subjects 6-11 years old (ppFEV1=95.8% at baseline) and a more progressed disease state in the adult subjects (ppFEV1 = 64.5% at baseline).(36)
The KIWI clinical trial was a two-part, open-label, phase 3 study to evaluate the safety, pharmacodynamics (PD), and pharmacokinetics (PK) of ivacaftor in CF patients between two and five years old with at least one CFTR gating mutation. Results from this study expanded the use of ivacaftor to patients as young as two years old (Table 1).(15)
Despite in vitro results demonstrating an increased Isc in F508del-CFTR expressing FRT and HBE cells upon forskolin stimulation,(22) no therapeutic benefit was observed in CF patients homozygous for F508del-CFTR. The DISCOVER trial was a phase 2 study to test
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Part 2 assessed multiple ascending doses of D9-ivacaftor (75mg, 150mg, and 225mg), each administered daily after a high-fat meal for 7 days, compared to placebo.(68) Results presented during the 39th European Cystic Fibrosis Conference demonstrated improved PK of D9-ivacaftor compared to Kalydeco®, including a 40% increase in half-life (D9-ivacaftor t1/2 of ~15hrs; Kalydeco® t1/2 of ~11hrs), reduced clearance rate (D9-ivacaftor CL/F of 3.8L/hr vs. Kalydeco® CL/F of 13.3L/hr), approximately 3-fold increase in exposure (D9-ivacaftor AUC0-inf of 44,916ng*hr/mL vs. Kalydeco® AUC0-inf of 12,925ng*hr/mL), and approximately 3-fold increase in plasma concentrations at 24-hours (D9-ivacaftor C24hrs of 712ng/mL vs. Kalydeco® C24hrs of 169ng/mL). Data shown here are for 150mg doses of both D9-ivacaftor and Kalydeco®.(14, 26, 77) The improved PK profile of D9-ivacaftor along with a safety profile comparable to that of Kalydeco® has allowed progression of D9-ivacaftor into a phase 2 clinical trial to evaluate its safety and efficacy in CF patients with CFTR gating mutations.(69)
QBW-251
QBW-251 is a CFTR potentiator developed by Novartis Pharmaceuticals Inc. In vitro results showed QBW-251 to be an effective potentiator for CFTR gating mutations, including F508del-CFTR. Promising in vitro results led to the initiation of a
Nearly 1 in every 30 Americans are a carrier of the recessive gene that leads to CF (About Cystic Fibrosis, n.d.). Although CF is a life-threatening condition, through the advancement of treatments and care, there has been a steady increase in life expectancy and improvement in the quality of life. The current mean age of survival is now 40. Although that does not seem very high, sixty years ago, a child diagnosed with CF did not survive childhood (About Cystic Fibrosis, n.d.). CF is a complex disease, where the types and severity of symptoms can differ widely from person to person. Symptoms may include fatigue, salty-tasting skin, persistent cough with phlegm, wheezing and shortness of breath, lung infections, and poor growth and weight loss (Cystic Fibrosis Symptoms, Causes & Risk Factors, 2018). Many different factors, such as the age of diagnosis, can affect an individual's health and the course of the
CF happens because two parents have a defect in the CF transmembrane conductor regulator (CFTR) gene. If a child has only one parent that has a
Scientists have found more than 1,700 different mutations in the CFTR that can cause CF. Scientist have spent years trying to put these thousands of mutations into groups. They’re so many types of mutations but here are just some of them. Protein Production Mutations include splice mutations. These interfere with the production of the CFTR protein. IF the CFTR gene has a splice mutation the protein building instructions send a signal that causes the production of CFTR protein to stop. Gating Mutations is another mutation of CF. The CFTR protein is shaped like a tunnel with a gate. The cell can open the gate when chloride needs to flow through the channel. Otherwise, the gate stays closed. Mutations lock the gate in the closed position so that chloride cannot get
Cystic Fibrosis (CF) is a disorder causing the body to release extremely thick and sticky mucus that clogs the lungs and pancreas, leading to problems with breathing and digestion, infection, and ultimately death. Abnormal secretion of sweat and saliva glands is also characteristic of CF. This disease a hereditary disorder of the exocrine glands that is characterized by respiratory and digestive problems and the most common inherited disease among Caucasians, affecting 3,600 live births in the Canada alone. CF affects men and women equally, but affects white people more than black people. This disease mainly affects children and young adults and is diagnosed by the age of three. Due to the advances in genetic research, diagnosis has been
