ABSTRACT
BACKGROUND: Epilepsy poses a significant global health challenge, particularly in regions with limited financial resources hindering access to treatment. Recent research highlights neuroinflammation, particularly involving cyclooxygenase-2 (COX-2) pathways, as a promising avenue for epilepsy management. METHODS: This study aimed to develop a Cyclooxygenase-2 inhibitor with potential anticonvulsant properties. A promising drug candidate was identified and chemically linked with phospholipids through docking analyses. The activation of this prodrug was assessed using phospholipase A2 (PLA2)-mediated hydrolysis studies. The conjugate's confirmation and cytotoxicity were evaluated using Fourier Transform Infrared Spectroscopy (FT-IR), Differential Scanning Calorimetry (DSC), and Sulphoramide B (SRB) assays. RESULTS: Docking studies revealed that the Celecoxib-Phospholipid conjugate exhibited a superior affinity for PLA2 compared to other drug-phospholipid conjugates. FT-IR spectroscopy confirmed the successful synthesis of the conjugate, while DSC analysis confirmed its purity and formation. PLA2-mediated hydrolysis experiments demonstrated selective activation of the prodrug depending on PLA2 concentration. SRB experiments indicated dose-dependent cytotoxic effects of Celecoxib, phospholipid non-toxicity, and efficient celecoxib-phospholipid conjugation. CONCLUSION: This study successfully developed a Celecoxib-phospholipid conjugate with potential anticonvulsant properties. The prodrug's specific activation and cytotoxicity profile makes it a promising therapeutic candidate. Further investigation into underlying mechanisms and in vivo studies is necessary to assess its translational potential fully.
Subject(s)
Anticonvulsants , Celecoxib , Molecular Docking Simulation , Phospholipases A2 , Phospholipids , Prodrugs , Celecoxib/pharmacology , Phospholipids/chemistry , Anticonvulsants/pharmacology , Anticonvulsants/chemical synthesis , Anticonvulsants/chemistry , Prodrugs/pharmacology , Prodrugs/chemistry , Prodrugs/chemical synthesis , Phospholipases A2/metabolism , Humans , Cyclooxygenase 2 Inhibitors/pharmacology , Cyclooxygenase 2 Inhibitors/chemistry , Cyclooxygenase 2 Inhibitors/chemical synthesis , Spectroscopy, Fourier Transform Infrared/methods , Animals , Calorimetry, Differential Scanning , Epilepsy/drug therapy , Hydrolysis , Cell Survival/drug effectsABSTRACT
Olanzapine is an atypical antipsychotic, undergoes extensive first pass metabolism, also has poor aqueous solubility and belongs to BCS (Biopharmaceutical Classification System) Class II drug) exhibit low oral bioavailability. To overcome this and to enhance the bioavailability, intestinal lymphatic transport of drugs can be exploited through Nano structured lipid carriers (NLCs). The NLCs were formulated by solvent diffusion method using solid lipid (glyceryl tripalmitate), liquid lipid (castor oil) and surfactants (Pluronic F-68, Soylecithin). The formulated NLCs were characterized for physico-chemical properties, in-vitro release studies and in-vivo oral bioavailability. F6 has shown average particle size of 158.5â¯nm with PI of 0.115 indicating narrow particle size distribution and follows uni modal distribution. It was found that the batch with stearyl amine has a zeta potential of 28.39â¯mV which confers stability to the dispersion. Bioavailability studies indicate that there was more than 5½-fold increase in oral bioavailability in case of NLCs (F6) compared to olanzapine suspension which indicates that NLCs provided sustained release of the drugs, and these systems can be the preferred as drug carriers for lipophilic drugs in long term disease conditions such as schizophrenia for enhanced bioavailability.
Subject(s)
Antipsychotic Agents , Benzodiazepines , Drug Carriers , Nanoparticles , Administration, Oral , Animals , Antipsychotic Agents/chemistry , Antipsychotic Agents/pharmacokinetics , Antipsychotic Agents/pharmacology , Benzodiazepines/chemistry , Benzodiazepines/pharmacokinetics , Benzodiazepines/pharmacology , Biological Availability , Castor Oil/chemistry , Castor Oil/pharmacokinetics , Castor Oil/pharmacology , Drug Carriers/chemistry , Drug Carriers/pharmacokinetics , Drug Carriers/pharmacology , Lecithins/chemistry , Lecithins/pharmacokinetics , Lecithins/pharmacology , Male , Nanoparticles/chemistry , Nanoparticles/therapeutic use , Olanzapine , Poloxamer/chemistry , Poloxamer/pharmacokinetics , Poloxamer/pharmacology , Rats , Rats, Wistar , Triglycerides/chemistry , Triglycerides/pharmacokinetics , Triglycerides/pharmacologyABSTRACT
Status epilepticus (SE) is an emergency situation, where immediate and effective treatment is required in least possible time as it is associated with neuronal damage, systemic complications, substantial morbidity and mortality depending on status type, duration, age and etiology. In the past few years, morbidity and mortality rate were improved, probably may be due to aggressive use of anti-epileptic drugs in emergency situations. Present literature gives an overview of the conditions leading to SE and its management guidelines in hospital and out of hospital setting emphasizing on the available drug therapies.
