Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 82
Filter
1.
Biomed Pharmacother ; 147: 112614, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1682939

ABSTRACT

Post-Covid pulmonary fibrosis is evident following severe COVID-19. There is an urgent need to identify the cellular and pathophysiological characteristics of chronic lung squeals of Covid-19 for the development of future preventive and/or therapeutic interventions. Tissue-resident memory T (TRM) cells can mediate local immune protection against infections and cancer. Less beneficially, lung TRM cells cause chronic airway inflammation and fibrosis by stimulating pathologic inflammation. The effects of Janus kinase (JAK), an inducer pathway of cytokine storm, inhibition on acute Covid-19 cases have been previously evaluated. Here, we propose that Tofacitinib by targeting the CD8+ TRM cells could be a potential candidate for the treatment of chronic lung diseases induced by acute SARS-CoV-2 infection.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , COVID-19/drug therapy , Janus Kinase Inhibitors/therapeutic use , Lung Injury/drug therapy , Piperidines/therapeutic use , Pyrimidines/therapeutic use , T-Lymphocyte Subsets/immunology , COVID-19/complications , COVID-19/immunology , Humans , Immunologic Memory/immunology , Lung/immunology , Lung Injury/etiology , Lung Injury/immunology , SARS-CoV-2 , T-Lymphocytes/immunology
2.
Nat Med ; 28(1): 39-50, 2022 01.
Article in English | MEDLINE | ID: covidwho-1641982

ABSTRACT

Immune dysregulation is an important component of the pathophysiology of COVID-19. A large body of literature has reported the effect of immune-based therapies in patients with COVID-19, with some remarkable successes such as the use of steroids or anti-cytokine therapies. However, challenges in clinical decision-making arise from the complexity of the disease phenotypes and patient heterogeneity, as well as the variable quality of evidence from immunotherapy studies. This Review aims to support clinical decision-making by providing an overview of the evidence generated by major clinical trials of host-directed therapy. We discuss patient stratification and propose an algorithm to guide the use of immunotherapy strategies in the clinic. This will not only help guide treatment decisions, but may also help to design future trials that investigate immunotherapy in other severe infections.


Subject(s)
Anticoagulants/therapeutic use , COVID-19/therapy , Complement Inactivating Agents/therapeutic use , Glucocorticoids/therapeutic use , Immunologic Factors/therapeutic use , Immunomodulation , Protein Kinase Inhibitors/therapeutic use , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Neutralizing/therapeutic use , Azetidines/therapeutic use , Bradykinin/analogs & derivatives , Bradykinin/therapeutic use , Bradykinin B2 Receptor Antagonists/therapeutic use , COVID-19/immunology , Dexamethasone/therapeutic use , Drug Combinations , Factor Xa Inhibitors/therapeutic use , Heparin/therapeutic use , Humans , Hydrocortisone/therapeutic use , Imatinib Mesylate/therapeutic use , Immunization, Passive , Interferon beta-1a/therapeutic use , Interferon beta-1b/therapeutic use , Interferon-gamma/therapeutic use , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Kallikrein-Kinin System , Piperidines/therapeutic use , Purines/therapeutic use , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , SARS-CoV-2 , Sulfonamides/therapeutic use
3.
Am J Trop Med Hyg ; 105(6): 1472-1475, 2021 Oct 04.
Article in English | MEDLINE | ID: covidwho-1629955

ABSTRACT

Human lives and nations' economies have been adversely affected worldwide by the COVID-19 pandemic. The hyperinflammatory state associated with the disease may be related to mortality. Systemic glucocorticoid is the first-line therapy for cytokine storm. Various immunomodulatory drugs such as tocilizumab and baricitinib have been used in those not responding to glucocorticoid monotherapy. Amid the peak crisis of COVID-19 in India, there was an extreme paucity of medications, oxygen, and hospital beds. We describe three patients with COVID-19 who received low-dose tofacitinib (an oral Janus kinase inhibitor) in addition to moderate-dose glucocorticoid. These patients were treated at their homes, as the hospitals were short of beds. Rapid reduction in hypoxemia along with gradual resolution of other signs of the disease were observed. The results are reassuring regarding the feasibility of managing of severe COVID-19 outside the hospital setting when healthcare resources are overwhelmed by pandemic-related caseload.


