DDInter557 DDInter1101
A 9,10alpha-dihydro derivative of [ergotamine]. Dihydroergotamine is used as an abortive therapy for migraines. Its use has largely been supplanted by triptans in current therapy due to the class's greater selectivity and more favourable side effect profile. Recent improvements have been made in the design of intranasal delivery devices allowing for greater delivery of dihydroergotamine solution to the vasculature-rich upper nasal cavity. The recently approved Precision Olfactory Delivery technology developed by Impel Neuropharma technology has correlated with an increase of 3-fold in Cmax and 4-fold in AUC despite the solution formulated at 75% of the strength of the existing intranasal product.
Lumacaftor is a drug used in combination with as the fixed dose combination product Orkambi for the management of Cystic Fibrosis (CF) in patients aged 6 years and older. Cystic Fibrosis is an autosomal recessive disorder caused by one of several different mutations in the gene for the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, a transmembrane ion channel involved in the transport of chloride and sodium ions across cell membranes of the lungs, pancreas, and other organs. Mutations in the CFTR gene result in altered production, misfolding, or function of the CFTR protein and consequently abnormal fluid and ion transport across cell membranes.[A20298, A20299] As a result, CF patients produce thick, sticky mucus that clogs the ducts of organs where it is produced making patients more susceptible to infections, lung damage, pancreatic insufficiency, and malnutrition. Lumacaftor improves CF symptoms and underlying disease pathology by aiding the conformational stability of F508del-mutated CFTR proteins, preventing misfolding and resulting in increased processing and trafficking of mature protein to the cell surface. Results from clinical trials indicated that treatment with Orkambi (lumacaftor/ivacaftor) results in improved lung function, reduced chance of experiencing a pulmonary exacerbation, increased weight gain, and improvements in CF symptoms.[FDA Label] This data has been heavily scrutinized, however, with clinical trials showing only modest improvements despite a hefty yearly cost of $259,000 for Orkambi. Improvements in lung function (ppFEV1) were found to be statistically significant, but minimal, with only a 2.6-3.0% change from baseline with more than 70% of patients failing to achieve an absolute improvement of at least 5%.[A20343, L936] A wide variety of CFTR mutations correlate to the Cystic Fibrosis phenotype and are associated with differing levels of disease severity. The most common mutation, affecting approximately 70% of patients with CF worldwide, is known as F508del-CFTR, or delta-F508 (ΔF508), in which a deletion in the amino acid phenylalanine at position 508 results in impaired production of the CFTR protein, thereby causing a significant reduction in the amount of ion transporter present on cell membranes. When used in combination with as the fixed dose combination product Orkambi, lumacaftor is specific for the management of CF in patients with delta-F508 mutations as it acts as a protein-folding chaperone, aiding the conformational stability of the mutated CFTR protein. Consequently, lumacaftor increases successful production of CFTR ion channels and the total number of receptors available for use at the cell membrane for fluid and ion transport. The next most common mutation, G551D, affecting 4-5% of CF patients worldwide, is characterized as a missense mutation, whereby there is sufficient amount of protein at the cell surface, but opening and closing mechanisms of the channel are altered. Treatment of patients with G551D and other rarer missense mutations is usually managed with (Kalydeco), as it aids with altered gating mechanisms by potentiating channel opening probability of CFTR protein. Prior to the development of lumacaftor and (Kalydeco), management of CF primarily involved therapies for the control of infections, nutritional support, clearance of mucus, and management of symptoms rather than improvements in the underlying disease process. Approved for use by the Food and Drug Administration in July 2015 and by Health Canada in January 2016, Orkambi was the first combination product approved for the management of Cystic Fibrosis with delta-F508 mutations. Ivacaftor is manufactured and distributed by Vertex Pharmaceuticals.
