For anyone interested in the MK-869 thread

[Guest guest]

I just came across an article saying Merck began phase III trials

for this in the third quarter of 2001, and expect to file for

regulatory approval in 2002, so maybe this will be another

possible option for treating cea by the end of this year,

especially for the people who have depression/anxiety that goes

along with it.

[Guest guest]

Adam, you're right, many small peptides are vasodilators, there's

nothing special about SP or NO in that regard. But the problem

confronting all researchers is that there's a big difference between

how a peptide impacts local tissues in the lab, and how a medication

that blocks a peptide receptor gets to and impacts local tissue in

the human body. I know you realize that intellectually.

FYI, here are two abstracts from www.biopsychiatry.com. The first

abstract says that MK869 is not being studied anymore; the second

abstract says that centrally acting substance P antagonists (like

MK869 or Zofran) have not been found effective for pain control

(although I don't know if either are the final word):

Substance P antagonists:

novel agents in the treatment of depression

by

Argyropoulos SV, Nutt DJ

Psychopharmacology Unit,

School of Medical Sciences,

University Walk, Bristol BS8 1TD, UK.

spilios.argyropoulos@...

Expert Opin Investig Drugs 2000 Aug; 9(8):1871-1875

ABSTRACT

The field of neuropeptides has been expanding very rapidly in recent

years. Apart from understanding their physiology and elucidating

their functional role as putative neurotransmitters, research has

focused on producing drugs that may treat a variety of illnesses in a

novel way. Substance P antagonists occupy a central role in this area

of intensive scientific activity. Substance P (SP), an undecapeptide,

is abundant both in the periphery and in the CNS, where it is usually

co-localised with one of the classical neurotransmitters, most

commonly serotonin (5-HT). A role for SP is proposed in the

regulation of pain, asthma, psoriasis, inflammatory bowel disease

and, in the CNS, emesis, migraine, schizophrenia, depression and

anxiety. A recently published positive study of MK 869, in

depression, a novel SP antagonist has generated excitement amongst

psychopharmacologists. It is the first time that a drug, not directly

related to monoamine transmitters, has showed efficacy in depression.

Although MK 869 has been suspended from further development, a host

of other compounds, with similar action and better pharmacological

profile, are currently under development. In this review, the

pharmacology of central SP and its receptors are discussed, together

with the exploration of the prospects and implications for future

treatments of depression.

Discovery of the antidepressant and anti-emetic efficacy of substance

P receptor (NK1) antagonists

by

Rupniak NM, Kramer MS

Merck Sharp & Dohme Neuroscience Research Centre,

Harlow, Essex, UK.

nadia_rupniak@...

Trends Pharmacol Sci 1999 Dec;20(12):485-90

ABSTRACT

The development of small-molecule antagonists of the substance P (SP)-

preferring tachykinin NK1 receptor during the past decade represents

an important opportunity to exploit these molecules as novel

therapeutic agents. On the basis of its anatomical localization and

function, SP has been implicated in diverse pathophysiologies; of

these, diseases of the CNS have been examined in the greatest detail.

Although SP is best known as a pain neurotransmitter, it also

controls vomiting and various behavioural, neurochemical and

cardiovascular responses to stress. Recent clinical trials have

confirmed the efficacy of NK1 receptor antagonists to alleviate

depression and emesis but, surprisingly, not pain. Thus, multiple

clinical trials, targeted to appropriate patient populations, are

necessary to define the therapeutic potential of novel

neurotransmitter ligands.

> So in the meantime I'm looking for anything that might make it

> possible to go out and have a normal

> day without my skin flushing as soon as i step outside in the sun,

> or into a warm room, or eat the wrong food, or try to

> exercise, or use the wrong soap etc, and make it possible to sleep

> without tossing and turning all night

> because my cheek hurts too much when pressed up against my

> pillow... "

I'm not going to victimize you, Adam. I'm seeing you as a man who

manages his rosacea as best he can, accepts that he's going to flush

under certain circumstances, and learns to sleep on his back.

On a practical level, if truly none of the medications and treatments

you listed have done anything for you, there may well be other

medical and/or psychological issues. For example, you didn't mention

trying any medications specifically for flushing.