Subject(s)
COVID-19/drug therapy , Piperidines/therapeutic use , Pyrimidines/therapeutic use , SARS-CoV-2 , Adult , Aged , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/therapeutic use , Anti-Inflammatory Agents/therapeutic use , Cytokine Release Syndrome/prevention & control , Cytokines/genetics , Cytokines/metabolism , Enoxaparin/administration & dosage , Enoxaparin/therapeutic use , Female , Gene Expression Regulation/drug effects , Humans , Methylprednisolone/administration & dosage , Methylprednisolone/therapeutic use , Middle Aged , Piperidines/administration & dosage , Prednisone/administration & dosage , Prednisone/therapeutic use , Pyrimidines/administration & dosage
5.
Ann Rheum Dis ; 81(1): 117-123, 2022 01.
Article in English | MEDLINE | ID: covidwho-1605885

ABSTRACT

OBJECTIVE: To compare the treatment efficacy and safety of tofacitinib (TOF) versus methotrexate (MTX) in Takayasu arteritis (TAK). METHODS: Fifty-three patients with active disease from an ongoing prospective TAK cohort in China were included in this study. Twenty-seven patients were treated with glucocorticoids (GCs) and TOF, and 26 patients were treated with GCs with MTX. The observation period was 12 months. Complete remission (CR), inflammatory parameter changes, GCs tapering and safety were assessed at the 6th, 9th and 12th month. Vascular lesions were evaluated at the 6th and 12th month, and relapse was analysed during 12 months. RESULTS: The CR rate was higher in the TOF group than in the MTX group (6 months: 85.19% vs 61.54%, p=0.07; 12 months: 88.46% vs 56.52%, p=0.02). During 12 months' treatment, patients in the TOF group achieved a relatively lower relapse rate (11.54% vs 34.78%, p=0.052) and a longer median relapse-free duration (11.65±0.98 vs 10.48±2.31 months, p=0.03). Average GCs dose at the 3rd, 6th and 12th month was lower in the TOF group than that in the MTX group (p<0.05). A difference was not observed in disease improvement or disease progression on imaging between the two groups (p>0.05). Prevalence of side effects was low in both groups (3.70% vs 15.38%, p=0.19). CONCLUSION: TOF was superior to MTX for CR induction, a tendency to prevent relapse and tapering of the GCs dose in TAK treatment. A good safety profile for TOF was also documented in patients with TAK.


Subject(s)
Antirheumatic Agents/therapeutic use , Janus Kinase Inhibitors/therapeutic use , Methotrexate/therapeutic use , Piperidines/therapeutic use , Pyrimidines/therapeutic use , Takayasu Arteritis/drug therapy , Adolescent , Adult , Antirheumatic Agents/adverse effects , Disease Progression , Drug Therapy, Combination , Female , Glucocorticoids/therapeutic use , Humans , Janus Kinase Inhibitors/adverse effects , Male , Methotrexate/adverse effects , Middle Aged , Piperidines/adverse effects , Prospective Studies , Pyrimidines/adverse effects , Recurrence , Time Factors , Treatment Outcome , Young Adult
6.
EBioMedicine ; 74: 103705, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1540597

ABSTRACT

BACKGROUND: Patients with immunocompromised disorders have mainly been excluded from clinical trials of vaccination against COVID-19. Thus, the aim of this prospective clinical trial was to investigate safety and efficacy of BNT162b2 mRNA vaccination in five selected groups of immunocompromised patients and healthy controls. METHODS: 539 study subjects (449 patients and 90 controls) were included. The patients had either primary (n=90), or secondary immunodeficiency disorders due to human immunodeficiency virus infection (n=90), allogeneic hematopoietic stem cell transplantation/CAR T cell therapy (n=90), solid organ transplantation (SOT) (n=89), or chronic lymphocytic leukemia (CLL) (n=90). The primary endpoint was seroconversion rate two weeks after the second dose. The secondary endpoints were safety and documented SARS-CoV-2 infection. FINDINGS: Adverse events were generally mild, but one case of fatal suspected unexpected serious adverse reaction occurred. 72.2% of the immunocompromised patients seroconverted compared to 100% of the controls (p=0.004). Lowest seroconversion rates were found in the SOT (43.4%) and CLL (63.3%) patient groups with observed negative impact of treatment with mycophenolate mofetil and ibrutinib, respectively. INTERPRETATION: The results showed that the mRNA BNT162b2 vaccine was safe in immunocompromised patients. Rate of seroconversion was substantially lower than in healthy controls, with a wide range of rates and antibody titres among predefined patient groups and subgroups. This clinical trial highlights the need for additional vaccine doses in certain immunocompromised patient groups to improve immunity. FUNDING: Knut and Alice Wallenberg Foundation, the Swedish Research Council, Nordstjernan AB, Region Stockholm, Karolinska Institutet, and organizations for PID/CLL-patients in Sweden.


