Propionyl-L-Carnitine Relieves Aching Legs

Take a Walk with Propionyl-L-Carnitine

Propionyl-L-Carnitine
Relieves Aching Legs

Carnitine derivative combats symptoms of
peripheral artery disease, including pain on walking
By Richard P. Huemer, M.D.

I like long walks, especially when they
are taken by people who annoy me.

— Noel Coward

o less an authority than Hippocrates, the father of Western medicine, declared that walking is man’s best medicine. His pronouncement has been echoed through the ages by other great men, including American presidents, such as Thomas Jefferson, who advised, “Walking is the best possible exercise. Habituate yourself to walk very far.” Harry S Truman recommended a two-mile walk every morning before breakfast. Theodore Roosevelt walked softly while carrying a big stick. Lyndon Johnson, who seemed unable to please the press (you’re not alone, GWB), lamented that, if he were to walk on water across the Potomac, the headlines would read, “President Can’t Swim.”

Mere mortals, presidents included, rarely walk on water except in their imaginations. Walking on dry land, however, is commonplace, and even angels do it (we’ve all seen the proof on TV). But some people can walk only very short distances, because their arteries are so clogged. They are the victims of peripheral artery disease, a form of cardiovascular disease.

An Emperor’s Leggy Legacy

Claudius I
Long before there was Medicare, there was claudicare, a Latin verb meaning “to limp” (it’s pronounced clow·dee·CAR·eh). Remember I, Claudius? It was the limp of Emperor Claudius I that spawned the word. From it derives our medical term claudication, meaning limping or lameness. When that condition is due to a walking-related, aching, cramping pain caused by inadequate blood flow to the legs, it’s called intermittent claudication, because the pain comes and goes (it begins after a certain distance but stops when the patient stops and rests). It is a cardinal symptom of peripheral artery disease (PAD).

Underlying most PAD is atherosclerosis, the same artery-clogging condition that afflicts our hearts, brains, and other parts of our bodies. Since atherosclerosis is an equal-opportunity aggressor that does not single out our legs for attack, it’s not surprising that people with PAD are at increased risk of heart attacks and strokes. Nor is it surprising that the risk-reduction strategies for both peripheral artery disease and coronary artery disease are the same, according to the American Heart Association.

The severity of PAD is graded according to stages. Stage I is without symptoms. Intermittent claudication occurs in stage II; as it worsens, the pain progressively limits walking distance to less than 100 meters (slightly more than a football field). In stage III, symptoms occur even at rest, and blood pressure at the ankles falls significantly. Stage IV is characterized by ulcers, gangrene, and amputation.1

Angina of the Legs

Intermittent claudication (IC) is sometimes called angina of the legs. Like angina of the chest, which is usually related to physical exertion and which usually stops when the exertion stops, IC usually signals severely obstructed arteries: the symptoms tend not to appear until a leg artery is about 70% obstructed (in cross section) at some point. Another major culprit in IC is smoking, which can cause severe constriction of the arteries.

The incidence of IC increases with age and certain health conditions: 18% of those over age 70 have it, with a disproportionately higher rate (50–75%) among over-70 smokers and diabetics.1 Shockingly, it is estimated that about three-quarters of the cases remain undiagnosed. (How do they know that? Educated guesswork based on indirect evidence.)

Natural Relief with Propionyl-L-Carnitine

Various drugs are available to treat IC, and some natural remedies are being studied as well. These include the cholesterol-lowering agent policosanol (a group of solid alcohols derived from sugar cane), the amino acid L-arginine, the herb Ginkgo biloba, the antioxidant vitamin C, and the amino acid L-carnitine and two of its derivatives. A deficiency of L-carnitine in our muscles is characteristic in severe cases of PAD. (For more on the carnitines, see the sidebar.)

Carnitinal Knowledge

It’s the vitamin that wasn’t. Once known as vitamin BT, L-carnitine (carnitine for short) turned out not to be a vitamin after all, because our bodies can make adequate amounts of it—under ordinary circumstances, anyway. Sometimes, however, we may need more, so it’s more correctly termed a conditionally essential nutrient.

Carnitine participates in energy production in most of our cells. It transports long-chain fatty acids to the interior of the cells’ mitochondria, where they are used as fuel for energy generation, and it transports some of the metabolic byproducts back out. Aside from the brain, which does not use fatty acids as fuel, this process is important throughout the body, especially in the energy-demanding heart and skeletal muscles.

Not surprisingly, a good natural source of carnitine is the flesh of animals (think “carnal,” from the Latin caro, carn-, flesh), as well as dairy products; with rare exceptions, it is not found in plants in any significant amounts. It can be taken as a nutritional supplement, but it is more commonly taken as its derivatives acetyl-L-carnitine (ALC) or propionyl-L-carnitine (PLC), both of which are excellent sources of the parent compound.

