4 articles: 1 on preventing flush to alcohol, 1 on Clonidine, 2 on Substance P

[Guest guest]

I chanced acrossed an interesting site, and wanted to share some

of the more interesting articles. Sorry if this bores anyone,

but figured just in case someone was interested... I'm curious

though if somebody knows what " Malar Hypothermia " is.. its

mentioned as a side effect of Clonidine and possible reason why

it doesnt always work so great for treating cea flushing, but

did a search for it on the 'net and didnt get a single hit. I

changed the font on each article in case people were skimming

through for one article in particular.

Fonts = Article 1 is Substance P, Article 2 is Substance P,

Article 3 is Clonidine, Article 4 is on Alcohol (its sorta nice

to know there is a way to maybe enjoy a few beers without paying

for it the rest of the night.)

If anyone is interested in the site, here's the link, but I think

these were the four most interesting articles on there.

http://www.angelfire.com/journal2/sadhelp/zofran.htm#1)

Article 1: Wollina U.

The response of erythematous rosacea to ondansetron.

Br J Dermatol. 1999 Mar;140(3):561-2. No abstract available.

PMID: 10233299 [PubMed - indexed for MEDLINE]

" The response of erythematous rosacea to ondansetron "

U. Wollina

Sir, cea is one of the most common chronic dermatoses in

adults. It affects the centrofacial skin and is characterized by

flushing, persistent erythema, telangiectasias, episodes of

inflammation with swelling, papules and pustules. cea is not

restricted to the skin but often affects the eyes, which is of

prognostic importance. An association of rosacea and migraine has

been noted.1 The cause of rosacea is not known, but the basic

abnormality seems to be microcirculatory. The neurotransmitter

substance P and neuropeptide vasoactive intestinal peptide have

been shown to be elevated in a small series of patients. In

rhinophyma, a special type of rosacea, an increase in vasoactive

intestinal peptide receptor-positive dermal cells has been

observed.2, 3

A 56-year-old woman with stage I rosacea with telangiectasias,

persistent oedema and erythema and severe eye involvement was

treated with minocyline 50 mg/day. Topical therapy included 2.0%

metronidazole cream. After a partial remission, the patient

experienced a severe relapse, although she continued the

treatment. In particular, she had severe eye involvement with a

keratitis sicca and a cornea verticillata causing vertigo.

Therefore, we decided to use the serotonin antagonist ondansetron

(Zofran). During 4 days of intravenous therapy with ondansetron,

12 mg/day, the patient showed a tremendous improvement of the eye

involvement and a partial remission of the cutaneous symptoms.

About 2 weeks after treatment, she had a partial relapse, which

promptly responded to oral ondansetron 8 mg twice daily.

Stimulated by this positive observation, a second 46-year old

woman with corticoid-induced erythematous rosacea and lupus

erythematosus was treated with ondansetron, 8 mg orally twice

daily. She had some problems with minocyline-induced

gastrointestinal side-effects and did not respond to topical

metronidazole alone. During a 1-week course of treatment, the

erythema improved markedly, and flushing decreased ( Fig. 1 ).

Treatment was continued with 4 mg twice daily. Both patients

tolerated the treatment very well. No unwanted side-effects were

noted.

Treatment of rosacea is difficult. Topical agents are not as

effective as in acne vulgaris. The systemic therapy of choice is

minocycline for both cutaneous and ocular manifestations. Other

antibiotics are in use. Oral isotretinoin may be appropriate for

severe or therapy-resistant forms, but it has a higher risk of

unwanted side-effects. Sobye's massage is of benefit in

persisting oedemas.1 Ondansetron is a 5-hydroxytryptamine

antagonist used in palliative therapy to prevent or treat

chemotherapy- and vertigo-induced nausea and vomiting that can

also suppress the associated flush.4 It has also been reported

that ondansetron inhibits the carotid chemoreflex, the baroreflex

and the Bezold-Jarisch reflex.5 Some of these effects are related

to an antagonism of ondansetron to substance P.6

In the past decades, several other vasoactive compounds have been

used to block the flushing reaction. Clonidine hydrochloride, an

agent effective in suppressing several types of flushing, was

unable to suppress the induced flushing reaction in rosacea but

caused malar hypothermia. Wilkin7 suggested that the beneficial

effect of clonidine hydrochloride might be related to the

reduction in vascular reactivity. Naloxone blocked the

alcohol-induced flushing reaction in rosacea, suggesting an

active role of endogenous neuropeptides in vascular

hyperreactivity.8 I observed a prompt and substantial response of

persistent erythema and flushing in rosacea to a serotonin 3

receptor antagonist. Although anecdotal, the present paper

provides further evidence for rosacea as a primary vascular

disease and offers a new therapeutic option.

