Pharmacology

The key effects of Pitolisant are thought to be mediated presynaptically through effects on histaminergic neurons in the brain. As an H3R competitive antagonist and inverse agonist, pitolisant blocks the inhibitory effect of histamine (or H3R agonist) on endogenous histamine release and enhances the entire central nervous system. Histamine release in the nervous system (CNS). Pitolisant also modulates other neurotransmitter systems, resulting in increased release of acetylcholine and dopamine DA in the cerebral cortex without increasing DA release in the striatal complex.

Does Wakix really work?

Studies have shown that Wakix is ​​effective in reducing the two main symptoms of narcolepsy, excessive daytime sleepiness and cataplexy, in adults, adolescents and children over 6 years of age.

side effect

Pharmacology

Solriamfetol inhibits DA and NE reuptake through DA and NE transporters (DAT, NET) respectively, without significant effects on other targets, including 5-HT, histamine H 1 , histamine H 3 , α 2 -adrenergic and orexin 2 receptors. In vivo, solriamfetol increases extracellular DA and NE concentrations in the striatum and prefrontal cortex; it does not have significant monoamine-releasing effects. The wake-promoting effects of solriamfetol are thought to be due to its action on DAT and NET, rather than to other neurotransmitter receptors involved in regulating sleep (eg, histamine, orexin). It is a norepinephrine-dopamine reuptake inhibitor (NDRI) and is thought to work by increasing levels of the neurotransmitters norepinephrine and dopamine in the brain.

Safety

Side effects of Soriamoto include headache, nausea, decreased appetite, insomnia, anxiety, irritability, nervousness, dizziness, chest discomfort, heart palpitations, dry mouth, increased sweating, abdominal pain, constipation, and diarrhea.

abuse potential

In the United States, solriamfetol is a Schedule IV controlled substance, which means it has recognized medical uses and a low potential for abuse, but abuse may lead to physical or psychological dependence. A prescription is required and can only be filled up to five times in a six-month period. Solriamfetol at higher than approved doses (specifically doses of 300, 600, and 1,200 mg, which are 2 to 4 times the maximum recommended dose) can produce drug-like reactions, including mood elevation and relaxation to a similar degree to phentermine. Elevated mood occurred in 2.4% of the placebo group, 8% to 24% of the solriamfetol group, and 10% to 18% of the phentermine group, compared with 5% of the placebo group and 5% to 19% of the solriamfetol group. , 15% to 20% of the phentermine group experienced a feeling of relaxation. Therefore solriamfetol has significant abuse potential. However, solriamfetol has a lower potential for abuse than Schedule II controlled stimulants such as amphetamines and cocaine.

Sunosi price

Sunosi oral tablets cost approximately $876 for 75 mg oral tablets (30 tablets), depending on which pharmacy you go to.

Pharmacology

Sodium oxybate is the sodium salt of γ-hydroxybutyrate (GHB), an endogenous compound and metabolite of the neurotransmitter GABA, and can be used as a (γ-aminobutyric acid B) GABA _B receptor agonist . The mechanism of action of sodium oxybate in the treatment of narcolepsy is unclear, but it is hypothesized that the therapeutic effect of sodium oxybate on cataplexy and EDS is through GABA B agonists on noradrenergic and dopaminergic neurons and Effects mediated by thalamocortical neurons.

Safety

Combine Lumryz with other CNS depressants (e.g., drugs used to fall asleep, including opiate analgesics, benzodiazepines, sedating antidepressants, antipsychotics, sedating antiepileptic drugs, general anesthetics, muscle relaxants taking alcohol, alcohol, or street drugs) may cause serious medical problems, including:

• Difficulty breathing (respiratory depression)
• hypotension (low blood pressure)
• Changes in alertness (drowsiness)
• Fainting (fainting)
• die

You should not take this medicine if you:

• Taking other sleep medications or sedatives (drugs that cause drowsiness)
• drinking alcoholic beverages
• There is a rare problem called succinate semialdehyde dehydrogenase deficiency

Lumryz price

Lumryz Oral Powder Infused Extended Release 4.5 grams costs approximately $2,154 for a supply of 7 infused powders, with the exact price depending on the pharmacy you go to. Avadel's Lumryz is priced at $64.67 per gram, or about $177,034 per year, which is comparable to twice-nightly oxybate products that require chronic middle-of-the-night awakenings.

