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Raynauds - New Treatment for Raynaud's Disease, Secondary to CREST Syndrome

New Treatment for Raynaud's Disease, Secondary to CREST Syndrome

Introduction

The following is an account of successful surgical treatment of Raynaud's written in August 1996 and sent to us by Roger Ison, r_ison@manticsoft.com son of a Raynaud' patient with CREST Syndrome.

Abstract

My mother, an elderly patient with Raynaud's disease as a complication of the CREST form of tissue sclerosis, has been treated very successfully for more than a year with a combination of L-arginine and piracetam. piracetam is widely available in Europe but not approved for use in the United States. This treatment was adopted after several years during which standard American treatments failed to prevent recurring, severe Raynaud's crises and gangrene. The case is being followed by her internist, a university medical center physician. Although it is hard to be certain, the treatment described appears so far to be remarkably free of side effects. This article describes her experience and provides literature references.

Readers unfamiliar with this disease should note that there are at least two forms of Raynaud's condition: primary (when it appears with no other symptoms) and secondary (as in the case described here, resulting from disease of the connective and vascular tissues). I suggest a variation of the treatment for people with primary Raynaud's; however, I have no direct experience with primary Raynaud's to report. This is discussed at the end of the article.

Case History & Standard Treatments That Were Tried

My mother was diagnosed some years ago with CREST. (This report is being posted with her permission.) CREST, a poorly understood syndrome, seems to be a limited form of scleroderma characterized by these symptoms:

  • C = calcinosis, lumpy calcium deposits in the skin and other tissues.
  • R = Raynaud's syndrome or disease. The blood vessels supplying the hands close spasmodically in response to cold temperatures and emotional stress. The fingers turn blue or white, and severe episodes can result in loss of the fingers due to gangrene.
  • E = esophagitis, dysfunction of the swallowing mechanisms of the esophagus.
  • S = sclerodactyly, hardening and wasting of the muscle tissue of the hands, particularly the fingers.
  • T = telangectasias, the appearance of blotchy red capillary proliferations under the skin on various parts of the body.

CREST is a serious disease which can be very difficult to manage. In addition to the points above, the disease seems to cause chronic high blood pressure, probably by reducing the flexibility of the blood vessels.

In my mother's case, the disease has been characterized mostly by Raynaud's and sclerodactyly. The hardening and wasting of the finger tissue causes some complications of its own. Blood flow is impeded by distortions of the capillaries, and the skin becomes very thin, so there's a tendency to get small, infected ulcers that don't heal properly. These heal slowly when treated with antibiotics.

Raynaud's has been the worst part of the problem. Any exposure to cold caused the blood vessels to her fingers to "shut down" for long periods of time - hours to days. Blood flow was not responsive to warming. Sleeping was painful since body and hand temperatures drop at night. Ultimately she lost two fingertips in three episodes of gangrene, an incredibly painful process physically and emotionally, that took months each time.

pretty much all the standard American treatments were tried including:

  • Calcium channel blockers. The goal with these drugs is to dilate the blood vessels. There are three main groups of calcium channel blocking drugs. We tried them all. They not only didn't work, but she had rather bad physical reactions to some of them. I suspect that these drugs may actually exacerbate Raynaud's in CREST patients; see below.
  • Nitroglycerine paste applied to the fingers. This is a localized way to dilate the capillaries, similarly to its use in treating heart disease. It worked a little bit for my mother, but caused the delicate, stretched skin to burn and she couldn't tolerate it. In any case it was not particularly effective.
  • Surgery to cut the nerve that enervates the blood vessel muscle contractions. Not successful in preventing gangrene once an episode began.
  • Amputation of diseased tissue, with grafting (one time the graft took, once it didn't work).

What Led Me To The Treatment Discussed Here

During the third Raynaud's crisis (each was more severe than the one before), it became clear the doctors didn't have any ideas that would work, despite the fact that Mom was being treated at a major university medical center.

