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Respir Care ; 66(1): 113-119, 2021 01.
Article in English | MEDLINE | ID: covidwho-1389654


BACKGROUND: Low airway surface pH is associated with many airway diseases, impairs antimicrobial host defense, and worsens airway inflammation. Inhaled Optate is designed to safely raise airway surface pH and is well tolerated in humans. Raising intracellular pH partially prevents activation of SARS-CoV-2 in primary normal human airway epithelial (NHAE) cells, decreasing viral replication by several mechanisms. METHODS: We grew primary NHAE cells from healthy subjects, infected them with SARS-CoV-2 (isolate USA-WA1/2020), and used clinical Optate at concentrations used in humans in vivo to determine whether Optate would prevent viral infection and replication. Cells were pretreated with Optate or placebo prior to infection (multiplicity of infection = 1), and viral replication was determined with plaque assay and nucleocapsid (N) protein levels. Healthy human subjects also inhaled Optate as part of a Phase 2a safety trial. RESULTS: Optate almost completely prevented viral replication at each time point between 24 h and 120 h, relative to placebo, on both plaque assay and N protein expression (P < .001). Mechanistically, Optate inhibited expression of major endosomal trafficking genes and raised NHAE intracellular pH. Optate had no effect on NHAE cell viability at any time point. Inhaled Optate was well tolerated in 10 normal subjects, with no change in lung function, vital signs, or oxygenation. CONCLUSIONS: Inhaled Optate may be well suited for a clinical trial in patients with pulmonary SARS-CoV-2 infection. However, it is vitally important for patient safety that formulations designed for inhalation with regard to pH, isotonicity, and osmolality be used. An inhalational treatment that safely prevents SARS-CoV-2 viral replication could be helpful for treating patients with pulmonary SARS-CoV-2 infection.

Antiviral Agents/therapeutic use , COVID-19/drug therapy , Epithelial Cells/drug effects , Glycine/pharmacology , Isotonic Solutions/pharmacology , Lung/drug effects , SARS-CoV-2 , Virus Replication/drug effects , Administration, Inhalation , Antiviral Agents/administration & dosage , Cells, Cultured/drug effects , Glycine/administration & dosage , Healthy Volunteers , Humans , Hydrogen-Ion Concentration/drug effects , Isotonic Solutions/administration & dosage
Ann Hematol ; 99(11): 2589-2598, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-746148


The induction therapy containing ixazomib, an oral proteasome inhibitor, has shown favorable efficacy and safety in clinical trials, but its experience in real-life remains limited. In routine practice, few patients received ixazomib-based induction therapy due to reasons including (1) patients' preference on oral regimens, (2) concerns on adverse events (AEs) of other intravenous/subcutaneous regimens, (3) requirements for less center visits, and (4) fears of COVID-19 and other infectious disease exposures. With the aim of assessing the real-life effectiveness and safety of ixazomib-based induction therapy, we performed this multi-center, observational study on 85 newly diagnosed multiple myeloma (NDMM) patients from 14 medical centers. Ixazomib-based regimens included ixazomib-lenalidomide-dexamethasone (IRd) in 44.7% of patients, ixazomib-dexamethasone (Id) in 29.4%, and Id plus another agent (doxorubicin, cyclophosphamide, thalidomide, or daratumumab) in 25.9%. Different ixazomib-based therapies were applied due to (1) financial burdens or limitations on local health insurance coverage, (2) concerns on treatment tolerance, and (3) drug accessibility issue. Ten patients received ixazomib maintenance. The median age was 67 years; 43.5% had ISS stage III disease; 48.2% had an Eastern Cooperative Oncology Group performance score ≥ 2; and 17.6% with high-risk cytogenetic abnormalities. Overall response rate for all 85 patients was 95.3%, including 65.9% very good partial response or better and 29.5% complete responses. The median time to response was 30 days. The response rate was similar across different ixazomib-based regimens. Median progression-free survival was not reached. Severe AEs (≥ grade 3) were reported in 29.4% of patients. No grade 3/4 peripheral neuropathy (PN) occurred. Patients received a median of 6 (range 1-20) cycles of ixazomib treatment; 56.6% remained on treatment at data cutoff; 15.3% discontinued treatment due to intolerable AEs. These results support that the ixazomib-based frontline therapy was highly effective with acceptable toxicity in routine practice and the ixazomib oral regimens could be good alternative options for NDMM patients.

Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Boron Compounds/administration & dosage , Glycine/analogs & derivatives , Multiple Myeloma/drug therapy , Peripheral Nervous System Diseases/chemically induced , Adolescent , Adult , Aged , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Boron Compounds/adverse effects , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Dexamethasone/administration & dosage , Dexamethasone/adverse effects , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Drug Administration Schedule , Female , Glycine/administration & dosage , Glycine/adverse effects , Humans , Lenalidomide/administration & dosage , Lenalidomide/adverse effects , Male , Middle Aged , Multiple Myeloma/mortality , Multiple Myeloma/pathology , Neoplasm Staging , Peripheral Nervous System Diseases/diagnosis , Peripheral Nervous System Diseases/physiopathology , Remission Induction , Survival Analysis , Thalidomide/administration & dosage , Thalidomide/adverse effects , Treatment Outcome