Pharmacology

As with the sodium oxybate product, the MOA of JZP-258 is not fully understood. It is hypothesized that the therapeutic effect of JZP-258 on sleep-wake symptoms is mediated through the regulation of GABA _B.

PK/DDI Potential

The PK of JZP-258 was compared with sodium oxybate in two Phase I studies. Compared with sodium oxybate, JZP-258 has a lower C _max , longer t _{max and similar AUC.} Food reduced C _max for both drugs, but to a lesser extent for JZP-258 than for sodium oxybate ( p < 0.05). Like FT218, the DDI potential of JZP-258 is generally expected to be similar to immediate-release sodium oxybate.

effect

The efficacy and safety of JZP-258 in the treatment of narcolepsy cataplexy in adults was evaluated in a Phase III multicenter, randomized withdrawal study. The study included a titration period of up to 12 weeks and a stable dosing period of 2 weeks, followed by randomization in a 1:1 ratio to JZP-258 or placebo for 2 weeks. A 24-week open-label safety extension period is optional for participants who complete a randomized withdrawal period. Study populations included participants who had previously received sodium oxybate, participants who had not received sodium oxybate, and participants who did or did not receive other anticonvulsant treatments. Of 201 participants recruited, 134 were randomly assigned to JZP-258 or placebo and evaluated for efficacy. The difference between the primary endpoint (change in the number of cataplexy episodes per week) and the key secondary endpoint (change in ESS score) between JZP-258 and placebo was statistically significant, indicating that the efficacy of JZP-258 is maintained. Clinical significance, and both experienced statistically significant worsening. Placebo endpoint. Additionally, a higher proportion of participants in the placebo group than those in the JZP-258 group experienced worsening of disease on PGI-C (44.6% vs. 4.3%) and CGI-C (60.0% vs. 5.9%; nominal p < 0.0001).

Safety

In the Phase III randomized study withdrawals, the most common TEAEs (≥ 5% of participants receiving JZP-258) were headache (22.4%), nausea (13.4%), and dizziness (11.4%); two participants reported related Treatment-Related Serious Adverse Events. A 24-week open-label safety study is ongoing.

treatment location

The lower-sodium formulation of JZP-258 may have advantages over sodium oxybate—it is expected to be more suitable for sodium-sensitive patients (such as those with hypertension, heart failure, or renal insufficiency) and may be less likely to cause fluid Accumulation/swelling, which may occur in some patients taking sodium oxybate.

Additionally, JZP-258 may be better tolerated than sodium oxybate (some patients associate the high sodium content of sodium oxybate with unpleasant taste and gastrointestinal effects). JZP-258 has the potential to be The preferred method of treatment for cataplexy and EDS, especially if it is better tolerated than sodium oxybate.

Pharmacology

AXS-12 selectively inhibits NE reuptake, but has a weak effect on 5-HT reuptake and has no effect on DA reuptake. Preclinical data indicate that orexin-deficient mice have reduced narcolepsy episodes (approximately 50% meet criteria for cataplexy; the remainder are sleep attacks)—an effect due to inhibition of NE reuptake.