Cystic Fibrosis (CF) also knows as (mucoviscidosis) is a single-gene disorders. This disorder is best described as an autosomal recessive of the exocrine glands. The disorder itself can be categorized as either pus- forming or hindering airflow. The responsible gene for this pulmonary disorder has been discovered to the be on the long part of the arm of chromosome 7 (Copstead & Banasik, 2013). Major signs and symptoms of CF will be associated with the gastrointestinal and respiratory system. We are able to diagnose CF though laboratory testing such as arterial blood measurements. Treatments for CF tend to be comprehensive including specialty physicians, nutritionists, physical and respiratory therapists and genetic counselors. Medicare
Cystic fibrosis (CF) is the most common lethal autosomal recessive disease affecting Canadians (2). CF can affect multiple organs; however, the most fatal symptoms occur in the lung. As of 2013, the median age of survival for CF is roughly 50 years old with treatment (3). However, patient life-span decreases dramatically when treatment options such as antibiotics and enzymes are not administered, and nutritional changes or lung transplants are not made (3). Currently, there is no cure for CF, although current treatments can improve patient outcome.
Cystic Fibrosis or CF is a life threatening genetic disorder that mainly affects the lungs and digestive system. Cystic Fibrosis is most common among the Caucasian population, particularly people of northwestern European descent and is less common in people of African ancestry and is very rare in people of Asian ancestry. According to the Cystic Fibrosis Foundation, “an estimated 30,000 children and adults in the United States (70,000 worldwide) have CF” (Cystic Fibrosis Foundation, 2014).
A variety of clinical studies on the G551D mutation have shown a wide range of positive effects from oral dosage of the drug testing a variety of age ranges. Ivacaftor showed improvements in forced expiratory volume in 1 second (FEV1) for CFTR patients after treatment with ivacaftor for 48 weeks ranging from 8.7% median change from baseline in adults (18 years and above) to 12.5% change in children aged 6-11 (P<0.001). Median sweat chloride levels also showed significant decrease in all age groups above 6 years with results ranging from -49.1mmol/L to -59.5mmol/L (P<0.001) (Accurso et al., 2010) (Ramsey et al., 2011) (Davies et al., 2013). Fewer patients on Ivacaftor treatment experienced a pulmonary exacerbation (PEx), however, on those patients who did experience a PEx despite ivacaftor treatment, it did not improve their rate of lung function recovery after the PEx as compared to placebo (Flume et al., 2017). Additionally, patients showed improve weight and BMI following ivacaftor dosage as compared to those on placebo with results showing between 2.7 to 2.8 kg weight gain of patients 6 years and above (Ramsey et al., 2011) (Davies et al., 2013). Interestingly, a new study investigated whether ivacaftor also improved patient outcomes
Cystic Fibrosis, or CF, is a genetic disease that affects children to young adults. It occurs when a child has two defective copies of the gene that causes cystic fibrosis, one from each parent. The disease primarily affects the digestive system and it also affects the respiratory system, mainly the lungs bronchi and bronchioles. Cystic fibrosis affects the cells that produce mucus and digestive juices, as it changes the protein that regulates the movement of salt in and out of cells. Which leads to people thick and sticky mucus and digestive juices, such as pancreatic juices. Whereas people who do not have CF have thin and slippery mucus and digestive juices. The severity of the disease differs from one person to the next, yet the
Cystic fibrosis is an inherited disease that ultimately leads to death. It affects every racial group worldwide, but its prevalence varies from country to country. In those with cystic fibrosis, the lungs and digestive system are primarily affected by the disease. With the new developments in treatment and management, the 50 percent survival rate from the 1970’s has greatly improved, allowing patients to continue to live their lives longer than ever expected in the past. The new developments in prevention of exacerbations, therapy drugs and methods to preserve lung function have done great things to help patients extend their lives.
