{"doi":"10.1101/2025.06.25.661332","title":"Assessment of pharmacokinetics, safety, and neuroprotective efficacy of an adjunct intramuscular verapamil therapy in a rat model of organophosphate DFP-induced status epilepticus","abstract":"Lethal organophosphate (OP) exposure leads to status epilepticus (SE), which, despite standard-of-care therapy, is associated with acute mortality and long-term morbidities. Neuronal injury and inflammation are reported following OP-SE, and drugs targeted at these processes have produced beneficial outcomes. Verapamil (VPM) is a calcium-channel blocker used as an antihypertensive drug. It exhibits neuroprotective and anti-inflammatory actions in experimental models of CNS injuries. Here, we investigated the feasibility of an adjunctive intramuscular (i.m.) VPM therapy in OP Diisopropyl Fluorophosphate (DFP)-induced SE. We also investigated the safety and toxicity of i.m. VPM and compared its pharmacokinetic (PK) profile to oral (p.o.) administration. Rats were injected with DFP (4 mg/kg, s.c.). One minute later, atropine (0.5 mg/kg, i.m.) and 2-PAM (25 mg/kg, i.m.) were injected, and at 1-hour post-SE, midazolam (1.78 mg/kg, i.m.) was administered. Rats were then treated with VPM (10 mg/kg, i.m, 3 days). Histological analysis was conducted to assess neuronal injury and injection-site pathology. In a separate group of rats, PK studies were conducted on blood and brain homogenates treated once with saline or VPM (10 mg/kg, p.o. or i.m.). Our data demonstrated that following DFP-SE, i.m. VPM achieved higher blood and brain levels and exhibited a favorable PK profile compared to p.o. route. VPM therapy did not cause significant muscle pathology and produced a robust neuroprotective response. Our studies provide evidence that the i.m. route is an effective method for delivering VPM following SE producing significant neuroprotective outcomes compared to treatment with the standard-of-care alone in OP-SE.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":569255,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9589,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1088008,"name":"Robert E. Blair","orcid":null,"position":1,"is_corresponding":false},{"id":994632,"name":"Elisa Hawkins","orcid":null,"position":2,"is_corresponding":false},{"id":509970,"name":"Matthew S. Halquist","orcid":"0000-0001-9591-3117","position":3,"is_corresponding":false},{"id":1474191,"name":"Melissa Morgan","orcid":"0000-0003-1663-7260","position":4,"is_corresponding":false},{"id":1474503,"name":"Jason Funderburk","orcid":null,"position":5,"is_corresponding":false},{"id":1474504,"name":"Daniel Calvano","orcid":null,"position":6,"is_corresponding":false},{"id":344255,"name":"Jennifer E. Koblinski","orcid":"0000-0002-7156-2030","position":7,"is_corresponding":false},{"id":1135927,"name":"Hope Richard","orcid":"0000-0002-5956-0585","position":8,"is_corresponding":false},{"id":432020,"name":"Laxmikant S. Deshpande","orcid":"0000-0003-1491-1561","position":9,"is_corresponding":false},{"id":1474190,"name":"Yam Nath Paudel","orcid":"0000-0002-8804-6331","position":0,"is_corresponding":true}],"reference_count":73,"raw_metadata":null,"created_at":"2026-07-19T02:56:59.652443Z","pmid":"40666862","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}