Subject(s)
/adverse effects , Immunocompromised Host/immunology , Immunogenicity, Vaccine/immunology , SARS-CoV-2/immunology , Adenine/adverse effects , Adenine/analogs & derivatives , Adenine/therapeutic use , Antibodies, Viral/blood , COVID-19/prevention & control , Female , Hematopoietic Stem Cell Transplantation , Humans , Immunotherapy, Adoptive , Leukemia, Lymphocytic, Chronic, B-Cell , Male , Middle Aged , Mycophenolic Acid/adverse effects , Mycophenolic Acid/therapeutic use , Organ Transplantation , Piperidines/adverse effects , Piperidines/therapeutic use , Primary Immunodeficiency Diseases/immunology , Prospective Studies , Seroconversion , Spike Glycoprotein, Coronavirus/immunology , Vaccination/adverse effects
7.
J Am Chem Soc ; 143(48): 20095-20108, 2021 12 08.
Article in English | MEDLINE | ID: covidwho-1531986

ABSTRACT

Chemical modifications of native proteins can affect their stability, activity, interactions, localization, and more. However, there are few nongenetic methods for the installation of chemical modifications at a specific protein site in cells. Here we report a covalent ligand directed release (CoLDR) site-specific labeling strategy, which enables the installation of a variety of functional tags on a target protein while releasing the directing ligand. Using this approach, we were able to label various proteins such as BTK, K-RasG12C, and SARS-CoV-2 PLpro with different tags. For BTK we have shown selective labeling in cells of both alkyne and fluorophores tags. Protein labeling by traditional affinity methods often inhibits protein activity since the directing ligand permanently occupies the target binding pocket. We have shown that using CoLDR chemistry, modification of BTK by these probes in cells preserves its activity. We demonstrated several applications for this approach including determining the half-life of BTK in its native environment with minimal perturbation, as well as quantification of BTK degradation by a noncovalent proteolysis targeting chimera (PROTAC) by in-gel fluorescence. Using an environment-sensitive "turn-on" fluorescent probe, we were able to monitor ligand binding to the active site of BTK. Finally, we have demonstrated efficient CoLDR-based BTK PROTACs (DC50 < 100 nM), which installed a CRBN binder onto BTK. This approach joins very few available labeling strategies that maintain the target protein activity and thus makes an important addition to the toolbox of chemical biology.


Subject(s)
Agammaglobulinaemia Tyrosine Kinase/chemistry , Fluorescent Dyes/chemistry , Ligands , Proto-Oncogene Proteins p21(ras)/antagonists & inhibitors , Adenine/analogs & derivatives , Adenine/chemistry , Adenine/metabolism , Agammaglobulinaemia Tyrosine Kinase/metabolism , Catalytic Domain , Coronavirus Papain-Like Proteases/chemistry , Coronavirus Papain-Like Proteases/metabolism , Half-Life , Humans , Piperidines/chemistry , Piperidines/metabolism , Proteolysis , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism , Pyrimidines/chemistry , Pyrimidines/metabolism , SARS-CoV-2/enzymology
8.
Clin Transl Sci ; 14(6): 2556-2565, 2021 11.
Article in English | MEDLINE | ID: covidwho-1526359

