ABSTRACT
Overly rapid correction of chronic hyponatremia can cause osmotic demyelination syndrome (ODS). Minocycline protects ODS associated with overly rapid correction of chronic hyponatremia with hypertonic saline infusion in rats. In clinical practice, inadvertent rapid correction frequently occurs due to water diuresis, when vasopressin action suddenly ceases. In addition, vasopressin receptor antagonists have been applied to treat hyponatremia. Here the susceptibility to and pathology of ODS were evaluated using rat models developed to represent rapid correction of chronic hyponatremia in the clinical setting. The protective effect of minocycline against ODS was assessed. Chronic hyponatremia was rapidly corrected by 1 (T1) or 10 mg/kg (T10) of tolvaptan, removal of desmopressin infusion pumps (RP), or administration of hypertonic saline. The severity of neurological impairment in the T1 group was significantly milder than in other groups and brain hemorrhage was found only in the T10 and desmopressin infusion removal groups. Minocycline inhibited demyelination in the T1 group. Further, immunohistochemistry showed loss of aquaporin-4 (AQP4) in astrocytes before demyelination developed. Interestingly, serum AQP4 levels were associated with neurological impairments. Thus, minocycline can prevent ODS caused by overly rapid correction of hyponatremia due to water diuresis associated with vasopressin action suppression. Increased serum AQP4 levels may be a predictive marker for ODS.
Subject(s)
Antidiuretic Hormone Receptor Antagonists/toxicity , Benzazepines/toxicity , Demyelinating Diseases/prevention & control , Diuresis/drug effects , Hyponatremia/therapy , Minocycline/pharmacology , Neuroprotective Agents/pharmacology , Saline Solution, Hypertonic/toxicity , Therapeutics/adverse effects , Animals , Aquaporin 4/blood , Astrocytes/drug effects , Astrocytes/metabolism , Astrocytes/pathology , Behavior, Animal/drug effects , Biomarkers/blood , Brain/drug effects , Brain/metabolism , Brain/pathology , Brain/physiopathology , Chemokines/genetics , Chemokines/metabolism , Cytokines/genetics , Cytokines/metabolism , Cytoprotection , Deamino Arginine Vasopressin , Demyelinating Diseases/blood , Demyelinating Diseases/chemically induced , Demyelinating Diseases/genetics , Demyelinating Diseases/pathology , Demyelinating Diseases/psychology , Disease Models, Animal , Hyponatremia/blood , Hyponatremia/chemically induced , Hyponatremia/physiopathology , Intracranial Hemorrhages/chemically induced , Intracranial Hemorrhages/prevention & control , Male , Matrix Metalloproteinases/genetics , Matrix Metalloproteinases/metabolism , Osmosis , Rats, Sprague-Dawley , Saline Solution, Hypertonic/administration & dosage , Sodium/blood , Time Factors , Tolvaptan , Water-Electrolyte Balance/drug effectsABSTRACT
We evaluated the effect of proton pump inhibitors (PPIs) and H2-receptor antagonists (H2RAs) on the efficacy and safety of dasatinib for chronic-phase chronic myeloid leukemia (CP-CML). Retrospective analyses were performed for patients with CP-CML who received dasatinib at seven hospitals between April 2009 and December 2016. Seventy-three patients were identified, 16 of whom received PPIs or H2RAs concurrently with dasatinib. Major molecular response at 12 months was observed in 13 of 13 patients (100%) with concurrent PPIs or H2RAs (combination group), and in 23 of 51 patients (45.1%) who received only dasatinib (dasatinib-alone group; P < 0.001). Deep molecular response at 12 months was observed in four of six patients (66.7%) in the combination group, and seven of 38 patients (18.4%) in the dasatinib-alone group (P = 0.027). Dasatinib chemotherapy was stopped after 18 months for 25 patients (43.9%) from the dasatinib-alone group, but for none from the combination group. Combination treatment with PPIs or H2RAs did not reduce the efficacy of dasatinib. PPIs and H2RAs reduce the incidence of dasatinib discontinuation due to adverse events and increase the efficacy of dasatinib chemotherapy for patients.