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Hmm "orexin Receptor Antagonists: A New Class Of Sleeping Pill"


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#1 sk8aplexy

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Posted 27 September 2013 - 05:52 PM

http://www.sleepfoun...s-sleeping-pill

 

http://www.sleepfoun...s-sleeping-pill

 

The opposite, an agonist, is what we need, no?



#2 ironhands

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Posted 27 September 2013 - 05:57 PM

more interested in a hypocretin AGONIST personally.  Having the brain produce more would likely help us all out a lot better.

 

It could also be used, potentially, as a dietary aid, and an anti-depressant, since marketability would be the key factor.



#3 Ferret

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Posted 27 September 2013 - 07:09 PM

So, if we don't have any orexin producing neurons in the brain, what's the agonist going to work on?



#4 sk8aplexy

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Posted 27 September 2013 - 08:44 PM

Good point =]



#5 SleepyDays

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Posted 29 September 2013 - 09:39 AM

This is from Drugs.com Note the last line..... Suvorexant

Generic Name: Suvorexant (DORA-22, MK4305)
Brand Name: Not Assigned
Approval Status: Not Approved; NDA submitted to FDA.
Company: Merck & Co.
Proposed Indication: Treatment of insomnia (difficulty in falling or staying asleep).

The New Drug Application (NDA) for suvorexant was submitted in November 2012 and is currently under FDA review; final FDA decision is expected by Q3 or Q4 2013. If approved, assignment of controlled status by the Drug Enforcement Agency (DEA) may push final launch out until early 2014. Suvorexant has also been filed with regulators in Japan.

Reportedly, patient trials have shown less effect on next-day drowsiness in 90 percent of patients. There is also the possibility that the drug can be used over the long-term for treatment of insomnia; however, it will most likely still be classified by the DEA as a controlled substance.

 
Market Potential

Analysts predict suvorexant could have sales close to $900 million per year if approved. Many generic sleep agents, such as zolpidem and lorazepam, are available at a low-cost in the U.S. market; however, they are controlled substances typically indicated for short-term use, and with a potential for dependence.

Insomnia is estimated to occur in roughly 10 percent of the U.S. population, and about 30 percent of these individuals take medications to help with sleep. Chronic insomnia is defined as persistent trouble sleeping more than three nights each week. Insomnia is more common in women and the elderly, and is common in patients who also have psychiatric comorbid conditions such as depression, anxiety, dementia, or substance abuse.

Possible future indications for dual orexin 1 and 2 receptor antagonists may include narcolepsy, and shift-work sleep disorders.

Strengths and Dosage Forms

In Phase III clinical trials published in December 2012, patients received suvorexant in 10, 20, 40 or 80 milligram strengths. Other studies have evaluated 15 and 30 milligram doses. Suvorexant was shown to improve sleep efficiency in a dose-related manner; however, side effects such as next-day drowsiness may be dose related, as well. Dosage forms (i.e., tablet, capsule) were not reported. Lower 15 and 30 mg doses have been studied in patients 65 years of age and older.

Mechanism of Action

Suvorexant, known as a dual orexin 1 and 2 receptor antagonist (DORA) blocks orexin, a brain chemical that is associated with sleep disruption. Orexin-A and -B peptides are produced in the hypothalamus and are necessary for normal wakefulness. Loss of orexin neurons in humans is linked with narcolepsy, a sleep disorder which involves excessive daytime sleepiness and cataplexy, a sudden loss of muscle tone. Normally, orexin levels increase during the day and fall at night. The loss of orexin in narcolepsy points to the importance of orexin to maintain a wakeful state. Suvorexant would be the first in a new drug class called orexin receptor antagonists.

Other drugs that treat insomnia affect the brain on a larger scale, and occupy γ-aminobutyric acid type A (GABA-A) and benzodiazepine receptors, but often lead to residual side effects like daytime drowsiness, forgetfulness (amnesia), or rebound insomnia. Sedating antidepressants, such as trazodone, doxepin, or amitriptyline, have also been used to induce sleep. Antihistamines, like diphenhydramine (Benadryl), and melatonin are available over-the-counter and used for sleep.

Suvorexant Phase III Clinical Trials

Suvorexant Effectiveness: Nine clinical trials have been completed for suvorexant as of May 2013. The NDA for suvorexant is based on data from a broad clinical development program looking at efficacy and safety in adult patients. Studies included:

  • Two pivotal, three-month effectiveness trials that evaluated the ability of suvorexant to help patients fall asleep and stay asleep.
  • A 12-month study, followed by a two-month discontinuation phase, that was designed to assess the safety of suvorexant, while also evaluating its longer term efficacy and the impact of stopping treatment.
  • Two next-day driving studies that provided an assessment of residual effects following evening use of suvorexant.