ABSTRACT

Nezulcitinib (TD-0903), a lung-selective pan-Janus-associated kinase (JAK) inhibitor designed for inhaled delivery, is under development for treatment of acute lung injury associated with coronavirus disease 2019 (COVID-19). This two-part, double-blind, randomized, placebo-controlled, single ascending dose (part A) and multiple ascending dose (part B) phase I study evaluated the safety, tolerability, and pharmacokinetics (PK) of nezulcitinib in healthy participants. Part A included three cohorts randomized 6:2 to receive a single inhaled dose of nezulcitinib (1, 3, or 10 mg) or matching placebo. Part B included three cohorts randomized 8:2 to receive inhaled nezulcitinib (1, 3, or 10 mg) or matching placebo for 7 days. The primary outcome was nezulcitinib safety and tolerability assessed from treatment-emergent adverse events (TEAEs). The secondary outcome was nezulcitinib PK. All participants completed the study. All TEAEs were mild or moderate in severity, and none led to treatment discontinuation. Overall (area under the plasma concentration-time curve) and peak (maximal plasma concentration) plasma exposures of nezulcitinib were low and increased in a dose-proportional manner from 1 to 10 mg in both parts, with no suggestion of clinically meaningful drug accumulation. Maximal plasma exposures were below levels expected to result in systemic target engagement, consistent with a lung-selective profile. No reductions in natural killer cell counts were observed, consistent with the lack of a systemic pharmacological effect and the observed PK. In summary, single and multiple doses of inhaled nezulcitinib at 1, 3, and 10 mg were well-tolerated in healthy participants, with dose-proportional PK supporting once-daily administration.


Subject(s)
Azetidines/adverse effects , COVID-19/drug therapy , Imidazoles/adverse effects , Indazoles/adverse effects , Piperidines/adverse effects , Administration, Inhalation , Adult , Area Under Curve , Azetidines/administration & dosage , Azetidines/pharmacokinetics , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Healthy Volunteers , Humans , Imidazoles/administration & dosage , Imidazoles/pharmacokinetics , Indazoles/administration & dosage , Indazoles/pharmacokinetics , Killer Cells, Natural/drug effects , Killer Cells, Natural/immunology , Lymphocyte Count , Male , Middle Aged , Piperidines/administration & dosage , Piperidines/pharmacokinetics , Young Adult
9.
Medicina (Kaunas) ; 57(10)2021 Oct 16.
Article in English | MEDLINE | ID: covidwho-1480866

ABSTRACT

Background and Objectives: Early postoperative recovery after surgery is a key point for patients' safety and comfort. Moreover, operating room turnover depends on recovery time. Our aim was to assess which method of remifentanil administration, manual (MI) or target-controlled infusion (TCI), could reduce patient time in recovery room. In this study, patients' recovery times were registered and compared among the groups. Materials and Methods: We enrolled 31 morbidly obese patients in this prospective study. All of them had undergone bariatric surgery at the Hospital of Lithuanian University of Health Sciences Kauno Klinikos in 2020. Sevoflurane/remifentanil anaesthesia was performed for all patients. The patients were randomly assigned to the manual infusion (MI) (control group) or target-controlled infusion (TCI) group for the method of the administration of remifentanil. While the patients were waking up after the surgery, we recorded spontaneous breathing and airway reflexes recovery time, time of extubation, eye opening, recovery of orientation and beginning of the following oral command. For the TCI group, we also documented remifentanil concentrations in the blood (automatic infusion pump). Results: Patients did not differ in demographic values and duration of remifentanil infusion. We found that remifentanil consumption in the TCI group was lower, p = 0.02. Despite lower remifentanil consumption in the TCI group patients, they demonstrated longer total recovery time than the control group patiens: 14 (12-20) vs. 10 (6-16), p = 0.001. Conclusions: The study showed that, upon comparing the TCI method with MI, manual infusion produced better results in postoperative patient recovery. Additionally, higher doses of remifentanil were consumed using MI. In conclusion, the dosage recommended by highly qualified anaesthesiologists is favourable for morbidly obesity patients when compared to the TCI method.