Dihydroergotamine {u} (Compound) resembles {v} (Compound) Ergotamine
Ergotamine {u} (Compound) resembles {v} (Compound) Methylergometrine
Methylergometrine {u} may cause a moderate interaction that could exacerbate diseases when taken with {v} Lumacaftor
Dihydroergotamine {u} (Compound) binds {v} (Gene) ABCB1
ABCB1 {u} (Gene) is bound by {v} (Compound) Amlodipine
Amlodipine {u} may lead to a major life threatening interaction when taken with {v} Lumacaftor
Dihydroergotamine {u} (Compound) resembles {v} (Compound) Ergotamine
Ergotamine {u} may cause a moderate interaction that could exacerbate diseases when taken with {v} Zafirlukast
Zafirlukast {u} may cause a moderate interaction that could exacerbate diseases when taken with {v} Lumacaftor
Dihydroergotamine {u} (Compound) binds {v} (Gene) ABCB1
ABCB1 {u} (Gene) is bound by {v} (Compound) Fesoterodine
Fesoterodine {u} may cause a moderate interaction that could exacerbate diseases when taken with {v} Lumacaftor
Dihydroergotamine {u} (Compound) resembles {v} (Compound) Ergotamine
Ergotamine {u} may cause a moderate interaction that could exacerbate diseases when taken with {v} Osimertinib
Osimertinib {u} may lead to a major life threatening interaction when taken with {v} Lumacaftor
Dihydroergotamine {u} (Compound) resembles {v} (Compound) Ergotamine
Ergotamine {u} may cause a moderate interaction that could exacerbate diseases when taken with {v} Sirolimus
Sirolimus {u} may lead to a major life threatening interaction when taken with {v} Lumacaftor
Dihydroergotamine {u} (Compound) resembles {v} (Compound) Bromocriptine
Bromocriptine {u} may cause a moderate interaction that could exacerbate diseases when taken with {v} Sirolimus
Sirolimus {u} may lead to a major life threatening interaction when taken with {v} Lumacaftor
Dihydroergotamine {u} (Compound) palliates {v} (Disease) migraine
migraine {u} (Disease) is palliated by {v} (Compound) Methylergometrine
Methylergometrine {u} may cause a moderate interaction that could exacerbate diseases when taken with {v} Lumacaftor
Dihydroergotamine {u} (Compound) downregulates {v} (Gene) CTNND1
CTNND1 {u} (Gene) is upregulated by {v} (Compound) Erlotinib
Erlotinib {u} may cause a moderate interaction that could exacerbate diseases when taken with {v} Lumacaftor
Dihydroergotamine {u} (Compound) downregulates {v} (Gene) SHB
SHB {u} (Gene) is downregulated by {v} (Compound) Toremifene
Toremifene {u} may lead to a major life threatening interaction when taken with {v} Lumacaftor
Dihydroergotamine (Compound) resembles Ergotamine (Compound) and Ergotamine (Compound) resembles Methylergometrine (Compound) and Methylergometrine may cause a moderate interaction that could exacerbate diseases when taken with Lumacaftor
Dihydroergotamine (Compound) binds ABCB1 (Gene) and ABCB1 (Gene) is bound by Amlodipine (Compound) and Amlodipine may lead to a major life threatening interaction when taken with Lumacaftor
Dihydroergotamine (Compound) resembles Ergotamine (Compound) and Ergotamine may cause a moderate interaction that could exacerbate diseases when taken with Zafirlukast and Zafirlukast may cause a moderate interaction that could exacerbate diseases when taken with Lumacaftor
Dihydroergotamine (Compound) binds ABCB1 (Gene) and ABCB1 (Gene) is bound by Fesoterodine (Compound) and Fesoterodine may cause a moderate interaction that could exacerbate diseases when taken with Lumacaftor
Dihydroergotamine (Compound) resembles Ergotamine (Compound) and Ergotamine may cause a moderate interaction that could exacerbate diseases when taken with Osimertinib and Osimertinib may lead to a major life threatening interaction when taken with Lumacaftor
Dihydroergotamine (Compound) resembles Ergotamine (Compound) and Ergotamine may cause a moderate interaction that could exacerbate diseases when taken with Sirolimus and Sirolimus may lead to a major life threatening interaction when taken with Lumacaftor
Dihydroergotamine (Compound) resembles Bromocriptine (Compound) and Bromocriptine may cause a moderate interaction that could exacerbate diseases when taken with Sirolimus and Sirolimus may lead to a major life threatening interaction when taken with Lumacaftor
Dihydroergotamine (Compound) palliates migraine (Disease) and migraine (Disease) is palliated by Methylergometrine (Compound) and Methylergometrine may cause a moderate interaction that could exacerbate diseases when taken with Lumacaftor
Dihydroergotamine (Compound) downregulates CTNND1 (Gene) and CTNND1 (Gene) is upregulated by Erlotinib (Compound) and Erlotinib may cause a moderate interaction that could exacerbate diseases when taken with Lumacaftor
Dihydroergotamine (Compound) downregulates SHB (Gene) and SHB (Gene) is downregulated by Toremifene (Compound) and Toremifene may lead to a major life threatening interaction when taken with Lumacaftor