Article 2: FC, Corbally N, D.

Substance P and rosacea.

J Am Acad Dermatol. 1993 Jan;28(1):132-3. No abstract available.

PMID: 7678842 [PubMed - indexed for MEDLINE]

This article is referenced in Dr. Nase's book along with a few

other Substance P developments. He mentioned another doc having

success treating rosacea patients with Zofran. I am most

surprised by the rapid onset of benefits & reported benefits on

ocular rosacea. Constipation is considered the most common side

effect & can be a significant issue for this antiemetic drug.

Another major drawback is a price of $15-$40 a pill in the USA

currently, often less than half this price abroad like at

http://www.canadameds.com (price likely based on lower volume

sales of limited indications & the country's price regulations).

*Cautionary Note About EPS/side effects*

There are much more powerful and specific Substance P antagonists

in development that could prove more effective, tolerable and

certainly affordable. I have heard that Merck's original drug

MK-869 referenced in Dr. Nase's book will be going for the same

market as Zofran while they develop an even more specific, potent

substance P drug for depression, anxiety & pain.

Many drugs don't mention their effects on substance P mainly

because there aren't ones whose primary pharmacological actions

are on it. Maxalt a migraine medication also doesn't mention in

the PDR (like Zofran) effects on substance P but has indicated

in part effects on Substance P under hypothesized mechanisms of

action in research studies.

There are other medications that have similar serotonin 3

receptor antagonist effects as Zofran (indicated as the primary

pharmacological mechanism of action) among their other varied

effects but have not been reported to date to have such a rosacea

& ocular rosacea response so it may be the antagonism of

substance P.

Substance P is better known as a neurotransmitter of pain that is

released by topical analgesic capsaicin creams like Zostrix (made

from hot peppers) which initially cause erythema/vasodilation &

burning sensations as substance P is released from neurons. The

reason it is used as an analgesic (& studied in inflammatory skin

disorders like psoriasis) is because after repeated applications,

substance P is depleted. With antagonists (instead of releasers)

the initial irritating skin effects should not be an issue &

better suited for rosacea.

(Another article is also mentioned available on medline titled

Kurkcuoglu N, Alaybeyi F.

Substance P immunoreactivity in rosacea.

J Am Acad Dermatol. 1991 Oct;25(4):725-6. No abstract available.

PMID: 1724248 [PubMed - indexed for MEDLINE]

but I don't have the full text for it)

Article 3: Arch Dermatol 1983 Mar;119(3):211-4 Related Articles,

Books, LinkOut

Effect of subdepressor clonidine on flushing reactions in

rosacea. Change in malar thermal circulation index during

provoked flushing reactions.

Wilkin JK.

The effects of clonidine hydrochloride, an agent effective in

suppressing other types of flushing reactions, were investigated

in patients with erythematotelangiectatic rosacea. Clonidine

hydrochloride, 0.05 mg, was given orally twice daily for two

weeks. Mean arterial BP was not altered during clonidine

treatment. Flushing reactions provoked with water at 60 degrees

C, red wine, and chocolate were not suppressed during clonidine

treatment. Clonidine did lead to malar hypothermia. It may be

that any treatment benefit obtained from the reduction in

vascular reactivity by clonidine in rosacea is offset by the

malar hypothermia.

Publication Types:

a.. Clinical trial

b.. Controlled clinical trial

PMID: 6218789 [PubMed - indexed for MEDLINE]

Article 4:

8)

Br J Dermatol 1982 Jul;107(1):59-61 Related Articles,

Books, LinkOut

Alcohol-induced rosacea flushing blocked by naloxone.

Bernstein JE, Soltani K.

We evaluated the roles of endogenous opioid peptides and

histamine in the pathophysiology of alcohol-induced facial

flushing in rosacea. Non-diabetic patients with rosacea ingested

360 ml of 6% ethanol after receiving either subcutaneous naloxone

hydrochloride or oral chloropheniramine maleate. Only

pretreatment with naloxone blocked the Alcohol-Induced cea

Flushing (AIRF), suggesting an active role of endogenous

enkephalin and/or endorphin in this vascular reactivity. In this

respect, AIRF is similar to chlorpropamide alcohol flushing and

menopausal flushing.

PMID: 6213251 [PubMed - indexed for MEDLINE]