Ganaxolone, sold under the brand name Ztalmy, is a

medication A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the medical field and ...

used to treat

seizure An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with l ...

s in people with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD). Ganaxolone was approved for medical use in the United States in March 2022.

Pharmacology

Mechanism of action

The exact mechanism of action for ganaxolone is unknown; however, results from animal studies suggest that it acts by blocking seizure propagation and elevating seizure thresholds. Ganaxolone is thought to modulate both synaptic and extrasynaptic GABA_A receptors to normalize over-excited

neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. ...

s. Ganaxolone's activation of the extrasynaptic receptor is an additional mechanism that provides stabilizing effects that potentially differentiates it from other drugs that increase GABA signaling. Ganaxolone binds to allosteric sites of the GABA_A receptor to modulate and open the chloride ion channel, resulting in a hyperpolarization of the neuron. This causes an inhibitory effect on

neurotransmission Neurotransmission (Latin: ''transmissio'' "passage, crossing" from ''transmittere'' "send, let through") is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron (the presynaptic neuron), ...

, reducing the chance of a successful

action potential An action potential occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells, ...

(

depolarization In biology, depolarization or hypopolarization is a change within a cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolarization is ess ...

) from occurring. It is unknown if ganaxolone possesses significant hormonal activity

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

, with a 2020 study finding evidence of

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology ...

binding to the membrane progesterone receptor.

Chemistry

Ganaxolone is a

analog Analog or analogue may refer to: Computing and electronics * Analog signal, in which information is encoded in a continuous variable ** Analog device, an apparatus that operates on analog signals *** Analog electronics, circuits which use analog ...

of the neuroactive steroid allopregnanolone which possesses no known hormonal activity and, instead, is thought to primarily function by binding to GABAa receptors as a positive allosteric modulator. Other pregnane neurosteroids include alfadolone, alfaxolone, allopregnanolone (brexanolone), hydroxydione, minaxolone, pregnanolone (eltanolone), and renanolone, among others.

Research

Ganaxolone is being investigated for potential medical use in the treatment of

epilepsy Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrica ...

. It is well tolerated in human trials, with the most commonly reported side effects being

somnolence Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...

(sleepiness),

dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a common medical c ...

, and fatigue. Trials in adults with focal onset seizures and in children with infantile spasms have recently been completed. There are ongoing studies in patients with focal onset seizures, PCDH19 pediatric epilepsy, and behaviors in Fragile X syndrome. Ganaxolone has been shown to protect against

s in animal models, and to act a

positive allosteric modulator In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimulus. Some of them, like benzodiazepines, are drugs. The site that an allosteric modulator binds to ...

of the GABA_A receptor.

Clinical trials

The most common adverse events reported across clinical trials have been

(sleepiness),

, and fatigue. In 2015, the MIND Institute at the University of California, Davis, announced that it was conducting, in collaboration with Marinus Pharmaceuticals, a randomized, placebo-controlled, Phase 2 clinical trial evaluating the effect of ganaxolone on behaviors associated with Fragile X syndrome in children and adolescents.

References

External links

* {{Portal bar , Medicine Sterols Anticonvulsants GABAA receptor positive allosteric modulators Ketones Neurosteroids Pregnanes Sedatives Orphan drugs