PK/DDI Potential

The PK of AXS-12 was linear after single doses up to 4.5 mg and after multiple doses up to 12 mg/day. AXS-12 is rapidly absorbed after oral administration ( tmax , 2-4 hours) and _is highly protein-bound (mainly _α1 -acid glycoprotein). The mean t _½ of AXS-12 is approximately 12.5 hours, and the mean plasma clearance is 2.21 L/h. Taking it with food will delay absorption and significantly reduce C _max , but AUC _∞ is not affected. AXS-12 is primarily eliminated through metabolism by CYP3A4. Systemic exposure (AUC _∞ ) and t _½ are approximately two times higher in patients with renal or hepatic impairment than in healthy volunteers. DDI studies in healthy volunteers indicate that strong CYP3A4 inhibitors increase AXS-12 exposure (AUC), decrease clearance, and prolong t _{½ .} Based on currently available reboxetine product information, AXS-12 should not be coadministered with drugs known to inhibit CYP3A4; lower reboxetine serum concentrations have been reported when coadministered with CYP3A4 inducers. In vitro data show that AXS-12 does not affect the activity of CYP1A2, CYP2C9, CYP2D6, CYP2E1, or CYP3A4. Concurrent use with MAOIs should be avoided. Concomitant use of ergot derivatives may result in an increase in blood pressure, and concomitant use of potassium-losing diuretics may result in hypokalemia.

effect

A 2-week pilot study evaluated the stimulant and anticonvulsant effects of AXS-12 in 12 consecutive participants (6 men, 6 women with narcolepsy) attending a sleep disorders clinic. The mean (standard deviation [SD]) age was 36.6 (11.7) years. Starting on Day 1, the dose of AXS-12 was gradually increased from 2 mg/day (single dose in the morning) to 10 mg/day (6 mg in the morning, 4 mg at lunchtime). All 12 participants completed the 2-week treatment period. Mean (SD) ESS score decreased from 20.58 (2.93) at baseline to 10.58 (7.21) on day 14 ( p < 0.01), and mean (SD) MSLT sleep latency increased approximately 55%, from 4.86 (4.01) minutes to Sleep latency increased approximately 55%, from 4.86 (4.01) minutes to 7.52 (4.97) minutes on sleep latency day 7 ( p < 0.05). Cataplexy episode frequency significantly improved, as measured by the decrease in mean (SD) Ullanlinna Narcolepsy Scale Cataplexy score, from 5.85 (2.67) at baseline to 1.71 (1.60) on Day 7 (p < 0.05 ) .

Safety

Adverse events reported in the two-week pilot study included dry mouth, excessive sweating, constipation and irritability. The most common AEs reported in clinical trials and postmarketing experience with AXS-12 for the treatment of depression include insomnia, dizziness, dry mouth, constipation, nausea, and hyperhidrosis.

Because noradrenergic reuptake inhibitors, such as venlafaxine, tend to be very effective in treating cataplexy, AXS-12 may find use as an antistroke agent. If AXS-12 also improves EDS, it could be an alternative for patients who cannot take sodium oxybate or Pitolisant. Given that AXS-12 is approved outside the United States for the treatment of major depression, it may be well suited for patients with both narcolepsy and depression (up to 57% of narcolepsy patients report symptoms of depression).

Pharmacology

Modafinil is a non-amphetamine drug with wake-promoting effects thought to be mediated by inhibition of DA reuptake. The therapeutic effects of modafinil may also be related to the regulation of connexins, as stellate cells and stellate cell connexins are thought to be involved in sleep-wake regulation. Specifically, experimental data indicate that in the cortex, modafinil increases messenger RNA (mRNA) expression and protein of connexin 30, a major astrocytic junction protein.

Flecainide is an inhibitor of stellate cell junction proteins. In preclinical studies, flecainide enhanced the wake-promoting and cognitive-promoting effects of modafinil in wild-type mice, and modafinil/flecainide coadministration reduced the direct transition to orexin knockout. The number and duration of rapid eye movement sleep (characteristic of narcolepsy episodes). mouse. Modafinil also enhanced connexin-mediated stellate cell coupling—an effect that was reversed by coadministration with flecainide.