I am lucky to have as a friend, a well known biophysicist who did pioneering research in the cellular role of calcium. Since CREST causes calcium deposits in strange places, and since calcium channel blockers are used to dilate blood vessels, I asked him if he had any ideas. I am not giving his name simply as a matter of privacy. He's not a medical researcher, and I don't want him inundated with e-mail on this subject.

He said, "Well, if I were researching this, I'd probably start with nitric oxide (NO). NO has been identified in the past few years as an important neurotransmitter. In fact, for a long time we didn't understand why nitroglycerine helps people with heart disease. But it turns out that one breakdown product of nitroglycerine is NO, and it acts as a nerve signal transmitter that causes the blood vessels supplying the heart to dilate."

He went on to describe the activation sequence: calcium ions enter a cell, interact with a protein called calmodulin, which eventually activates cGMp and NO-synthase, finally creating NO by acting on another substrate, the amino acid L-arginine.

That description got me into the scientific literature, and there is a lot of it. I learned many interesting things. For instance, the molecular "pore" or receptor that passes calcium into cells in the heart is produced from the same gene that produces the calcium pores for the "vascular bed" tissue. The pores in these two tissues differ only slightly as a result of post-RNA splicing.

I then asked quite a few pharmacologists why blocking calcium's entry into cells is a good strategy, if calcium is needed to activate calmodulin and eventually produce NO. Frankly, I never got a consistent answer despite discussing the question with some very prominent pharmacologists who specialize in NO research. I do not believe I misunderstood their explanations, they simply didn't know or didn't agree exactly. If anybody can explain it to me IN DETAIL, I'd appreciate it. Somebody must know the answer to this question by now.

We decided to stop the calcium blockers since they were not helping my mother's Raynaud's problem, made her feel ill, didn't reduce her blood pressure much, caused extreme swelling in her feet and legs, and had this interesting molecular issue which made me suspect these drugs might not act in capillaries the same way they do on larger blood vessels.

The obvious things to look for, then, were ways to improve the calcium to NO pathway. You can't mess with people's calcium levels safely. There are NO donor drugs, but they are obscure, short-acting and possibly not safe. So, what about increasing the amount of argenine substrate perhaps that would produce more NO.

Bingo Number One

See "L-Argenine therapy in Raynaud's phenomenon", in Int. J. Clin. Lab. Res. 21:202-203, 1991 by Angelo Agostoni et al. at the University of Milan. Their introduction:

"Some experimental evidence has suggested that an impairment of nitric oxide production in damaged or L-arginine-depleted endothelial cells might be responsible for abnormalities in vascular reactivity. The proposed role for L-arginine, the substrate for nitric oxide synthesis by vascular endothelial cells, in peripheral vasodilation prompted us to study the effect of L-arginine treatment on the digital vascular response to local stimuli in patients with Raynaud's disease."

These Italians had already had the same idea, and they'd actually tried it in a VERY SMALL study, carefully measuring the capillary blood flow with sensitive instruments. They reported very positive results and one surprising observation.

L-argenine is always present in quite high levels in the human metabolism. It's a pretty basic substance. So they gave 12 patients (5 with primary Raynaud's an 7 with systemic sclerosis-related Raynaud's) large doses of L-argenine: 4 grams twice daily. The paper does not indicate how this dosage level was chosen. These patients had no arterial hypertension and no renal failure. The results:

"pre-treatment warming of the test hand resulted in vasodilation in all patients. Warming after L-argenine treatment produced a further increase in digital pulse amplitude, significant only in patients with systemic sclerosis. Moreover, in these patients, but not in those with primary Raynaud's phenomenon, hand cooling resulted in digital vasodilation after L-argenine treatment. plasma levels of natural t-pA significantly increased after therapy in secondary patients, but not in primary patients. Heart rate and blood pressure remained unchanged."