Animal studies in rhesus monkey and rats show suvorexant has less of an effect on cognitive abilities, such as attention or memory. When common sedative-hypnotics such as zolpidem (Ambien), eszopiclone (Lunesta), or diazepam (Valium) were administered to the animals, there was a comparatively greater effect on cognitive abilities. Human comparative trials with currently marketed insomnia medications are not available.

Placebo-controlled trials have shown that patients who took suvorexant reported that they fell asleep faster, remained asleep longer, and spent less time awake during the night compared with patients who received placebo (P < .001; all results significant during the first month). Results occurred as early as the first night of dosing.

Suvorexant met statistical significance for all primary endpoints except for one measurement at month three; the difference in time to fall into continuous sleep did not reach statistical significance compared to placebo (-32.2 minutes vs. -28.6 minutes, p=0.265). The objective data showed that patients taking suvorexant spent less time awake during the night by 54.2 minutes (vs. 24.8 minutes with placebo) compared to before they started taking suvorexant.

In the 12-month study, which was followed by a discontinuation phase, those who switched from suvorexant to placebo in the final two months had no clinically meaningful evidence of withdrawal or rebound insomnia.

Suvorexant Safety

Official FDA labeling is not yet available for suvorexant; however, clinical trials reports have identified possible side effects. Reported suvorexant side effects (greater than or equal to 5 percent and more often than placebo):

  • headaches (roughly 7 percent vs. 6 percent with placebo)
  • next-day sleepiness (roughly 10 percent vs. 3 percent with placebo)

No serious drug-related side effects were reported in either of two trials with the highest doses of suvorexant. It is important to note that the long-term side effects of using orexin antagonists are unknown. Merck reports they have not seen any cases of narcolepsy, a sleep disorder marked by daytime sleepiness and daytime sleep attacks, or cataplexy - these patients were excluded from studies.



#6 Potato

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Posted 30 September 2013 - 12:29 AM

So, if we don't have any orexin producing neurons in the brain, what's the agonist going to work on?

 

For simplicity's sake it is common to say "serotonin agonist" or "dopamine agonist." Or, in this case, "orexin agonist." These are all neurotransmitter molecules that just float around in the synapse, so it's technically improper to say that you have a neurotransmitter agonist or a neurotransmitter antagonist. Really what is being said is that you have a neurotransmitter RECEPTOR agonist or antagonist. It is the receptor, and not the neurotransmitter molecule itself, to which agonists and antagonists bind.

 

So when it is said narcoleptics would benefit from an orexin agonist, the drug being sought is one which agonizes the orexin receptor in the brain. Agonists function by binding to the receptors and essentially filling in for the neurotransmitter, even when the neurotransmitter itself is wholly absent.



#7 Ferret

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Posted 30 September 2013 - 06:54 AM

Thank you Chemist! That makes a lot more sense.



#8 sk8aplexy

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Posted 30 September 2013 - 09:51 AM

Thanks!  Knew I wasn't entirely off base, in saying such.

 

I can remember Dr. Mignot saying such quite specifically, at a group discussion I attended...



#9 kevers

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Posted 19 October 2013 - 05:04 PM

This is from Drugs.com Note the last line..... Suvorexant

Generic Name: Suvorexant (DORA-22, MK4305)
Brand Name: Not Assigned
Approval Status: Not Approved; NDA submitted to FDA.
Company: Merck & Co.
Proposed Indication: Treatment of insomnia (difficulty in falling or staying asleep).

The New Drug Application (NDA) for suvorexant was submitted in November 2012 and is currently under FDA review; final FDA decision is expected by Q3 or Q4 2013. If approved, assignment of controlled status by the Drug Enforcement Agency (DEA) may push final launch out until early 2014. Suvorexant has also been filed with regulators in Japan.

Reportedly, patient trials have shown less effect on next-day drowsiness in 90 percent of patients. There is also the possibility that the drug can be used over the long-term for treatment of insomnia; however, it will most likely still be classified by the DEA as a controlled substance.

 
Market Potential

Analysts predict suvorexant could have sales close to $900 million per year if approved. Many generic sleep agents, such as zolpidem and lorazepam, are available at a low-cost in the U.S. market; however, they are controlled substances typically indicated for short-term use, and with a potential for dependence.

