely to underestimate the level of inconsistency between the results of the studies due to over-inflation of confidence intervals from the individual studies.There is no evidence on the long-term effectiveness and risks associated with pancreatic enzyme replacement therapy. There is also no evidence on the relative dosages of enzymes needed for people with different levels of severity of pancreatic insufficiency, optimum time to start treatment and variations based on differences in meals and meal sizes. There is a need for a properly designed study that can answer these questions.
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Affiliation(s)
- Usha Rani Somaraju
- Malla Reddy Medical College for WomenDepartment of BiochemistrySuraram Main RoadJeedimetla Qutbullapur MunicipalityHyderabadIndia500 055
| | - Arturo Solis‐Moya
- Hospital Nacional de NiñosServicio de NeumologíaCaja Costarricense del Seguro SocialPO Box 220 ‐ 1017San JoséCosta Rica
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Ianiro G, Pecere S, Giorgio V, Gasbarrini A, Cammarota G. Digestive Enzyme Supplementation in Gastrointestinal Diseases. Curr Drug Metab 2016; 17:187-93. [PMID: 26806042 PMCID: PMC4923703 DOI: 10.2174/138920021702160114150137] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Revised: 09/11/2015] [Accepted: 10/30/2015] [Indexed: 12/28/2022]
Abstract
BACKGROUND Digestive enzymes are able to break down proteins and carbohydrates and lipids, and their supplementation may play a role in the management of digestive disorders, from lactose intolerance to cystic fibrosis. To date, several formulations of digestive enzymes are available on the market, being different each other in terms of enzyme type, source and origin, and dosage. METHODS This review, performed through a non-systematic search of the available literature, will provide an overview of the current knowledge of digestive enzyme supplementation in gastrointestinal disorders, discussion of the use of pancreatic enzymes, lactase (β-galactosidase) and conjugated bile acids, and also exploring the future perspective of digestive enzyme supplementation. RESULTS Currently, the animal-derived enzymes represent an established standard of care, however the growing study of plant-based and microbe-derived enzymes offers great promise in the advancement of digestive enzyme therapy. CONCLUSION New frontiers of enzyme replacement are being evaluated also in the treatment of diseases not specifically related to enzyme deficiency, whereas the combination of different enzymes might constitute an intriguing therapeutic option in the future.
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Affiliation(s)
- Gianluca Ianiro
- Department of Medical Sciences, Division of Internal Medicine, Gastroenterology and Liver Unit, Catholic University, School of Medicine and Surgery, A. Gemelli Hospital Rome, Italy, Largo A. Gemelli 8, IT-00168 Rome, Italy.
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Heubi JE, Schaeffer D, Ahrens RC, Sollo N, Strausbaugh S, Graff G, Jain R, Witte S, Forssmann K. Safety and Efficacy of a Novel Microbial Lipase in Patients with Exocrine Pancreatic Insufficiency due to Cystic Fibrosis: A Randomized Controlled Clinical Trial. J Pediatr 2016; 176:156-161.e1. [PMID: 27297209 DOI: 10.1016/j.jpeds.2016.05.049] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Revised: 04/12/2016] [Accepted: 05/12/2016] [Indexed: 12/18/2022]
Abstract
OBJECTIVE To evaluate the safety and efficacy of a novel microbial lipase (NM-BL) in a liquid formulation for the treatment of exocrine pancreatic insufficiency (EPI) in patients with cystic fibrosis (CF) in a phase IIa proof-of-concept study. STUDY DESIGN We conducted a double-blind, randomized, placebo controlled crossover study in patients with cystic fibrosis and exocrine pancreatic insufficiency. Adolescent and adult patients with CF were randomized to receive NM-BL or placebo for 1 week as replacement for their usual pancreatic enzyme formulation. They were subsequently crossed-over to the alternate study treatment. The coefficient of fat absorption was evaluated as the primary endpoint. Symptoms and adverse events were evaluated as secondary endpoints. RESULTS A total of 35 patients were randomized into the study and 22 patients completed both treatment periods. During treatment with NM-BL, the coefficient of fat absorption was significantly greater (72.7%) compared with placebo (53.8%) with a difference between groups of 18.8% (P < .001). Subjective assessment of stool fat and stool consistency also improved under treatment with NM-BL. Adverse events were mostly gastrointestinal in nature and were more common in the group receiving NM-BL. CONCLUSIONS Currently available pancreatic enzyme products are limited because of the lack of liquid formulations and being largely porcine based. The novel microbial lipase NM-BL was safe and effective in this short term trial. The trial provided clinical proof-of-concept for this novel microbial lipase as a treatment for EPI in CF. A larger phase 2 dose ranging trial is warranted. TRIAL REGISTRATION ClinicalTrials.gov: NCT01710644.