In other words, not only did warming cause the blood vessels to dilate, as you'd expect naturally, but so did cooling! but only in patients with secondary Raynaud's. The authors hypothesize that in normal tissue, the level of argenine is already as high as it can usefully be. This suggests argenine may not be particularly useful for patients who only have primary Raynaud's.

Related to this, T. Nakaki et al reported in Lancet, 1990, 336:696 on "L-argenine-induced hypotension", and a follow-up note in Lancet, 1991, 337:684. These researchers do find that enough L-argenine can reduce blood pressure. This result could be considered at odds with the Italian report, but the Italians were working with humans, not test animals, so they didn't try huge doses.

The point is: it should not be assumed that large doses of L-argenine are totally benign.

Also, D-argenine probably doesn't work. It requires the left-handed isomer, L-argenine.

We also considered recombinant t-pA treatment. There is at least one report of systemic sclerosis being suddenly and dramatically reversed after an incidental use of t-pA; but we thought this obviously too dangerous. Recombinant t-pA is used to treat blood clots in heart attack or stroke, but it is so powerful that patients can, in effect, "leak blood" into dangerous places. Like, cerebral hemorrhage. Not a good choice if you're not dying already, and CREST patients seem to have fragile blood vessels. Certainly not appropriate for gangrene of the fingertips. In any case t-pA can't be used on a continuous basis to prevent clot formation. Many so-called "blood thinners" such as warfarin have similar, though less extreme, risks.

So part one of the treatment we developed for my mother is: 4 grams of L-argenine powder, twice daily--the same dose the Italian study used. This powder is available as a "nutrition supplement". It dissolves readily in orange juice and doesn't have much taste in the juice. 4 grams is quite a lot, it must be purchased as powder. Swallowing that much in capsules would be difficult, especially if the patient has esophagitis as is commonly the case in CREST and scleroderma.

Bingo Number Two

Bingo number two was found the old-fashioned way: looking for treatments of Raynaud's in recent medical literature.

"Treatment of the Raynaud's phenomenon with piracetam", by M. Moriau et al in Arnzeim.-Forsch / Drug Research 1993, 43(1), Nr. 5. professor Moriau is at the Catholic University of Louvain in Belgium.

prof. Moriau did not answer letters, even polite ones with introductions in French, and does not use e-mail. I did not try to contact the co-authors.

piracetam, marketed as Nootropil and a number of other brand names, is a standard and in fact fairly old drug in Europe. Its primary use has been to treat vascular blockage in stroke and heart attack. However, as I will explain later, it has a large number of additional applications. It is found, in Europe, have very few side effects.

piracetam is a "rheological" agent. It affects blood flow by making blood cell membranes more flexible, reduces platelet aggregation, and increases clotting time. All three effects are key to its success in treating Raynaud's. By making the blood cells more flexible, piracetam enables them to wiggle through the distorted capillaries associated with hardened tissue in scleroderma, as well as letting them slip through constrictions induced by Raynaud's. When blood flow is blocked, the blood tends to clot, which is probably a significant factor in producing gangrene; even if you can get the vessels to relax, once, they're blocked, you get tissue death. That is why nitroglycerine alone is helpful but ultimately not very successful. So logically, piracetam has all the right properties.

The drug also increases prostaglandin I2 and inhibits thromboxane A2. So it should increase clotting time. This would imply some risk of bleeding problems. For instance, a hemorrhage might be hard to stop. But see comments below about our experience with hip replacement surgery.

Moriau's paper shows piracetam is effective for primary and secondary Raynaud's. He describes three sequential, complementary studies of 20, 58, and 30 patients with primary and secondary Raynaud's. It is a long article that should be read carefully.

The experiments Moriau describes tried various doses: 4, 8 and 12 grams of piracetam daily. 4 grams helps a lot, 8 is even better, and 12 is not really better than 8. The paper compares piracetam treatment to four other standard treatments, including calcium channel blockers. piracetam is the clear winner. And as the paper concludes, "In addition, the administration of piracetam appears to be devoided sic of adverse effects."

