Thread: arginine: regarding my protein-S defficiency

It's effect on the endothelial function is probably what worries him. Traditionally, some other vasodilators can have a cross reaction with coumadin. To be honest, I don't think we really know since there have been no studies of the two in combination. If anything, its effect would be neutral or it would enhance the blood thinning properties of coumadin. (gingko is one that comes to mind). I don't think he is anti supplement as much as we really don't know what the effect is. I will try to look \it up in the advese directory database. (PS. have you already had a clot from your Protein S deficiency?)

Originally posted by bandaidwoman
It's effect on the endothelial function is probably what worries him. Traditionally, some other vasodilators can have a cross reaction with coumadin. To be honest, I don't think we really know since there have been no studies of the two in combination. If anything, its effect would be neutral or it would enhance the blood thinning properties of coumadin. (gingko is one that comes to mind). I don't think he is anti supplement as much as we really don't know what the effect is. I will try to look \it up in the advese directory database. (PS. have you already had a clot from your Protein S deficiency?)

hey there. thanks for the great reply.
well, he said that he didnt recomend supplementing with AAs in general, continuing onto a tangent about their effect on the kidneys, yadda yadda yadda...

Yes, i have had one. about a year ago, a pulmonary embolism...definitly not a good thing. but im fine now so its cool...im not one to whine

that would be absolutly great if you could do that.
do you think that it would be somewhat safer if I were use it prior to an upcoming pro-time? at least that way if it shoots through the roof they will know to take me off of it right away.

It's main effect is if you already have bad kidneys, it causes hyperphospatemia. Interesting, it seems to protect kidneys from damage by cyclosporine (a kidney toxic drug used for many diseaseses such as Lupus, cancer etc) by increasing the flow of blood via the renal arteries to the kidneys.

It is also the least toxic of the amino acids, the below shows the safe dosing guidelines.

Additionally, arginine has very low toxicity. Doses of 0.5 grams per kilogram up to 30 grams total given within 20 to 30 minutes has caused no untoward reactions and is considered safe. Patients diagnosed with renal or hepatic insufficiency and those with insulin-dependent diabetes should avoid large doses of arginine, or be medically monitored. Normal persons can tolerate 30 to 60 grams per day arginine. While food-source arginine is necessary for growth in children, free-form L-arginine is not recommended for anyone under the age of 23.

Originally posted by sentricyphen

that would be absolutly great if you could do that.
do you think that it would be somewhat safer if I were use it prior to an upcoming pro-time? at least that way if it shoots through the roof they will know to take me off of it right away.

Anytime a physician is not sure of the effect of a drug on coumadin, the rule of thumb is to check the PT 1 week after starting it then another one 2 weeks after. If the PT/INR remains the same, then you can resume the q 4 week schedule on the one condition that the dose is not increased.

By the way you may want to start talking to him about the new oral anticoagulant that does not require pt monitoring and has fewer drug interactions: Ximelagatran.

Ximelagatran is termed a "direct thrombin inhibitor" because it slows the coagulation cascade by directly binding to thrombin, a clotting factor essential in the clotting process. If thrombin is blocked, clot formation is delayed (as with warfarin).

Does ximelagatran work differently than warfarin and what does this mean clinically?

Warfarin and ximelagatran both delay clot formation, but they do so in different ways. Warfarin binds to different clotting factors (II, VII, IX, X) within the coagulation cascade to delay the formation of a clot. A major difference between the two medications is the following: warfarin is prevented from working vitamin K and ximelagatran is not.erefore, ximelagatran is not affected by changes in vitamin K intake from diet or medications.le that are currently taking warfarin, will quickly recognize how this small difference may affect their lifestyle. erson may no longer have to be concerned about bleeding or clotting based upon changes in their diet or vitamin consumption.

What type of monitoring is involved?

According to current studies and manufacturer data,melagatran will not involve coagulation monitoring (INR/PT).ike with warfarin, dosing and patient response may be more predictable with ximelagatran. Dose proportionality studies have shown that changes in drug dose produce predictable and consistent changes of drug levels in the blood. Therefore, it is expected that ximelagatran may have one dose that is effective for most patients without the variability in dosing that is seen with warfarin.

What drugs interact with ximelagatran?

Manufacturers state that there are "no known pharmacokinetic drug interactions with ximelagatran." Pharmacokinetics is the study of "what the body does to the drug." This process often involves absorption, distribution to tissues, metabolism, and elimination of drugs. The majority of the drug interactions observed with warfarin are due to changes in distribution and/or metabolism as a result of concurrent and often times conflicting drug therapy. Ximelagatran has different drug properties than warfarin that make it less likely to interfere with other medications in this way. Potential drug interactions could include those seen between anticoagulants and other medications that may cause or worsen bleeding effects (such as aspirin or ibuprofen). this point, drug interaction data is still limited but ximelagatran may be better than warfarin in this regard. Note this point well - if there is a drug that may cause bleeding on its own, it will still be likely that it cannot be used with ximelagatran.