Primarily because of their role in enhancing cellular energy metabolism, the carnitines offer a wide array of health benefits:

Cardiovascular problems? The carnitines are cardiotonic, circulation-enhancing, and kidney-protective. Evidence suggests that PLC, in particular, may be helpful in treating congestive heart failure, angina pectoris, and intermittent claudication. Complementing PLC’s inhibitory effects on homocysteine and endothelin-1 (see article text), ALC lowers triglycerides and raises levels of HDL-cholesterol (the “good cholesterol”), thus striking at the biochemical roots of atherosclerosis.

Erectile dysfunction? In a recent head-to-head trial, PLC and ALC worked as well as or better than testosterone (see “Carnitines—Better than Testosterone for Impotence,” June 2006). If a man’s sperm won’t swim strongly (poor motility), ALC will help energize them. If his penis curves abnormally due to Peyronie’s disease, ALC can help straighten it (see the sidebar “Acetyl-L-Carnitine for Peyronie’s Penis” in “Acetyl-L-Carnitine Protects Cellular Function,” August 2006).

Low disease resistance? ALC activates heat-shock proteins that protect our tissues from a wide variety of stresses (not just heat). In AIDS patients, carnitine improved the ability of immune cells to multiply when challenged with foreign substances.

Not even the brain, despite its lack of dependence on fatty acids for energy, is beyond the reach of carnitine’s benefits. ALC helps slow the progression of Alzheimer’s disease, most likely by reducing oxidative stress, boosting production of glutathione and heat-shock proteins, and providing the acetyl component of two vital brain molecules: acetylcholine and acetyl-coenzyme A. As for the peripheral nerves, ALC’s neuroprotective effect significantly relieved the pain of peripheral neuropathy in many of the diabetics who received it (see the sidebar “ALC Helps Nerve Pain in Diabetes” in “Acetyl L-Carnitine Protects Memory and Intellectual Functions,” August 2005).

European researchers have been studying the use of propionyl-L-carnitine (PLC) for intermittent claudication for some years. A 12-month, multicenter study published in 1999 was designed to identify what categories of claudicants (as the researchers dispassionately called their 485 subjects) would most benefit from PLC, given as 1 g twice daily.2 Those with mild impairment, i.e., relatively long pain-free walking distances, did not benefit, but those who were initially unable to walk as far as 250 meters experienced improved walking distance and quality of life as a result of the treatment.

PLC Helps in Diabetes-Associated PAD

Recently, researchers at the University of Catania in Italy took a closer look at the use of propionyl-L-carnitine in type-2 diabetics with PAD (remember that diabetics are especially prone to this condition).3 In a 12-month, randomized, double-blind trial with 74 patients (average age 62) receiving 2 g/day of PLC or placebo, they evaluated pain-free walking distance (on a treadmill) and ankle/brachial index. The latter is the systolic blood pressure in the higher-reading ankle divided by that in the higher-reading arm. Normally, this ratio should be greater than 0.9, meaning that the ankle pressure is almost as great as the arm pressure; lower values mean severely obstructed blood flow in the legs.


The ankle/brachial index increased
from 0.78 at baseline to 0.88 at 12
months. The pain-free walking
distance increased from 366 meters
to 520 meters over the same period.


The ankle/brachial index in the PLC group increased from 0.78 at baseline to 0.83 at 6 months and 0.88 at 12 months. The pain-free walking distance increased from a baseline value of 366 meters to 442 meters and then 520 meters over the same period. There were no improvements in the control group.

This success with relatively mild cases of PAD is gratifying, but it conflicts with the results of the prior study, in which the mild cases saw no benefit. The discrepancy might have something to do with the fact that the patients in the first study were not diabetic, whereas those in the second study were. Type 2 diabetes is a disease in which oxidative stress due to free radical production is a major factor; thus, the efficacy of an anti-PAD agent may depend more on its antioxidant properties, if any, in cases of diabetes-associated PAD than in cases in the general population.

As it happens, PLC is an antioxidant, a fact that seemed to be confirmed in the second study. The researchers examined four measures of oxidative stress in the patients and found that all of them improved with PLC treatment (the controls showed little or no improvement). They speculated, in fact, that this may be the mechanism by which PLC works to improve intermittent claudication.

When Is an Antioxidant Not an Antioxidant?

Curiously, although propionyl-L-carnitine is an antioxidant, its close chemical relative acetyl-L-carnitine (ALC) can be either an antioxidant or the opposite, a prooxidant—and that has consequences, as we will see in a moment. ALC is a valuable nutritional supplement for promoting enhanced energy metabolism in the mitochondria of our cells, where fuels are “burned” (oxidized) to produce the chemical energy upon which life processes depend. The mitochondria, however, are vulnerable to attack by the free radical byproducts of the oxidation reactions occurring within them—it’s as though they were tiny furnaces made of combustible material.