8 grams daily is a considerably larger dose of piracetam than is normally used by European physicians to treat blood clots in the brain.

To shorten this story, my mother's doctor read the papers, accepted the proposed treatment (although she could not prescribe it or be directly responsible for it), and agreed to follow Mom's blood chemistry carefully. We got some piracetam from France. And it has produced truly dramatic, visible results. Before trying this drug, my mother's hands were gray and cold all the time. In a very short time, they became warm and pink. Her brother, also a physician, could hardly believe the improvement - it is so apparent to the "naked eye".

She has now been using the combination of piracetam and L-arginine for more than a year, and has had no episodes of gangrene. Occasionally one finger or another will turn blue, but putting her hands in a bowl of warm water is generally sufficient to stop Raynaud's attacks quickly. She is less sensitive to winter temperatures. Even when a crisis goes on for a day or so, her finger tips don't get white and then clot.

The incidence of ulcers on her fingers also seems to have decreased significantly. And her blood pressure problem has been relatively manageable, with diuretics instead of calcium channel antagonists. The orange juice twice daily probably helps keep her potassium electrolyte balanced despite the use of diuretic medication.

This summer, she has cut back the piracetam to 6 grams daily (the stuff is expensive), but will return to 8 grams in cold weather.

Since this report was first written, my mother fell in a restaurant and broke her hip. The hip was replaced with an artificial joint. There was an initial concern that surgery might be very risky due to excess bleeding caused by the high doses of piracetam. But direct clotting time tests showed her clotting time to be simply at the high end of the normal range. Moreover, the half-life of piracetam in the blood is about 6 hours. Most of the drug is excreted quickly, unchanged, in the urine. The hip surgery was performed successfully on an emergency basis in a community hospital, and she has continued taking piracetam and argenine essentially without interruption.

Also, I have recently learned that she cut her L-argenine dosage in half. It may be increased again during the winter--we'll have to see how it works. It does appear that piracetam is the more important component of the treatment. The argenine is mainly to improve circulatory response to warming the hands.

Issues in the Use of piracetam

It appears the FDA doesn't much like piracetam or L-argenine. I discussed this treatment at length with an FDA drug safety officer before we tried it. This officer was knowledgeable, very helpful, open and friendly - quite unlike the FDA's bad-guy reputation. It seems that both these drugs are so-called "smart drugs". Some people take them because they are believed to increase intelligence! In fact, the marketing name Nootropil comes from "nootropic", meaning a drug that makes you smarter.

FDA evidently feels the smart-drug reputation is likely to lead to substance abuse. Some people import piracetam for treatment of Alzheimer's disease, for which it is probably useless.

The smart drug literature I found is unimpressive--lots of assertions, very little science. I rather doubt these "nootropic" assertions since the drug is rapidly and thoroughly excreted unchanged (so it wouldn't be much use blocking receptor sites), and it looks a rather small a molecule to act as an enzyme.

On the other hand, its characterization as a smart drug may be not totally unfounded: if a patient has restricted blood vessels in the brain, piracetam could increase blood flow substantially. It is used specifically to treat stroke.

piracetam is also used by European mountain climbers because it reduces the incidence and problems associated with frostbite. The drug seems to be regarded in Europe as quite safe, though there is little experience at these high dosage levels.

Cost & Sources Of piracetam

piracetam can be purchased from ordinary, legitimate pharmaceutical suppliers in various countries for prices ranging from $300 (France) to $600 (Switzerland) to $800 (Belgium via Canada from UCB pharma, a drug manufacturer) for a 3-month treatment at 8 grams per day. There appear to be numerous manufacturers, and piracetam looks like it should be easy to synthesize. It ought to be cheap. The sad fact seems to be that manufacturers charge the maximum each country will allow.

If you prowl the Web, you'll pretty quickly find some suppliers, some of them probably disreputable. There are even illegal importers who bring piracetam powder into the USA and distribute it in capsules. You'd have to be nuts to buy from them; you'd have no idea what you're really getting.

please don't write to ask the supplier we use; our family is fortunate to have a branch in France, and a French physician helped out with a prescription honored by a French pharmacy. You'll have to find your own supplier, I'm afraid.