Subject(s)
Bariatric Surgery , Obesity, Morbid , Propofol , Anesthetics, Intravenous , Humans , Obesity, Morbid/surgery , Piperidines , Prospective Studies , Remifentanil
10.
Ann Rheum Dis ; 81(1): 34-40, 2022 01.
Article in English | MEDLINE | ID: covidwho-1462913

ABSTRACT

OBJECTIVES: To update the EULAR points to consider (PtCs) on the use of immunomodulatory therapies in COVID-19. METHODS: According to the EULAR standardised operating procedures, a systematic literature review up to 14 July 2021 was conducted and followed by a consensus meeting of an international multidisciplinary task force. The new statements were consolidated by formal voting. RESULTS: We updated 2 overarching principles and 12 PtC. Evidence was only available in moderate to severe and critical patients. Glucocorticoids alone or in combination with tocilizumab are beneficial in COVID-19 cases requiring oxygen therapy and in critical COVID-19. Use of Janus kinase inhibitors (baricitinib and tofacitinib) is promising in the same populations of severe and critical COVID-19. Anti-SARS-CoV-2 monoclonal antibodies and convalescent plasma may find application in early phases of the disease and in selected subgroups of immunosuppressed patients. There was insufficient robust evidence for the efficacy of other immunomodulators with further work being needed in relation to biomarker-based stratification for IL-1 therapy CONCLUSIONS: Growing evidence supports incremental efficacy of glucocorticoids alone or combined with tocilizumab/Janus kinase inhibitors in moderate to severe and critical COVID-19. Ongoing studies may unmask the potential application of other therapeutic approaches. Involvement of rheumatologists, as systemic inflammatory diseases experts, should be encouraged in clinical trials of immunomodulatory therapy in COVID-19.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/drug therapy , Glucocorticoids/therapeutic use , Janus Kinase Inhibitors/therapeutic use , Azetidines/therapeutic use , Consensus Development Conferences as Topic , Drug Therapy, Combination , Humans , Immunomodulation , Piperidines/therapeutic use , Purines/therapeutic use , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , SARS-CoV-2 , Sulfonamides/therapeutic use
11.
Ann Intern Med ; 174(10): JC111, 2021 10.
Article in English | MEDLINE | ID: covidwho-1450938

ABSTRACT

SOURCE CITATION: Guimarães PO, Quirk D, Furtado RH, et al. Tofacitinib in patients hospitalized with Covid-19 pneumonia. N Engl J Med. 2021;385:406-15. 34133856.


Subject(s)
COVID-19 , Respiratory Insufficiency , Humans , Piperidines , Pyrimidines , SARS-CoV-2
12.
Am J Trop Med Hyg ; 105(6): 1472-1475, 2021 Oct 04.
Article in English | MEDLINE | ID: covidwho-1450911

ABSTRACT

Human lives and nations' economies have been adversely affected worldwide by the COVID-19 pandemic. The hyperinflammatory state associated with the disease may be related to mortality. Systemic glucocorticoid is the first-line therapy for cytokine storm. Various immunomodulatory drugs such as tocilizumab and baricitinib have been used in those not responding to glucocorticoid monotherapy. Amid the peak crisis of COVID-19 in India, there was an extreme paucity of medications, oxygen, and hospital beds. We describe three patients with COVID-19 who received low-dose tofacitinib (an oral Janus kinase inhibitor) in addition to moderate-dose glucocorticoid. These patients were treated at their homes, as the hospitals were short of beds. Rapid reduction in hypoxemia along with gradual resolution of other signs of the disease were observed. The results are reassuring regarding the feasibility of managing of severe COVID-19 outside the hospital setting when healthcare resources are overwhelmed by pandemic-related caseload.


Subject(s)
COVID-19/drug therapy , Piperidines/therapeutic use , Pyrimidines/therapeutic use , SARS-CoV-2 , Adult , Aged , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/therapeutic use , Anti-Inflammatory Agents/therapeutic use , Cytokine Release Syndrome/prevention & control , Cytokines/genetics , Cytokines/metabolism , Enoxaparin/administration & dosage , Enoxaparin/therapeutic use , Female , Gene Expression Regulation/drug effects , Humans , Methylprednisolone/administration & dosage , Methylprednisolone/therapeutic use , Middle Aged , Piperidines/administration & dosage , Prednisone/administration & dosage , Prednisone/therapeutic use , Pyrimidines/administration & dosage
14.
J Mol Model ; 27(10): 276, 2021 Sep 04.
Article in English | MEDLINE | ID: covidwho-1391881

