First‐in‐man allopregnanolone use in super‐refractory status epilepticus

Vaitkevicius, Henrikas; Husain, Aatif M.; Rosenthal, Eric S.; Rosand, Jonathan; Bobb, Wendell; Reddy, Kiran; Rogawski, Michael A.; Cole, Andrew J.

doi:10.1002/acn3.408

Cited by 38 publications

(34 citation statements)

References 15 publications

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“…14,18 Both agents have been proposed as treatments for SE, and there is evidence that intravenously administered allopregnanolone may be of benefit in the treatment of refractory SE in humans. 12,13 To be optimally useful in the pre-hospital emergency treatment of SE, intramuscular dosing is preferred. 25 In the present study, we have shown that intramuscular administration of both neuroactive steroids are effective in stopping SE induced by the chemical threat agent TETS; both agents also improve survival.…”

Section: Discussionmentioning

confidence: 99%

“…8 Moreover, allopregnanolone has been tried on an emergency basis as a treatment for refractory SE in humans and clinical trials are ongoing. 12,13 …”

Section: Introductionmentioning

confidence: 99%

“…8 Moreover, allopregnanolone has been tried on an emergency basis as a treatment for refractory SE in humans, and clinical trials are ongoing. 12,13 Allopregnanolone, an endogenous metabolite of the female sex steroid progesterone, is poorly absorbed when administered by the oral route. 14 Ganaxolone, its 3b-methyl synthetic analog, has modestly improved oral bioavailability, and oral formulations have been shown in some preliminary clinical trials to be effective in the treatment of epilepsy.…”

Section: Introductionmentioning

confidence: 99%

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Intramuscular allopregnanolone and ganaxolone in a mouse model of treatment‐resistant status epilepticus

Żółkowska

Rogawski

2018

Epilepsia

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Allopregnanolone (5α-pregnan-3α-ol-20-one) and its synthetic 3β-methyl analog, ganaxolone, are positive allosteric modulators of synaptic and extrasynaptic γ-aminobutyric acid (GABA) receptors that exhibit antiseizure activity in diverse animal seizure models, including models of status epilepticus (SE). The 2 neuroactive steroids are being investigated as treatments for SE, including as a treatment for SE induced by chemical threat agents. Intramuscular injection is the preferred route of administration in the prehospital treatment of SE. The objective of this study was to assess the efficacy of intramuscular allopregnanolone and ganaxolone in the treatment of SE induced by the chemical threat agent tetramethylenedisulfotetramine (TETS). The test agents were administered 40 minutes after the onset of SE when mice are refractory to treatment. Allopregnanolone and ganaxolone (each at 3 mg/kg) terminated SE in, respectively, 92% and 75% of animals, and prevented mortality in 85% and 50% of animals; the mean times to termination of behavioral seizures were, respectively, 172 ± 16 and 447 ± 52 seconds. In a separate series of experiments, mice were dosed with the neuroactive steroids by intramuscular injection, and plasma and brain levels were sampled at various time points following injection to estimate pharmacokinetic parameters. Plasma C (maximum concentration) values for allopregnanolone and ganaxolone were 645 and 550 ng/mL, respectively. Brain exposure of both steroids was approximately 3-fold the plasma exposure. Two-compartment pharmacokinetic analysis revealed that the central compartment V (volume of distribution), CL (clearance), t (terminal half-life), and F (intramuscular bioavailability) values for allopregnanolone and ganaxolone were, respectively, 4.95 L/kg 12.88 L/kg/h,16 minutes, 97%, and 5.07 L/kg, 8.35 L/kg/h, 25 minutes, 95%. Allopregnanolone and ganaxolone are effective in the treatment of TETS-induced SE when administered by the intramuscular route. Allopregnanolone is more rapidly acting and modestly more effective, possibly because it has greater potency on GABA receptors.

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Section: Discussionmentioning

confidence: 99%

“…8 Moreover, allopregnanolone has been tried on an emergency basis as a treatment for refractory SE in humans and clinical trials are ongoing. 12,13 …”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Intramuscular allopregnanolone and ganaxolone in a mouse model of treatment‐resistant status epilepticus