How effective is ximelagatran?

Clinical trials are still ongoing, but finalized studies indicate that ximelagatran is at least as effective as warfarin and enoxaparin (Lovenox®) when studied for short-term use following total knee and total hip arthroplasty (replacement), respectively. These two orthopedic studies demonstrated ximelagatran efficacy for the prevention of venous thromboembolism such as deep vein thrombosis or pulmonary embolism (clots in legs or lungs, respectively) that was comparable to that observed with traditional agents such as warfarin and enoxaparin.

Long term studies to evaluate the use of ximelagatran in deep vein thrombosis (DVT) treatment, atrial fibrillation (irregular heartbeat), and arterial conditions (following a heart attack) have recently been completed and published. These studies are often given catchy names so that they can be easily referred to. When a study is published in a reputable medical journal, it has undergone scrutiny by peers of the authors to weed out false reports and conclusions.

THRIVE III evaluated the safety and efficacy of ximelagatran for secondary prevention of venous thromboembolism (VTE) in over 1200 patients with documented deep vein thrombosis (DVT) or pulmonary embolism (PE). After 6 months of standard anticoagulation therapy, the patients were randomized to receive either 24 mg of ximelagatran or placebo twice daily for an additional 18 months. In the ximelagatran group, a significantly lower number of patients suffered a confirmed secondary thromboembolic event (VTE) than in the placebo group (2.8% vs. 12.6%). Both groups had similar rates of major bleeding events (less than 1%). The use of vitamin K antagonists, such as warfarin, is associated with an annual major bleeding event risk of 3 – 4%. The researchers concluded that long-term treatment with ximelagatran, without dose adjustment or monitoring of coagulation, is safe and effective in reducing the incidence of recurrent venous thrombosis.

EXULT A compared the safety and efficacy of two different fixed doses of ximelagatran with warfarin in prevention of DVT after total knee replacement. Over 2300 patients were randomly assigned to receive either ximelagatran 24 mg twice daily, 36 mg twice daily, or warfarin adjusted to an INR of 2.5 for 7 – 12 days post surgery. When the study endpoints of DVT, PE, and all-cause mortality were combined, ximelagatran 36mg twice daily proved to be significantly more effective than warfarin, but when each endpoint was evaluated separately, there was no significant difference in safety or efficacy between any of the treatment groups. The study authors concluded that fixed dose ximelagatran, 36 mg twice daily administered without coagulation monitoring, is significantly more effective than warfarin and has a similar incidence of bleeding.

SPORTIF V compared ximelagatran 36 mg twice daily with warfarin adjusted to a target INR of 2.0 to 3.0 in 3922 patients with nonvalvular atrial fibrillation (AF) and one other stroke risk factor (age 75 or older, previous stroke, or history of hypertension or congestive heart failure). Ximelagatran was shown to be "noninferior" to dose-adjusted warfarin in the prevention of all strokes and systemic embolic events. There was no significant difference in rates of major bleeding or intracerebral hemorrhage between the treatment groups. However, when all bleeding was considered ximelagatran did have a lower rate of major and minor bleeding compared to warfarin.

There have been no studies on the safety and efficacy of ximelagatran use for patients with mechanical heart valves or clotting factor abnormalities.



How safe is ximelagatran and what side effects are possible?

The most common and expected side effect from ximelagatran (and any other anticoagulant) is bleeding. Clinical trials indicate that the bleeding risk associated with ximelagatran is comparable to that of traditional anticoagulants (warfarin and enoxaparin) and is not statistically better or worse than either tested medication. However, bleeding and safety issues will always be a concern for patients on anticoagulant medications.

Elevations in liver enzymes (as high three times normal - that is the level when they start to become worrisome) have been seen in up to 6% of the patients in the first two to six months of treatment with ximelagatran. In most of the patients, enzyme levels returned to normal whether or not ximelagatran was discontinued. Since the significance of this effect on liver enzymes cannot be adequately evaluated until after the drug is released and used in a wider patient population, routine monitoring of liver enzymes would be prudent during the first months of treatment.

When will ximelagatran be available in the United States?

An expected date of arrival on the U.S. drug market is unknown, since it has not yet been submitted to the FDA for approval (as of Nov. 2003).

Phase III clinical trial results have recently been published in the United States and the manufacturer hopes to submit the application for approval to the FDA by the first of 2004. Application for approval of both the injectable (melagatran) and oral (ximelagatran) dosage forms was submitted in Europe in July 2002 (not yet approved), but it is expected that only the oral dosage form will be submitted for approval in the USA. If approved, it may be available in late 2004.

Why would a person want to switch from warfarin to ximelagatran when it becomes available?