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Affiliation(s)
- James E Heubi
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
| | | | - Richard C Ahrens
- Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA
| | - Natalie Sollo
- University of Kansas School of Medicine-Wichita/Via Christi Research, Wichita, KS
| | | | - Gavin Graff
- Penn State Milton S. Hershey Medical Center, Hershey, PA
| | - Raksha Jain
- The University of Texas Southwestern Medical Center, Dallas, TX
| | - Stephan Witte
- Nordmark Arzneimittel GmbH & Co. KG, Uetersen, Germany
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Murphy MP, Caraher E. Current and Emerging Therapies for the Treatment of Cystic Fibrosis or Mitigation of Its Symptoms. Drugs R D 2016; 16:1-17. [PMID: 26747453 PMCID: PMC4767716 DOI: 10.1007/s40268-015-0121-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Clinical presentation of the chronic, heritable condition cystic fibrosis (CF) is complex, with a diverse range of symptoms often affecting multiple organs with varying severity. The primary source of morbidity and mortality is due to progressive destruction of the airways attributable to chronic inflammation arising from microbial colonisation. Antimicrobial therapy combined with practises to remove obstructive mucopurulent deposits form the cornerstone of current therapy. However, new treatment options are emerging which offer, for the first time, the opportunity to effect remission from the underlying cause of CF. Here, we discuss these therapies, their mechanisms of action, and their successes and failures in order to illustrate the shift in the nature of how CF will likely be managed into the future.
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Affiliation(s)
- Mark P Murphy
- Centre for Microbial-Host Interactions, Centre of Applied Science for Health, Institute of Technology Tallaght, Dublin 24, Ireland.
| | - Emma Caraher
- Centre for Microbial-Host Interactions, Centre of Applied Science for Health, Institute of Technology Tallaght, Dublin 24, Ireland.
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16
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What Is the Role of Nutrition Therapy in the Management of the Adult Cystic Fibrosis Patient? Curr Nutr Rep 2015. [DOI: 10.1007/s13668-015-0136-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Ledder O, Haller W, Couper RT, Lewindon P, Oliver M. Cystic fibrosis: an update for clinicians. Part 2: hepatobiliary and pancreatic manifestations. J Gastroenterol Hepatol 2014; 29:1954-62. [PMID: 25238538 DOI: 10.1111/jgh.12785] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/20/2014] [Indexed: 12/14/2022]
Abstract
This paper, the second in the series, will build on the first and explore the importance of liver and pancreatic manifestations of cystic fibrosis (CF) and the effect on morbidity and mortality of this multifaceted genetic condition. It will also further develop the critical role of the gastroenterologist as part of the multidisciplinary group of clinicians and allied health staff in the effective management of patients with CF.
