Lorazepam

Formulating a poorly water soluble drug into an oral solution suitable for paediatric patients; lorazepam as a model drug.[Pubmed:28126558]

Eur J Pharm Sci. 2017 Mar 30;100:205-210.

INTRODUCTION: Many drugs are unavailable in suitable oral paediatric dosage forms, and pharmacists often have to compound drugs to provide paediatric patients with an acceptable formulation in the right dose. Liquid formulations offer the advantage of dosing flexibility and ease of administration to young patients, but drug substances often show poor aqueous solubility. The objective of this work was to study different solvents and matrices to design a liquid formulation for poorly water soluble drugs, using Lorazepam as model drug. METHODS: Three different formulation strategies were explored to improve the solubility. Firstly, water-soluble organic solvents were used to improve the aqueous solubility directly, secondly, ionic surfactants were used to solubilise the model drug, and thirdly, complexation of Lorazepam with cyclodextrin was studied. Specific attention was paid to excipients, adequate taste correction and palatability. For the final formulation, physical and chemical stability and microbiological quality were assessed for 12months. RESULTS: An organic solvent based formulation, containing a mixture of polyethylene glycol and glycerol 85%, with a minimum amount of propylene glycol, proved to be physically and chemically stable. Development of the non-ionic surfactants formulation was discontinued due to taste problems. The cyclodextrin formulations were physically stable, but Lorazepam content declined to 90% within five months. The final formulation contained in volume concentration (%v/v) 87% glycerol, 10% polyethylene glycol 400 and 3% propylene glycol. Orange essence was the preferred taste corrector. The formulation remained stable for 12months at 4 degrees C, with Lorazepam content remaining >95%. Related substances increased during the study period but remained below 2%. In-use stability was proven up to 4weeks. CONCLUSION: An organic solvent based oral formulation was shown to be superior to a non-ionic surfactant based formulation or a cyclodextrin formulation. These results may help to formulate paediatric formulations of other poorly water soluble drugs, to aid pharmacy compounding.

A novel animal model of acquired human temporal lobe epilepsy based on the simultaneous administration of kainic acid and lorazepam.[Pubmed:28157273]

Epilepsia. 2017 Feb;58(2):222-230.

OBJECTIVE: Kainic acid (KA) is a potent glutamate analog that is used to induce neurodegeneration and model temporal lobe epilepsy (TLE) in rodents. KA reliably induces severe, prolonged seizures, that is, convulsive status epilepticus (cSE), which is typically fatal without pharmacologic intervention. Although the use of KA to model human epilepsy has proven unquestionably valuable for >30 years, significant variability and mortality continue to confound results. These issues are probably the consequence of cSE, an all-or-nothing response that is inherently capricious and uncontrollable. The relevance of cSE to the human condition is dubious, however, as most patients with epilepsy never experienced it. We sought to develop a simple, KA-based animal model of TLE that avoids cSE and its confounds. METHODS: Adult, male Sprague-Dawley rats received coincident subcutaneous injections of KA (5 mg) and Lorazepam (0.25 mg), approximately 15.0 and 0.75 mg/kg, respectively. Continuous video-electroencephalography (EEG) was used to monitor acute seizure activity and detect spontaneous seizures. Immunocytochemistry, Fluoro-Jade B staining, and Timm staining were used to characterize both acute and chronic neuropathology. RESULTS: Acutely, focal hippocampal seizures were induced, which began after about 30 min and were self-terminating after a few hours. Widespread hippocampal neurodegeneration was detected after 4 days. Spontaneous, focal hippocampal seizures began after an average of 12 days in all animals. Classic hippocampal sclerosis and mossy fiber sprouting characterized the long-term neuropathology. Morbidity and mortality rates were both 0%. SIGNIFICANCE: We show here that the effects of systemic KA can be limited to the hippocampus simply with coadministration of a benzodiazepine at a low dose. This means that Lorazepam can block convulsive seizures without truly stopping seizure activity. This novel, cSE-free animal model reliably mimics the defining characteristics of acquired mesial TLE: hippocampal sclerosis and spontaneous hippocampal-onset seizures after a prolonged seizure-free period, without significant morbidity, mortality, or nonresponders.

Effects of Intramuscular Midazolam and Lorazepam on Acute Agitation in Non-Elderly Subjects - A Systematic Review.[Pubmed:28293921]

Pharmacopsychiatry. 2017 Jul;50(4):129-135.

Benzodiazepines are commonly used for the treatment of acute agitation in a psychiatric setting.We searched MEDLINE, EMBASE, PsycINFO, and the Cochrane Central Register of Controlled Trials (CENTRAL) for relevant publications. Randomized trials evaluating intramuscular (IM) midazolam or Lorazepam given as monotherapy or as add-on treatment, with more than 10 patients aged 18-65 years, conducted in a psychiatric setting, and published between January 1, 1980, and February 3, 2016, were included. 16 studies from a search result of 5 516 studies were included. In total, 577 patients were treated with Lorazepam IM 2-4 mg, and 329 patients were treated with midazolam IM 5-15 mg. It is unclear whether Lorazepam IM or midazolam IM is as efficacious as an antipsychotic IM. It is a bit more certain that the combination of benzodiazepines IM and a low dose antipsychotic IM is more efficacious than the benzodiazepine and the antipsychotic alone. However, there is no doubt that benzodiazepines are less likely to be associated with treatment emergent side effects, as compared to antipsychotics.