If it were not for our bodies’ homegrown army of antioxidants protecting our mitochondria, they would be quickly destroyed, and we would quickly die. Fortunately, we do have our own antioxidants, and we can supplement with more. That brings us back to ALC, for which there is recent evidence of antioxidant activity in experimental animals when given in low to moderate amounts. When given in very large amounts to aged rats, however, the evidence shows the opposite: ALC is then a prooxidant—a source of oxidative stress rather than a mitigator of it.

This is further evidence, if any be needed, that physiology is an exceedingly complicated subject, and nothing about it should ever be taken for granted. Reasonable assumptions can always be made by experts in the field, but only hard experimental evidence can tell us how a substance will actually behave under given conditions.

We Are Not Aged Rats, and ALC Is an Antioxidant

Although we are not aged rats, and we don’t take the very large amounts that they got, it’s good to play it safe. To that end, it is recommended that supplemental ALC be accompanied by the potent antioxidant lipoic acid, which eliminates the possibility (however remote) of any prooxidant effect and which brings a host of health benefits of its own to the table. Together, ALC and lipoic acid represent a formidable combination of benefits for mitochondrial function. (For more on this, see “Can Acetyl L-Carnitine and Lipoic Acid Slow the Aging Process?” and “Acetyl L-Carnitine Protects Memory and Intellectual Functions” in the October 2004 and August 2005 issues, respectively.)

In several recent articles on acetyl-L-carnitine in Life Enhancement, it was stated that ALC is not an antioxidant. As indicated above, however, we now know that it is an antioxidant (even though it can also be a prooxidant). For more details on this vexing subject, see the article on page 4 of this issue.

PLC Helps in End-Stage Renal Disease

As mentioned earlier, atherosclerosis in the peripheral arteries implies atherosclerosis elsewhere. One of the worst places to have poor circulation is the kidneys, where it can lead to chronic kidney failure and, ultimately, end-stage renal disease (ESRD). The outcome is death unless the patient goes on hemodialysis (the artificial kidney machine).

ESRD is strongly associated with peripheral artery disease and with cardiovascular disease (CVD) in general; the mortality rate from CVD is high in these patients. ESRD is also associated with elevated levels of two deleterious compounds—the all-around villainous amino acid homocysteine and the potent vasoconstrictor endothelin-1both of which damage blood vessels, promote atherosclerosis, and serve as predictors of CVD. Finally, ESRD is associated with a deficiency of L-carnitine in the blood and muscles.

All this prompted the same Italian research team mentioned above to study the effects of propionyl-L-carnitine on 64 patients (average age 66) with both ESRD and stage II PAD, a frightful combination.4 As part of their hemodialysis regimen, the patients were given 600 mg of PLC or placebo intravenously thrice weekly for 1 year. Measurements of ankle/brachial index and of homocysteine and endothelin-1 levels were made at baseline, 6 months, and 12 months.

As in the authors’ other study, the ankle/brachial index improved progressively in the PLC group, this time from 0.71 to 0.76 to 0.78 (the control group worsened). Plasma levels of homocysteine decreased substantially relative to the control group, but the endothelin-1 levels decreased only slightly relative to control. Thus, PLC proved to have significant positive effects even in this group of doubly afflicted patients.

Clinical Trials and Happy Trails

I hope you’ve enjoyed this little foray into the thicket of recent clinical research, and I’d like to encourage you to get outdoors regularly and do some walking for real—it will do you good. (Even if you don’t care to take my advice, you wouldn’t dispute Hippocrates, Jefferson, etc., would you?) All you need is a healthy pair of legs—and it wouldn’t hurt if you boosted the blood flow to those legs with some propionyl-L-carnitine.

References

  1. Meru AV, Mittra S, Thyagarajan B, Chugh A. Intermittent claudication: an overview. Atherosclerosis 2006;187:221-37.
  2. Brevetti G, Diehm C, Lambert D. European multicenter study on propionyl-L-carnitine in intermittent claudication. J Am Coll Cardiol 1999;34(5): 1618-24.
  3. Signorelli SS, Neri S, Di Pino L, Marchese G, Ferrante M, Oliveri Conti G, Fallico R, Celotta G, Pennisi G, Anzaldi M. Effect of PLC on functional parameters and oxidative profile in type 2 diabetes-associated PAD. Diab Res Clin Pract 2006;72:231-7.
  4. Signorelli SS, Fatuzzo P, Rapisarda F, Neri S, Ferrante M, Oliveri Conti G, Fallico R, Di Pino L, Pennisi G, Celotta G, Anzaldi M. Propionyl-L-carnitine therapy: effects on endothelin-1 and homocysteine levels in patients with peripheral arterial disease and end-stage renal disease. Kidney Blood Press Res 2006;29:100-7.


Dr. Richard P. Huemer received his M.D. from UCLA and did postdoctoral research in cancer immunology at CalTech. He has specialized in orthomolecular medicine for most of his career, has written and lectured extensively on alternative medicine, and has served on the editorial boards of professional journals. His published books include The Roots of Molecular Medicine: A Tribute to Linus Pauling and, with coauthor Jack Challem, The Natural Health Guide to Beating the Supergerms.

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