If you're looking for a normal day, forget it -- that's a rumor. No

day is ever normal, for anyone.

Marjorie

Marjorie Lazoff, MD

[Guest guest]

Adam, you're right, many small peptides are vasodilators, there's

nothing special about SP or NO in that regard. But the problem

confronting all researchers is that there's a big difference between

how a peptide impacts local tissues in the lab, and how a medication

that blocks a peptide receptor gets to and impacts local tissue in

the human body. I know you realize that intellectually.

FYI, here are two abstracts from www.biopsychiatry.com. The first

abstract says that MK869 is not being studied anymore; the second

abstract says that centrally acting substance P antagonists (like

MK869 or Zofran) have not been found effective for pain control

(although I don't know if either are the final word):

Substance P antagonists:

novel agents in the treatment of depression

by

Argyropoulos SV, Nutt DJ

Psychopharmacology Unit,

School of Medical Sciences,

University Walk, Bristol BS8 1TD, UK.

spilios.argyropoulos@...

Expert Opin Investig Drugs 2000 Aug; 9(8):1871-1875

ABSTRACT

The field of neuropeptides has been expanding very rapidly in recent

years. Apart from understanding their physiology and elucidating

their functional role as putative neurotransmitters, research has

focused on producing drugs that may treat a variety of illnesses in a

novel way. Substance P antagonists occupy a central role in this area

of intensive scientific activity. Substance P (SP), an undecapeptide,

is abundant both in the periphery and in the CNS, where it is usually

co-localised with one of the classical neurotransmitters, most

commonly serotonin (5-HT). A role for SP is proposed in the

regulation of pain, asthma, psoriasis, inflammatory bowel disease

and, in the CNS, emesis, migraine, schizophrenia, depression and

anxiety. A recently published positive study of MK 869, in

depression, a novel SP antagonist has generated excitement amongst

psychopharmacologists. It is the first time that a drug, not directly

related to monoamine transmitters, has showed efficacy in depression.

Although MK 869 has been suspended from further development, a host

of other compounds, with similar action and better pharmacological

profile, are currently under development. In this review, the

pharmacology of central SP and its receptors are discussed, together

with the exploration of the prospects and implications for future

treatments of depression.

Discovery of the antidepressant and anti-emetic efficacy of substance

P receptor (NK1) antagonists

by

Rupniak NM, Kramer MS

Merck Sharp & Dohme Neuroscience Research Centre,

Harlow, Essex, UK.

nadia_rupniak@...

Trends Pharmacol Sci 1999 Dec;20(12):485-90

ABSTRACT

The development of small-molecule antagonists of the substance P (SP)-

preferring tachykinin NK1 receptor during the past decade represents

an important opportunity to exploit these molecules as novel

therapeutic agents. On the basis of its anatomical localization and

function, SP has been implicated in diverse pathophysiologies; of

these, diseases of the CNS have been examined in the greatest detail.

Although SP is best known as a pain neurotransmitter, it also

controls vomiting and various behavioural, neurochemical and

cardiovascular responses to stress. Recent clinical trials have

confirmed the efficacy of NK1 receptor antagonists to alleviate

depression and emesis but, surprisingly, not pain. Thus, multiple

clinical trials, targeted to appropriate patient populations, are

necessary to define the therapeutic potential of novel

neurotransmitter ligands.

> So in the meantime I'm looking for anything that might make it

> possible to go out and have a normal

> day without my skin flushing as soon as i step outside in the sun,

> or into a warm room, or eat the wrong food, or try to

> exercise, or use the wrong soap etc, and make it possible to sleep

> without tossing and turning all night

> because my cheek hurts too much when pressed up against my

> pillow... "

I'm not going to victimize you, Adam. I'm seeing you as a man who

manages his rosacea as best he can, accepts that he's going to flush

under certain circumstances, and learns to sleep on his back.

On a practical level, if truly none of the medications and treatments

you listed have done anything for you, there may well be other

medical and/or psychological issues. For example, you didn't mention

trying any medications specifically for flushing.

If you're looking for a normal day, forget it -- that's a rumor. No

day is ever normal, for anyone.

Marjorie

Marjorie Lazoff, MD