The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. I. The influence of administration vehicles

Löscher, Wolfgang; Nolting, Björn; Fassbender, C. P.

doi:10.1016/0920-1211(90)90013-l

Cited by 44 publications

(34 citation statements)

References 14 publications

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“…Furthermore, when a new vehicle is employed, it is also important to verify that the vehicle does not possess any untoward effects that could compromise the interpretation of the study. An important example here is ethanol, which is often used to dissolve hydrophobic drugs, but may exert anticonvulsant effects of its own and synergistically enhance the anticonvulsant (and various other) effects of drugs dissolved in this vehicle [14][15][16][17].…”

Section: Definitionsmentioning

confidence: 99%

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

White

Löscher²

2014

Neurotherapeutics

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A major unmet medical need is the lack of treatments to prevent (or modify) epilepsy in patients at risk, for example, after epileptogenic brain insults such as traumatic brain injury, stroke, or prolonged acute symptomatic seizures like complex febrile seizures or status epilepticus. Typically, following such brain insults there is a seizure-free interval ("latent period"), lasting months to years before the onset of spontaneous recurrent epileptic seizures. The latent period after a brain insult offers a window of opportunity in which an appropriate treatment may prevent or modify the epileptogenic process induced by a brain insult. A similar latent period occurs in patients with epileptogenic gene mutations. Studies using animal models of epilepsy have led to a greater understanding of the factors underlying epileptogenesis and have provided significant insight into potential targets by which the development of epilepsy may be prevented or modified. This review focuses largely on some of the most common animal models of epileptogenesis and their potential utility for evaluating proposed antiepileptogenic therapies and identifying useful biomarkers. The authors also describe some of the limitations of using animal models in the search for therapies that move beyond the symptomatic treatment of epilepsy. Promising results of previous studies designed to evaluate antiepileptogenesis and the role of monotherapy versus polytherapy approaches are also discussed. Recent data from both models of genetic and acquired epilepsies strongly indicate that it is possible to prevent or modify epileptogenesis, and, hopefully, such promising results can ultimately be translated into the clinic.

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Section: Definitionsmentioning

confidence: 99%

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

White

Löscher²

2014

Neurotherapeutics

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“…Furthermore, increased adverse effects of the CBZ/glycofurol solution were still observed at times at which brain CBZ levels were not higher than those achieved with the CBZMPPCD solution, indicating that the interactions between CBZ and glycofurol in mice were predominantly pharmacodynamic rather than pharmacokinetic. Although glycofurol is generally considered to have low toxicity (20,21), it has been shown to increase central drug effects, including anticonvulsant and neurotoxic effects, in rodents (19,22,23). Direct comparison with drug solutions in other vehicles showed that the effects of glycofurol were due not only to inhibitory effects on drug metabolism but also to pharmacodynamic effects of glycofurol (23).…”

Section: Discussionmentioning

confidence: 99%

“…Although glycofurol is generally considered to have low toxicity (20,21), it has been shown to increase central drug effects, including anticonvulsant and neurotoxic effects, in rodents (19,22,23). Direct comparison with drug solutions in other vehicles showed that the effects of glycofurol were due not only to inhibitory effects on drug metabolism but also to pharmacodynamic effects of glycofurol (23). This was also demonstrated by recent experiments in dogs, in which glycofurol doses lower than those previously reported to be inert in mice (21) produced marked cardiovascular and behavioral adverse effects.…”

Section: Discussionmentioning

confidence: 99%

Intravenous Carbamazepine: Comparison of Different Parenteral Formulations in a Mouse Model of Convulsive Status Epilepticus