Insomnia is estimated to occur in roughly 10 percent of the U.S. population, and about 30 percent of these individuals take medications to help with sleep. Chronic insomnia is defined as persistent trouble sleeping more than three nights each week. Insomnia is more common in women and the elderly, and is common in patients who also have psychiatric comorbid conditions such as depression, anxiety, dementia, or substance abuse.

Possible future indications for dual orexin 1 and 2 receptor antagonists may include narcolepsy, and shift-work sleep disorders.

Strengths and Dosage Forms

In Phase III clinical trials published in December 2012, patients received suvorexant in 10, 20, 40 or 80 milligram strengths. Other studies have evaluated 15 and 30 milligram doses. Suvorexant was shown to improve sleep efficiency in a dose-related manner; however, side effects such as next-day drowsiness may be dose related, as well. Dosage forms (i.e., tablet, capsule) were not reported. Lower 15 and 30 mg doses have been studied in patients 65 years of age and older.

Mechanism of Action

Suvorexant, known as a dual orexin 1 and 2 receptor antagonist (DORA) blocks orexin, a brain chemical that is associated with sleep disruption. Orexin-A and -B peptides are produced in the hypothalamus and are necessary for normal wakefulness. Loss of orexin neurons in humans is linked with narcolepsy, a sleep disorder which involves excessive daytime sleepiness and cataplexy, a sudden loss of muscle tone. Normally, orexin levels increase during the day and fall at night. The loss of orexin in narcolepsy points to the importance of orexin to maintain a wakeful state. Suvorexant would be the first in a new drug class called orexin receptor antagonists.

Other drugs that treat insomnia affect the brain on a larger scale, and occupy γ-aminobutyric acid type A (GABA-A) and benzodiazepine receptors, but often lead to residual side effects like daytime drowsiness, forgetfulness (amnesia), or rebound insomnia. Sedating antidepressants, such as trazodone, doxepin, or amitriptyline, have also been used to induce sleep. Antihistamines, like diphenhydramine (Benadryl), and melatonin are available over-the-counter and used for sleep.

Suvorexant Phase III Clinical Trials

Suvorexant Effectiveness: Nine clinical trials have been completed for suvorexant as of May 2013. The NDA for suvorexant is based on data from a broad clinical development program looking at efficacy and safety in adult patients. Studies included:

  • Two pivotal, three-month effectiveness trials that evaluated the ability of suvorexant to help patients fall asleep and stay asleep.
  • A 12-month study, followed by a two-month discontinuation phase, that was designed to assess the safety of suvorexant, while also evaluating its longer term efficacy and the impact of stopping treatment.
  • Two next-day driving studies that provided an assessment of residual effects following evening use of suvorexant.

Animal studies in rhesus monkey and rats show suvorexant has less of an effect on cognitive abilities, such as attention or memory. When common sedative-hypnotics such as zolpidem (Ambien), eszopiclone (Lunesta), or diazepam (Valium) were administered to the animals, there was a comparatively greater effect on cognitive abilities. Human comparative trials with currently marketed insomnia medications are not available.

Placebo-controlled trials have shown that patients who took suvorexant reported that they fell asleep faster, remained asleep longer, and spent less time awake during the night compared with patients who received placebo (P < .001; all results significant during the first month). Results occurred as early as the first night of dosing.

Suvorexant met statistical significance for all primary endpoints except for one measurement at month three; the difference in time to fall into continuous sleep did not reach statistical significance compared to placebo (-32.2 minutes vs. -28.6 minutes, p=0.265). The objective data showed that patients taking suvorexant spent less time awake during the night by 54.2 minutes (vs. 24.8 minutes with placebo) compared to before they started taking suvorexant.

In the 12-month study, which was followed by a discontinuation phase, those who switched from suvorexant to placebo in the final two months had no clinically meaningful evidence of withdrawal or rebound insomnia.

Suvorexant Safety

Official FDA labeling is not yet available for suvorexant; however, clinical trials reports have identified possible side effects. Reported suvorexant side effects (greater than or equal to 5 percent and more often than placebo):

  • headaches (roughly 7 percent vs. 6 percent with placebo)
  • next-day sleepiness (roughly 10 percent vs. 3 percent with placebo)

No serious drug-related side effects were reported in either of two trials with the highest doses of suvorexant. It is important to note that the long-term side effects of using orexin antagonists are unknown. Merck reports they have not seen any cases of narcolepsy, a sleep disorder marked by daytime sleepiness and daytime sleep attacks, or cataplexy - these patients were excluded from studies.

 

 

 

ah they were excluded hopefully well see more in the future about this.