Cystic Fibrosis (CF or CFTR) is a life threatening disease that causes the buildup of thick and sticky mucus in many organs and body systems, and the mutated genes are passed down from parent to child. It affects about 30,000 people in the US, about 5% of the U.S Population carries the disease, but they do not have it. CF is most commonly present in Caucasians and some Hispanic. CF is less common in African Americans and Asians. Although cystic fibrosis is rare in most race, if it is inherited, it can life threatening when it isn’t treated in the early stages.
Most people have two working copies of the gene, but only one is needed to prevent CF. CF develops when neither copes can produce a functional CFTR protein. The CFTR gene tells cells in the body to produce proteins called CFTR proteins. These proteins act as pathways inside and outside of cells, which allows water and particles such as chloride ions to flow in and out of cells. This helps maintain a balance of salt and water. In those that have CFTR gene mutations the pathways don’t work correctly and what this means for people with the gene mutation is that those pathways don’t stay open long enough for chloride ions to flow through or they don’t open as often as they should. Water and salt cannot freely flow into and out of cells, the water and salt lead to thick, sticky mucus in the lungs as well as other parts of the
Cystic fibrosis is a common hereditary, a long term disease that could affect several parts of the body. It is an inherited disease triggered through “changes in a gene on chromosome 7, one of the 23 pairs of chromosomes that children inherit from their parents” (kidshealth.org). CF happens because of alterations in the gene that makes a protein called CFTR also known as cystic fibrosis transmembrane regulator. There’s at least about 2,000 different mutations in the CFTR gene, all with different phenotypes. One study actually suggested that most of these mutations have no compulsive effect at
Cystic fibrosis (CF) is an autosomal recessive disease that affects the cystic fibrosis trans membrane conductance regulator (CFTR) gene located on Chromosome 7, in a persons DNA. Autosomal means that the gene for CF is not carried on the sex chromosomes and both male and females are affected by the mutation. The disease is a recessive disease meaning that it requires 2 abnormal genes to be expressed; only one gene would mean that the person is a carrier of the disease. This is because the normal CFTR gene dominated the abnormal CFTR gene. For the disease to be present and show in the person, they must have inherited 2 abnormal CFTR genes, one from each parent. Being a ‘carrier’ does not mean that you have CF but it does mean that you can pass the defective CFTR genes onto your children, possibly leading the off-spring being affected by the CFTR genes. It is the most common fatal genetic disease in the US today with an average life span of 25-30 years. (Ndsu.edu, Cystic Fibrosis and Gene Therapy Ndsu.edu,. (2014). Cystic Fibrosis and Gene Therapy. Retrieved 14 August 2014, from http://www.ndsu.edu/pubweb/~mcclean/plsc431/st). CF is a genetic disorder that affects the digestive and respiratry systems. The CFTR gene causes a protein to not work properly blocking the movement of NaCl (Sodium Chloride) in and out of the cell, causing an abnormally sticky and thick mucus to be produced on the out side of the cells. This mucus clogs the lungs leading to infection. It also blocks
Cystic Fibrosis (CF) is an autosomal recessive gene that causes a wide range of symptoms because there are over 1,000 changes or mutations that can occur within the cystic fibrosis transmembrane receptor (CFTR) protein. The CFTR protein is generally a chloride ion chain “regulated by cyclic adenosine monophosphate and therefore can act as a regulator of other electrolyte channels”(Grossman, S., & Grossman, L. 2005, p. 46). Typically this protein allows chloride ions to exit mucus-producing cells allowing water to flow in and thin the mucus. However, if the CFTR protein has been mutated, such as in cystic fibrosis, chloride ions cannot exit. This causes the mucus to thicken, become sticky, and obstruct the various channels it passes through. This build up of mucus also prevents bacteria from being cleaned from cells thoroughly increasing the patients risk for infections (Grossman, S., & Grossman, L. 2005). However, the severity of CF depends on whether the patients have complete or partial loss of the CFTR gene. If the person has the classic form of CF abnormalities of CFTR will commonly affect “…the respiratory, gastrointestinal, endocrine and metabolic, and genitourinary systems”(Schram, C. 2012). However, if people have atypical forms of CF their genetic disorder may only affect one of the organ systems and may not be found until the patient develops symptoms in their late childhood, early adolescence, or adulthood