Löscher

Hönack

1997

Epilepsia

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Summary:Purpose: A drawback of carbamazepine (CBZ), a major antiepileptic drug (AED) with clinical efficacy against partial and generalized convulsive seizures, is its isolubility in aqueous vehicles, which is generally considered a contraindication to parenteral administration in epileptic patients. However, CBZ can be dissolved in glycofurol, a solvent used clinically as a vehicle for parenteral preparations of drugs such as diazepam (DZP) and phenytoin (PHT). Furthermore, aqueous CBZ solutions can be prepared by complexing CBZ with 2-hydroxypropyl-P-cyclodextrin (HPPCD), an inert P-cyclodextrin derivative believed to have acceptable tolerability for human use. Such solutions of CBZ have been proposed to be suitable for intravenous administration in treatment of convulsive (grand mal) status epilepticus (CSE).Methods: A series of five generalized tonic-clonic seizures (GTCS) in 30 min was induced by repeated transauricular electrical stimulation in mice. In this model of convulsive (grand mal) SE, the anticonvulsant potency of intravenous CBZ dissolved in aqueous dilutions of either HPBCD or glycofurol was evaluated.Results: In both solutions, CBZ rapidly suppressed seizures after intravenous bolus injection. Potent anticonvulsant activity was obtained as early as 30 s after injection, and peak effects were observed at -3 min. ED,, for blockade of GTCS throughout the 30-min period of repeated electrical stimulation was -7 mg/kg, similar to the potency of DZP in this model. Whereas the HPPCD/CBZ solutions were tolerated by the animals, with no pronounced behavioral or motor adverse effects, the glycofurol/CBZ solutions induced marked sedation and motor impairment, indicating interactions between drug and solvent. Determination of CBZ in plasma and brain demonstrated that the rapid onset of anticonvulsant action after intravenous bolus injection was related to rapid drug penetration into brain tissue.Conclusions: An intravenous formulation of CBZ achieved through complexing with HPPCD might be suitable for parenteral use in acute clinical conditions such as SE, particularly because CBZ has the advantage of being almost free of respiratory or cardiovascular adverse effects.

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“…Sodium valproate and phenytoin sodium were received as gifts from Abbott Laboratories and Adamjee Pharmaceuticals (Pakistan) Ltd, respectively. Nutmeg oil was dissolved in polyethylene glycol 400, which was diluted in water at a ratio of 30:70; this dilution has no effect on seizure threshold (Loscher et al, 1990). PTZ, STN, sodium valproate and phenytoin sodium were dissolved in normal saline, whereas BIC was dissolved in saline slightly acidified with 0.1 N HCl and was used within 60 min after preparation.…”

Section: Methodsmentioning

confidence: 99%

Anticonvulsant activities of nutmeg oil of Myristica fragrans

Wahab

Haq

Ahmed

et al. 2008

Phytotherapy Research

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The purpose of this study was to investigate the anticonvulsant activity of the volatile oil of nutmeg, the dried seed kernel of Myristica fragrans Houtt, using well-established animal seizure models and to evaluate its potential for acute toxicity and acute neurotoxicity. The volatile oil of nutmeg (nutmeg oil) was tested for its effects in maximal electroshock, subcutaneous pentylenetetrazole, strychnine and bicuculline seizure tests. All the experiments were performed at the time of peak effect of nutmeg oil. Nutmeg oil showed a rapid onset of action and short duration of anticonvulsant effect. It was found to possess significant anticonvulsant activity against electroshock-induced hind limb tonic extension. It exhibited dose dependent anticonvulsant activity against pentylenetetrazole-induced tonic seizures. It delayed the onset of hind limb tonic extensor jerks induced by strychnine. It was anticonvulsant at lower doses, whereas weak proconvulsant at a higher dose against pentylenetetrazole and bicuculline induced clonic seizures. Nutmeg oil was found to possess wide therapeutic margin, as it did not induce motor impairment when tested up to 600 microL/kg in the inverted screen acute neurotoxicity test. Furthermore, the LD(50) (2150 microL/kg) value was much higher than its anticonvulsant doses (50-300 microL/kg). The results indicate that nutmeg oil may be effective against grand mal and partial seizures, as it prevents seizure spread in a set of established animal models. Slight potentiation of clonic seizure activity limits its use for the treatment of myoclonic and absence seizures.

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The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. I. The influence of administration vehicles

Cited by 44 publications

References 14 publications

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

Intravenous Carbamazepine: Comparison of Different Parenteral Formulations in a Mouse Model of Convulsive Status Epilepticus

Anticonvulsant activities of nutmeg oil of Myristica fragrans

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