Żółkowska

Rogawski

2018

Epilepsia

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“…; Vaitkevicius et al . ). SRSE represents the most severe form of SE and is characterized by treatment failure with first/second/third‐line drugs, including anesthetics (Shorvon and Ferlisi ).…”

mentioning

confidence: 97%

“…To overcome this phenomenon, stimulation of GABA A extrasynaptic receptors composed by the d subunit could be attained with neurosteroids such as allopregnanolone (Rogawski et al 2013). This possibility has been initially supported by evidence of beneficial effects in patients affected by super-refractory SE (SRSE) and treated with allopregnanolone (Broomall et al 2014;Vaitkevicius et al 2017). SRSE represents the most severe form of SE and is characterized by treatment failure with first/second/third-line drugs, including anesthetics (Shorvon and Ferlisi 2011).…”

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confidence: 99%

Low levels of progesterone and derivatives in cerebrospinal fluid of patients affected by status epilepticus

Meletti

Lucchi

Monti³

et al. 2018

Journal of Neurochemistry

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Neurosteroids such as allopregnanolone may play a role in epilepsy as positive modulators of inhibitory currents mediated by γ-aminobutyric acid type A (GABA ) receptor. Indeed, these molecules have been consistently shown to be anticonvulsants in animal models, but their role is still unclear in patients. For this reason, we investigated neurosteroids in the cerebrospinal fluid (CSF) of patients with status epilepticus (SE) by liquid chromatography tandem-mass spectrometry. Patients were retrospectively identified within subjects who received a lumbar puncture in the 2007-2017 period. Seventy-three patients (median age 65, ranging from 13 to 94 years; 67% women) with SE were evaluated. Controls (n = 52, median age 53, ranging from 16 to 93 years; 65% women) were patients presenting with symptoms for which a lumbar puncture was required by clinical guidelines, and who were negative at the end of the diagnostic work-up. Progesterone was 64% lower in patients with SE (p < 0.001). With respect to progesterone, upstream pregnenolone sulfate and pregnenolone did not change. Instead, downstream 5α-dihydroprogesterone, pregnanolone and allopregnanolone were, respectively, 49% (p < 0.001), 21% (p < 0.01) and 37% (p < 0.001) lower than in controls. Duration or type of SE, age and sex did not consistently affect CSF neurosteroid levels in the SE cohort. Instead, pregnenolone sulfate (Spearman's ρ = 0.4335, p < 0.01), allopregnanolone (ρ = 0.4121, p < 0.05) and pregnanolone (ρ = 0.592, p < 0.001) levels significantly increased by aging in controls. We conclude that neurosteroidogenesis is defective in patients with SE.

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In the fast lane: Receptor trafficking during status epilepticus

Naylor

2023

Epilepsia Open

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Status epilepticus (SE) remains a significant cause of morbidity and mortality and often is refractory to standard first‐line treatments. A rapid loss of synaptic inhibition and development of pharmacoresistance to benzodiazepines (BZDs) occurs early during SE, while NMDA and AMPA receptor antagonists remain effective treatments after BZDs have failed. Multimodal and subunit‐selective receptor trafficking within minutes to an hour of SE involves GABA‐A, NMDA, and AMPA receptors and contributes to shifts in the number and subunit composition of surface receptors with differential impacts on the physiology, pharmacology, and strength of GABAergic and glutamatergic currents at synaptic and extrasynaptic sites. During the first hour of SE, synaptic GABA‐A receptors containing γ2 subunits move to the cell interior while extrasynaptic GABA‐A receptors with δ subunits are preserved. Conversely, NMDA receptors containing N2B subunits are increased at synaptic and extrasynaptic sites, and homomeric GluA1 (“GluA2‐lacking”) calcium permeant AMPA receptor surface expression also is increased. Molecular mechanisms, largely driven by NMDA receptor or calcium permeant AMPA receptor activation early during circuit hyperactivity, regulate subunit‐specific interactions with proteins involved with synaptic scaffolding, adaptin‐AP2/clathrin‐dependent endocytosis, endoplasmic reticulum (ER) retention, and endosomal recycling. Reviewed here is how SE‐induced shifts in receptor subunit composition and surface representation increase the excitatory to inhibitory imbalance that sustains seizures and fuels excitotoxicity contributing to chronic sequela such as “spontaneous recurrent seizures” (SRS). A role for early multimodal therapy is suggested both for treatment of SE and for prevention of long‐term comorbidities.

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First‐in‐man allopregnanolone use in super‐refractory status epilepticus

Cited by 38 publications

References 15 publications

Intramuscular allopregnanolone and ganaxolone in a mouse model of treatment‐resistant status epilepticus

Intramuscular allopregnanolone and ganaxolone in a mouse model of treatment‐resistant status epilepticus

Low levels of progesterone and derivatives in cerebrospinal fluid of patients affected by status epilepticus

In the fast lane: Receptor trafficking during status epilepticus

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