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Affiliation(s)
- Oren Ledder
- Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital Parkville, Melbourne, Victoria
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19
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Abstract
BACKGROUND Most people with cystic fibrosis (80% to 90%) need pancreatic enzyme replacement therapy to prevent malnutrition. Enzyme preparations need to be taken whenever food is taken, and the dose needs to be adjusted according to the food consumed. A systematic review on the efficacy and safety of pancreatic enzyme replacement therapy is needed to guide clinical practice, as there is variability between centres with respect to assessment of pancreatic function, time of commencing treatment, dose and choice of supplements. OBJECTIVES To evaluate the efficacy and safety of pancreatic enzyme replacement therapy in children and adults with cystic fibrosis and to compare the efficacy and safety of different formulations of this therapy and their appropriateness in different age groups. Also, to compare the effects of pancreatic enzyme replacement therapy in cystic fibrosis according to different diagnostic subgroups (e.g. different ages at introduction of therapy and different categories of pancreatic function). SEARCH METHODS We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Most recent search: 14 August 2014.We also searched an ongoing trials website and the websites of the pharmaceutical companies who manufacture pancreatic enzyme replacements for any additional trials. Most recent search: 12 May 2014. SELECTION CRITERIA Randomised and quasi-randomised controlled trials in people of any age, with cystic fibrosis and receiving pancreatic enzyme replacement therapy, at any dosage and in any formulation, for a period of not less than four weeks, compared to placebo or other pancreatic enzyme replacement therapy preparations. DATA COLLECTION AND ANALYSIS Two authors independently assessed trials and extracted outcome data. They also assessed the risk of bias of the trials included in the review. MAIN RESULTS One parallel trial and 11 cross-over trials of children and adults with cystic fibrosis were included in the review. The number of participants in each trial varied between 14 and 129 with a total of 426 participants included in the review. All the included trials were for a duration of four weeks. The included trials had mostly an unclear risk of bias from the randomisation process as the details of this were not given; they also mostly had a high risk of attrition bias and reporting bias.We could not combine data from all the trials as they compared different formulations. Findings from individual studies provided insufficient evidence to determine the size and precision of the effects of different formulations. Ten studies reported information on the review's primary outcome (nutritional status); however, we were only able to combine data from two small cross-over studies (n = 41). The estimated gain in body weight was imprecise, 0.32 kg (95% confidence interval -0.03 to 0.67, P = 0.07). Combined data from the same studies gave statistically significant results favouring enteric-coated microspheres over enteric-coated tablets for our secondary outcomes stool frequency, abdominal pain and fecal fat excretion. Data from another single small cross-over study also favoured enteric-coated microspheres over non-enteric-coated tablets with adjuvant cimetidine in terms of stool frequency. AUTHORS' CONCLUSIONS There is limited evidence of benefit from enteric-coated microspheres when compared to non-enteric coated pancreatic enzyme preparations up to one month. In the only comparison where we could combine any data, the fact that these were cross-over studies is likely to underestimate the level of inconsistency between the results of the studies due to over-inflation of confidence intervals from the individual studies.There is no evidence on the long-term effectiveness and risks associated with pancreatic enzyme replacement therapy. There is also no evidence on the relative dosages of enzymes needed for people with different levels of severity of pancreatic insufficiency, optimum time to start treatment and variations based on differences in meals and meal sizes. There is a need for a properly designed trial that can answer these questions.
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Affiliation(s)
- Usha Rani Somaraju
- Department of Biochemistry, Malla Reddy Medical College for Women, Suraram Main Road, Jeedimetla Qutbullapur Municipality, Hyderabad, India, 500 055
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Hetrick EM, Sperry DC, Nguyen HK, Strege MA. Characterization of a novel cross-linked lipase: impact of cross-linking on solubility and release from drug product. Mol Pharm 2014; 11:1189-200. [PMID: 24606399 DOI: 10.1021/mp4006529] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Liprotamase is a novel non-porcine pancreatic enzyme replacement therapy containing purified biotechnology-derived lipase, protease, and amylase together with excipients in a capsule formulation. To preserve the structural integrity and biological activity of lipase (the primary drug substance) through exposure of the drug product to the low-pH gastric environment, the enzyme was processed through the use of cross-linked enzyme crystal (CLEC) technology, making the lipase-CLEC drug substance insoluble under acidic conditions but fully soluble at neutral pH and in alkaline environments. In this report we characterize the degree of cross-linking for lipase-CLEC and demonstrate its impact on lipase-CLEC solubility and release from the drug product under relevant physiological pH conditions. Cross-linked lipase-CLEC was characterized via size exclusion chromatography (SEC) and capillary electrophoresis sodium dodecyl sulfate polyacrylamide gel electrophoresis (CE-SDS-PAGE). A combination of methodologies was developed to understand the impact of cross-linking on drug product release. Dissolution evaluation using USP Apparatus 2 at pH 5.0 with an enzyme activity-based end point demonstrated solubility discrimination based on degree of cross-linking, while full release was demonstrated at pH 6.5. The dissolution of the drug product was also evaluated using a dual-stage test employing a USP Apparatus 4 flow-through system to mimic the changing pH environments experienced in the stomach and intestine to understand the impact of cross-linking on drug product performance. Use of USP Apparatus 4 to characterize the pH-dependent release of lipase-CLEC represents a novel approach compared to the Apparatus 1 test employing an acid-challenge stage outlined in the USP for delayed-release pancrelipase, and the advantages of this approach may prove useful for understanding the pH-dependence of release for other drug products. Collectively, these studies confirmed that degree of cross-linking is a critical parameter that may impact in vivo release of lipase-CLEC, and also provided a risk assessment tool for understanding the potential impact of under- and over-cross-linked drug substance.