PK/DDI Potential

PK and potential DDI data for THN102 have not been reported specifically. However, data from mouse models suggest that flecainide does not affect the PK parameters or bioavailability of modafinil. The DDI profile of THN102 is expected to be consistent with its individual components (modafinil and flecainide).

effect

THN102 was evaluated in a Phase II double-blind, randomized, placebo-controlled, three-way crossover trial in approximately 48 adults with narcolepsy with and without cataplexy. Participants received modafinil/flecainide 300 mg/3 mg, modafinil/flecainide 300 mg/27 mg, and modafinil 300 mg in each of three two-week treatment periods. mg/placebo. Preliminary results do not show any difference in efficacy between THN102 and modafinil alone. This finding may be due to an overrepresentation of participants with severe narcolepsy who had a lower response to modafinil.

Safety

In a press release, the sponsor said the safety and tolerability profile of THN102 was "very satisfactory" based on the Phase II data. Specific safety data have not been reported.

The potential role of THN102 in narcolepsy is unknown. Development in narcolepsy was put on hold due to lack of efficacy in Phase II studies; further development is awaiting results from Phase II studies in Parkinson's disease.

________________________________________

Other agents (early development stage)

SUVN-G3031 (Samelisant, 17v) - Histamine _H3 receptor inverse agonist

SUVN-G3031 is an orally active histamine H3 receptor antagonist being developed to treat cognitive deficits in Alzheimer's disease and schizophrenia. It is an H3R inverse agonist in Phase II development. Preclinical data have demonstrated wake-promoting and anticonvulsant effects in rodents.

In several species, SUVN-G3031 caused significant increases in acetylcholine, histamine, DA, and NE levels in the cortex but did not alter DA levels in the striatum and nucleus accumbens, suggesting that it may not have abuse potential. . SUVN-G3031 does not inhibit or induce major CYP isoforms, nor is it a substrate or inhibitor of major uptake transporters. Preclinical studies have shown no negative effects on electrocardiographic parameters, fertility or embryofetal development, and no central nervous system safety concerns.

CRO Quintiles conducted two Phase 1 safety, tolerability and pharmacokinetic studies in 108 healthy individuals (primarily men) in Kansas between September 2014 and August 2017. The results of both trials have been published (Nirogi et al., 2020). Single doses up to 20 mg and multiple doses up to 6 mg are safe and well tolerated. The most common adverse events were unusual dreams, difficulty falling or staying asleep, and hot flashes. Pharmacokinetics are dose-proportional and not affected by food, sex, or age.

There are currently no trials registered for cognitive impairment. A Phase 2 study in narcolepsy was completed in June 2023 and enrolled 190 participants, with results expected in mid-2024.

TAK-925 - Hypotocretin/orexin 2 receptor selective agonist

TAK-925, a potent, selective, brain-penetrating orexin 2 receptor (OX2R) agonist, [methyl (2 R ,3 S )-3-((methylsulfonyl)amino)-2-((( cis - 4-Phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate, 16 ] was identified through the optimization of compound 2 discovered through a high-throughput screening (HTS) campaign. Subcutaneous administration of compound 16 produced wake-promoting effects in mice during sleep stages. Compound 16 (TAK-925) is being developed for the treatment of narcolepsy and other related disorders.

For people with narcolepsy type 1, the best medications are oral medications that can replace the missing orexin neuropeptide and restore normal circadian patterns of orexin signaling, thereby reversing debilitating symptoms such as sleep attacks and cataplexy . This goal presents a complex set of pharmacokinetic challenges, as the drug must be orally bioavailable, brain permeable, and have clearance kinetics on the order of hours. TAK-925 is administered intravenously, and other small molecules have recently been found to improve oral absorption. The structure of active OX2R bound to TAK-925 presented here will help understand the important interactions that must be maintained for small molecule agonists to effectively and fully activate the receptor.

Another hypocretin/orexin 2 receptor selective agonist, TAK-994 (oral), improves wakefulness and reduces cataplexy-like episodes in mouse models; despite positive efficacy, safety concerns have led to Orexin being Phase 2 trial of TAK-994 in vivo for the treatment of narcolepsy type 1 has been discontinued.