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

[Guest guest]

Adam, malar is the center area of the face -- fleshy portion of

cheeks and the nose area between them. Hypothermia is lower-than-

normal temperature.

I know you're extremely hopeful, Adam, but be skeptical when reading

letters and studies from more than 1-2 ago in areas of active

research. Again, much of the clinical work hypothesized hasn't panned

out as hoped. (When work doesn't pan out it is rarely published, so

silence says a lot in an active area of research.)

Marjorie

Marjorie Lazoff, MD

> 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]

>

>

>