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Affiliation(s)
- Evan M Hetrick
- Small Molecule Design and Development, Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285, United States
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Prayle AP, Smyth AR. From pipeline to patient: new developments in cystic fibrosis therapeutics. Expert Opin Pharmacother 2013; 14:323-9. [DOI: 10.1517/14656566.2013.769958] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Rowe SM, Borowitz DS, Burns JL, Clancy JP, Donaldson SH, Retsch-Bogart G, Sagel SD, Ramsey BW. Progress in cystic fibrosis and the CF Therapeutics Development Network. Thorax 2012; 67:882-90. [PMID: 22960984 PMCID: PMC3787701 DOI: 10.1136/thoraxjnl-2012-202550] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Cystic fibrosis (CF), the most common life-shortening genetic disorder in Caucasians, affects approximately 70 000 individuals worldwide. In 1998, the Cystic Fibrosis Foundation (CFF) launched the CF Therapeutics Development Network (CF-TDN) as a central element of its Therapeutics Development Programme. Designed to accelerate the clinical evaluation of new therapies needed to fulfil the CFF mission to control and cure CF, the CF-TDN has conducted 75 clinical trials since its inception, and has contributed to studies as varied as initial safety and proof of concept trials to pivotal programmes required for regulatory approval. This review highlights recent and significant research efforts of the CF-TDN, including a summary of contributions to studies involving CF transmembrane conductance regulator (CFTR) modulators, airway surface liquid hydrators and mucus modifiers, anti-infectives, anti-inflammatories, and nutritional therapies. Efforts to advance CF biomarkers, necessary to accelerate the therapeutic goals of the network, are also summarised.
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Affiliation(s)
- Steven M Rowe
- Department of Medicine, University of Alabama at Birmingham, 1819 University Boulevard (MCLM 768), Birmingham, AL 35294, USA.
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Kalnins D, Wilschanski M. Maintenance of nutritional status in patients with cystic fibrosis: new and emerging therapies. DRUG DESIGN DEVELOPMENT AND THERAPY 2012; 6:151-61. [PMID: 22787388 PMCID: PMC3392141 DOI: 10.2147/dddt.s9258] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Poor clinical outcomes in cystic fibrosis are often associated with undernutrition. Normal growth and development should be achieved in cystic fibrosis, and nutritional counseling is paramount at all ages. Prevention and early detection of growth failure is the key to successful nutritional intervention. The advance in nutritional management is certainly one factor that has contributed to the improved survival in recent decades. This review outlines the major nutritional parameters in the management of the patient with cystic fibrosis, including recent advances in pancreatic enzyme replacement therapy and fat-soluble vitamin therapy. There are sections on complicated clinical situations which directly affect nutrition, for example, before and after lung transplantation, cystic fibrosis-related diabetes, and bone health.
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Affiliation(s)
- Daina Kalnins
- Clinical Dietetics, Respiratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada
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