A patient may want to switch to ximelagatran from warfarin for the following reasons (based on current data):

No coagulation monitoring (INR measurements)
Fewer drug/food interactions
Similar efficacy and safety to warfarin (so far)
Better overall quality of life for many patients (due to less monitoring and interactions)
Reduced costs from lab tests and visits related to coagulation monitoring
Why might a person NOT want to switch from warfarin to ximelagatran?

A patient needs to keep the following issues in mind when considering a switch from warfarin to ximelagatran:

Limited long-term data to support ximelagatran use
- Longest clinical trails have lasted only 18 months.

Expensive cost of the medication compared to generic warfarin
Compliance issues
-Less monitoring and fewer clinic visits may translate (for some patients) into thoughts that the drug is very safe and that missed doses are not harmful (when this can actually be very dangerous).

-Twice daily dosing increases potential to miss doses. Since no monitoring is required, the first indication that a patient is non-compliant could be a serious clotting episode.

Potential loss of relations with anti-coagulation provider
-From my experience as a pharmacy student in Al Lodwick’s clinic, I have found that patients come into the clinic for the following reasons: to have their INR measured for warfarin management and to visit with Al.

-Many patients have developed great relationships with their anti-coagulation providers and the loss of monthly visits is certainly a consideration for many patients that may want to switch medications.

Overall patient care may suffer from fewer clinic visits
-More frequent provider visits (of any kind) have been shown to play a critical role in preventive healthcare by detecting problems early for better treatment outcomes. Anti-coagulation providers not only give advice about warfarin, but about all types of health conditions and medications (since they are trained healthcare professionals).

Safety data is not fully established
-Hesitation and caution need to accompany any anticoagulant therapy changes because of the risk of bleeding or clotting that can result.

- Liver enzyme elevations seen in a small percentage of the patients in the longer term studies may or may not prove to be significant once the drug is released for general use. Patients selected for clinical trial are very carefully screened before being chosen for the study. Once a drug is released for uncontrolled prescribing by the medical community, minor or transient adverse effects may prove to be a major problem. More than one new drug has had to be recalled because of adverse effects that were not seen until after they were being prescribed for the general patient population.

There is no known reversal agent (antidote) for ximelagatran so far
-If a patient consumes too much warfarin and providers worry about excessive bleeding, injectable or oral vitamin K can be given to reverse the effects of the warfarin

-Ximelagatran does not stay in the body nearly as long as warfarin so this may not be as much of a concern (because it will be eliminated from the body much faster anyway).

I highlighted the significant ones. As you can see, it was studied in those with pulmonary embolisms but not in those with blood clottng abnormalities such as your Protein S deficiency....but don't worry, they are coming down the pipeline.

Originally posted by bandaidwoman
Anytime a physician is not sure of the effect of a drug on coumadin, the rule of thumb is to check the PT 1 week after starting it then another one 2 weeks after. If the PT/INR remains the same, then you can resume the q 4 week schedule on the one condition that the dose is not increased.

By the way you may want to start talking to him about the new oral anticoagulant that does not require pt monitoring and has fewer drug interactions: Ximelagatran.





I highlighted the significant ones. As you can see, it was studied in those with pulmonary embolisms but not in those with blood clottng abnormalities such as your Protein S deficiency....but don't worry, they are coming down the pipeline.

wow it sounds very interesting. i have always wanted to supplement with more omega 3's, espcially fish oil. ximelagatran apparently would allow that.

also its good to know that they havent come across any know antidotes. thats the main problem w/warfarin, regarding v.K & E.

THe other suprising thing is that it prevents clots without actualy thining the blood. When on warfarin, If someone were to get into a car accident, they could very well bleed to death.

one thing im am wondering about is, it said that it is not recommended for those under the age of 23 to use arginine?
Is that much precaution actually neccesary? I'm 20 BTW.

and do you know if the fda has approved it yet? says in the article that it hadnt been ,as of nov '03.

definitly something to ask my doc.

BTW, im surprised that you specifically knew about protein-S, what field are you in?

Originally posted by sentricyphen
and do you know if the fda has approved it yet? says in the article that it hadnt been ,as of nov '03.

definitly something to ask my doc.

BTW, im surprised that you specifically knew about protein-S, what field are you in?

I think the caution about argine use in those less than 23 years of age is due to the fact that studies weren't done in that age group and also its effect on growth hormone release and may be problematic in an age when you are at maximum gh release.

Internal medicine......the only difference between a hematologist and internist is 1 year of training. Protien S, C, defiency and antithrombin III def as well as Factor V workup is standard for any young person with clotting problems. It's also standard textbook workup for anyone with PE among any of the nonsurgical fields. So it really is common knowledge among alot of practicioners wether it's family practice, pediatrics, Internal medicine, pulmonology and cardiology. No biggy.

As for FDA approval, it was just submitted in december of 2003. You can keep track of its approval http://www.astrazeneca.com/pressrelease/1096.aspx