Although piracetam is not approved for use in the United States, there is an FDA policy ("pilot guidance for the release of mail importation", 20 July 1988) that allows individuals to import up to 3 months' supply at a time for use under a physician's supervision. This policy was originally put in place for AIDS patients. Essentially, it allows the patient, not the physician, to import the drug. It's a contorted policy. physicians in the USA aren't supposed to prescribe unapproved drugs; so YOU have to import the medication, and YOU assert that the named physician is caring for you.

You can get a copy of the pilot guidance document from the FDA in Maryland. Essentially this document states that the patient must supply a statement of intended use, show that the quantity imported is reasonable (3 month supply or less) and not for resale, and affirm that the importation is for personal use under care of a physician who must be named. All this must be in writing, and it is supposed to get medications through customs unless the supplier is on an FDA blacklist, or the substance being imported is specifically prohibited for some reason (e.g., an illegal narcotic).

The FDA officer, mentioned above, told me that piracetam or its combination with L-argenine could also be submitted by the physician as an "IND" or investigational new drug. Then, it is essentially an approved drug for the particular patient and protocol, and it would zip right through customs with its IND number. He was fascinated with the application, and even sent me the paperwork. But it takes 84 hours (FDA estimate) to fill out the forms, you need to provide literature references, and for a real experiment one would like to set it up with a group of patients, and get the experiment funded. So far we have not been able to get this done. It's too time consuming for our doctor, and anyway there is a workable way to get the medication.

Nonetheless, I really feel a US-based experiment should be done so piracetam could be imported for this application. Every physician I know who's read the Moriau paper has been impressed. There is a rheological medication available in the US ("Trental"), but piracetam is reported to be better, with fewer side effects.

Is there an ambitious medical student out there

In Summary, Cautions

Do not use an unapproved medication, especially at high dosage levels, without a doctor to follow the case closely and regularly; at minimum have regular blood chemistry workups to make sure kidney and liver function, and electrolytes, remain normal.

It is impossible to be certain there are no adverse side-effects of this treatment. patients with CREST, including the case described here, have peculiar symptoms and conditions that could mask drug effects or make them difficult to recognize.

My mother has developed a tremor in one hand that becomes more pronounced when she is very tired. We do not know the cause; it could simply be "essential tremor", or it could be a drug effect (although it would be surprising for such an effect to be confined to one hand), or it could have an entirely unrelated cause.

piracetam or L-argenine may have long-term consequences that have not been identified. There may even be short-term effects that are important but have not been identified. Different people may be affected in different ways. These are all dangers that must be weighed BY A pHYSICIAN against the seriousness of the patient's disease.

We obtained a poison center report on piracetam which mentions that the drug can cause irritability, depression, and insomnia. This is the only reference I have seen to these effects, but obviously the poison center got its information from some published report. These are relatively subjective conditions, hard to pin down or quantify when they're subtle.

All I can really report is that the combination of 4 grams L-arginine 2x daily, plus 8 grams piracetam divided into 3 daily doses (ie, 8/3 gram 3x daily), appears to have been very helpful for my mother. Not a cure, but an effective treatment that appears to substantially reduce the severity of Raynaud's disease secondary to CREST. It seems to be possible to reduce the dosages in warm weather.

For primary Raynaud's, it is not clear whether L-argenine is helpful or not. Based on the Italian study, I would use only piracetam. On the other hand, Nakaki reports L-arginine lowering blood pressure, which could be caused by vasodilation. I have heard of one woman, a nurse with primary Raynaud's, who tried L-argenine after hearing my mother's story; this nurse believes L-argenine helps her. I'm happy for her, but it's not clear the literature justifies her experiment.

I have not followed the literature on this subject for about a year. There may be more recent, relevant publications that I have not seen.

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