ABSTRACT

Rimegepant is a new medicine developed for the management of chronic headache due to migraine. This manuscript is an attempt to study the various structural, physical, and chemical properties of the molecules. The molecule was optimized using B3LYP functional with 6-311G + (2d,p) basis set. Excited state properties of the compound were studied using CAM-B3LYP functional with same basis sets using IEFPCM model in methanol for the implicit solvent atmosphere. The various electronic descriptors helped to identify the reactivity behavior and stability. The compound is found to possess good nonlinear optical properties in the gas phase. The various intramolecular electronic delocalizations and non-covalent interactions were analyzed and explained. As the compound contain several heterocyclic nitrogen atoms, they have potential proton abstraction features, which was analyzed energetically. The most important result from this study is from the molecular docking analysis which indicates that rimegepant binds irreversibly with three established SARS-CoV-2 proteins with ID 6LU7, 6M03, and 6W63 with docking scores - 9.2988, - 8.3629, and - 9.5421 kcal/mol respectively. Further assessment of docked complexes with molecular dynamics simulations revealed that hydrophobic interactions, water bridges, and π-π interactions play a significant role in stabilizing the ligand within the binding region of respective proteins. MMGBSA-free energies further demonstrated that rimegepant is more stable when complexed with 6LU7 among the selected PDB models. As the pharmacology and pharmacokinetics of this molecule are already established, rimegepant can be considered as an ideal candidate with potential for use in the treatment of COVID patients after clinical studies.


Subject(s)
Molecular Dynamics Simulation , Piperidines/chemistry , Protons , Pyridines/chemistry , SARS-CoV-2/chemistry , Viral Proteins/chemistry , SARS-CoV-2/metabolism , Viral Proteins/metabolism
15.
Int J Mol Sci ; 22(14)2021 Jul 16.
Article in English | MEDLINE | ID: covidwho-1389404

ABSTRACT

In the past few years, Bruton's tyrosine Kinase (Btk) has emerged as new target in medicinal chemistry. Since approval of ibrutinib in 2013 for treatment of different hematological cancers (as leukemias and lymphomas), two other irreversible Btk inhibitors have been launched on the market. In the attempt to overcome irreversible Btk inhibitor limitations, reversible compounds have been developed and are currently under evaluation. In recent years, many Btk inhibitors have been patented and reported in the literature. In this review, we summarized the (ir)reversible Btk inhibitors recently developed and studied clinical trials and preclinical investigations for malignancies, chronic inflammation conditions and SARS-CoV-2 infection, covering advances in the field of medicinal chemistry. Furthermore, the nanoformulations studied to increase ibrutinib bioavailability are reported.


Subject(s)
Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Protein Kinase Inhibitors/administration & dosage , Adenine/administration & dosage , Adenine/analogs & derivatives , Agammaglobulinaemia Tyrosine Kinase/metabolism , COVID-19/drug therapy , Chemistry, Pharmaceutical/methods , Drug Delivery Systems/methods , Hematologic Neoplasms/drug therapy , Humans , Inflammation/drug therapy , Neoplasms/drug therapy , Piperidines/administration & dosage , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrimidines/administration & dosage , SARS-CoV-2/drug effects
17.
J Oncol Pharm Pract ; 27(7): 1810, 2021 10.
Article in English | MEDLINE | ID: covidwho-1367652
18.
N Engl J Med ; 385(8): 695-706, 2021 08 19.
Article in English | MEDLINE | ID: covidwho-1364626

ABSTRACT

BACKGROUND: Atogepant is an oral, small-molecule, calcitonin gene-related peptide receptor antagonist that is being investigated for the preventive treatment of migraine. METHODS: In a phase 3, double-blind trial, we randomly assigned adults with 4 to 14 migraine days per month in a 1:1:1:1 ratio to receive a once-daily dose of oral atogepant (10 mg, 30 mg, or 60 mg) or placebo for 12 weeks. The primary end point was the change from baseline in the mean number of migraine days per month across the 12 weeks. Secondary end points included headache days per month, a reduction from baseline of at least 50% in the 3-month average of migraine days per month, quality of life, and scores on the Activity Impairment in Migraine-Diary (AIM-D). RESULTS: A total of 2270 participants were screened, 910 were enrolled, and 873 were included in the efficacy analysis; 214 were assigned to the 10-mg atogepant group, 223 to the 30-mg atogepant group, 222 to the 60-mg atogepant group, and 214 to the placebo group. The mean number of migraine days per month at baseline ranged from 7.5 to 7.9 in the four groups. The changes from baseline across 12 weeks were -3.7 days with 10-mg atogepant, -3.9 days with 30-mg atogepant, -4.2 days with 60-mg atogepant, and -2.5 days with placebo. The mean differences from placebo in the change from baseline were -1.2 days with 10-mg atogepant (95% confidence interval [CI], -1.8 to -0.6), -1.4 days with 30-mg atogepant (95% CI, -1.9 to -0.8), and -1.7 days with 60-mg atogepant (95% CI, -2.3 to -1.2) (P<0.001 for all comparisons with placebo). Results for the secondary end points favored atogepant over placebo with the exceptions of the AIM-D Performance of Daily Activities score and the AIM-D Physical Impairment score for the 10-mg dose. The most common adverse events were constipation (6.9 to 7.7% across atogepant doses) and nausea (4.4 to 6.1% across atogepant doses). Serious adverse events included one case each of asthma and optic neuritis in the 10-mg atogepant group. CONCLUSIONS: Oral atogepant once daily was effective in reducing the number of migraine days and headache days over a period of 12 weeks. Adverse events included constipation and nausea. Longer and larger trials are needed to determine the effect and safety of atogepant for migraine prevention. (Funded by Allergan; ADVANCE ClinicalTrials.gov number, NCT03777059.).


Subject(s)
Calcitonin Gene-Related Peptide Receptor Antagonists/administration & dosage , Migraine Disorders/prevention & control , Piperidines/administration & dosage , Pyridines/administration & dosage , Pyrroles/administration & dosage , Spiro Compounds/administration & dosage , Adolescent , Adult , Aged , Calcitonin Gene-Related Peptide Receptor Antagonists/adverse effects , Calcitonin Gene-Related Peptide Receptor Antagonists/therapeutic use , Constipation/chemically induced , Dose-Response Relationship, Drug , Double-Blind Method , Female , Humans , Intention to Treat Analysis , Male , Middle Aged , Nausea/chemically induced , Piperidines/adverse effects , Piperidines/therapeutic use , Pyridines/adverse effects , Pyridines/therapeutic use , Pyrroles/adverse effects , Pyrroles/therapeutic use , Spiro Compounds/adverse effects , Spiro Compounds/therapeutic use , Young Adult
20.
Expert Rev Hematol ; 14(9): 819-830, 2021 09.
Article in English | MEDLINE | ID: covidwho-1349725

ABSTRACT

INTRODUCTION: Ibrutinib is a highly effective drug for patients with chronic lymphocytic leukemia (CLL), and is well tolerated even by older patients and those unfit to receive conventional immuno-chemotherapy. AREAS COVERED: The occurrence of adverse events was revealed as a major cause of ibrutinib failure in the real-world. Ibrutinib-induced lymphocytosis carries the risk of an untimely interruption of therapy because it may be misinterpreted as disease progression. In addition, drug interactions can worsen ibrutinib-associated toxicities by increasing the plasma concentration of ibrutinib. In this review, we present a case of major hemorrhage and atrial fibrillation (AF) during ibrutinib use and summarize the adverse events associated with ibrutinib. Furthermore, the practical management of ibrutinib-associated toxicities was covered with reference to a drug interaction mechanism. EXPERT OPINION: Clinicians should examine the prescribed drugs prior to ibrutinib initiation and carefully monitor toxicities while taking ibrutinib. A reduced dose of ibrutinib with the concurrent use of CYP3A inhibitors such as antifungal agents could be an attractive strategy to reduce toxicities and may confer financial benefits. Reducing unexpected toxicities is as significant as achieving treatment response in the era of life-long therapy with ibrutinib in patients with CLL.


Subject(s)
Adenine/analogs & derivatives , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Piperidines/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Adenine/adverse effects , Adenine/pharmacology , Adenine/therapeutic use , Aged , COVID-19/complications , Disease Management , Drug Interactions , Drug-Related Side Effects and Adverse Reactions/etiology , Drug-Related Side Effects and Adverse Reactions/therapy , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/complications , Male , Piperidines/adverse effects , Piperidines/pharmacology , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacology
SELECTION OF CITATIONS
SEARCH DETAIL