Pink Magic Heart Concerns – Should I Be Worried?

There have been some concerns lately on the BB.com forums regarding potential toxicity in one of Pink Magic’s ingredients, and how it could negatively affect the heart. The ingredient in question is Rhamnus Nakaharai.

Although these concerns are troubling at first, once you look into the details of the situation, they are easily dismissed. Let’s dig in – things are going to get a bit technical here, but we’ll keep it general at first.

First, the concerns:

“The third ingredient in Pink Magic [Rhamnus Nakaharai], the PDE Inhibitor here is: ’3-O-methylquercetin 5,7,3′,4′-O-tetraacetate’

It should be noted that it is suggested that you do NOT take a PDE3 inhibitor for any extended period of time and its pharmacological uses are limited, due to the fact that PDE3A controls heart contractillity.

In fact, research on PDE3 inhibitors for treating heart conditions has pretty much ceased because the stuff they tried led to increased mortality rates

PDE3A inhibition during development also reduces fertility. (obvious warning sign if your endocrine system is still developing)

PDE4 also has effects on heart contractillity, and inhibitors of PDE4 are also avoided for their cardiac side effects, with the exception of some acute dosing medicines for cardiac failure and asthma.”

Essentially, Rhamnus Nakaharai’s active ingredient is a PDE inhibitor (Phosphodiesterase inhibitor). cAMP-dependent PDE inhibitors cause cardiac stimulation, which increases cardiac output, and reduced systemic vascular resistance, which tends to lower arterial pressure. At normal therapeutic doses, PDE3 inhibitors have a greater vascular than cardiac effect so that arterial pressure is lowered in the presence of augmented cardiac output.

This is actually no surprise to anyone taking Pink Magic – you do become more vascular when on it! The question is, are these PDE3 inhibitors bad for your hearts in healthy, active people taking Pink Magic?

Currently, there are no studies indicating that Rhamnus Nakaharai (and the other plants in Pink Magic) are toxic in normal humans. Animal model studies indicate no such toxicity either!

There is a long history of safe consumption in food preparations and medicines with these plants – bodies are not piling up. What you are being subjected to is “FUD” spread by other supplement companies – Fear, Uncertainty, and Doubt.

Now let us go into the gory details to prove it:

USP Labs is aware of the implications of PDE3A with respects to potential myocardial damage to those with significant heart issues. However, it is not a significant issue, just as it isn’t with caffeine. Yes, there is “potential” for cardiac damage from anything that increases catecholamine (specifically epinephrine and/or norepinephrine) levels. This is the case for safe compounds such as caffeine, ephedrine, yohimbine, or any sympathomimetic!

So, while a “risk” is there, the risk for toxicity needs to be put into perspective. The PDE inhibitor we’re worried about here (Milrinone) is selective to the 3A subtype has been shown to possess far less cardiotoxicity as compared to norepinephrine and epinephrine themselves – which are of our own biological processes! That alone casts doubt on the concerns for Pink Magic’s ingredients to cause any significant myocardial damage, since we can handle our own norepinephrine and epinephrine at much higher levels.

Additionally, there are derivatives of these inhibitors that have been shown to be completely non-toxic with large doses. This means that PDE3A inhibition in and of itself does not necessarily indicate cardiotoxicity, because if it were, these derivatives would have displayed the same degree of myotoxicity as their parent compounds.

But let’s play the devil’s advocate and say that PDE3A inhibition alone was sufficient for these negative side effects. Even so, the data indicate that the level of toxicity is far below that seen with our own catecholamines, which are released in larger quantities than those seen in the abstract below when using various CNS stimulant type products! And again – PDE3A inhibition alone does NOT necessarily indicate cardiotoxicity.

So if you’re going to stop using Pink Magic because of a concern for PDE3A inhibition, then by that logic, you’d also stop taking caffeine, ephedrine, yohimbine, theophylline, theomobrine, 1,3-dimethylamylamine and almost every other common stimulant, since they all elicit a far greater catecholamine release than the amounts seen in the studies below, which were way more cardiotoxic than one of the standard compounds in selective PDE3A therapy:

Cardiovasc Toxicol. 2005 Fall;5(4):355-64.
Relative toxicity of cardiotonic agents: some induce more cardiac and skeletal myocyte apoptosis and necrosis in vivo than others.

Burniston JG, Ellison GM, Clark WA, Goldspink DF, Tan LB.

Abstract
We sought to determine the relative myotoxicity of a sample of cardiotonic (catecholaminergic and PDE Inhibitory) agents currently available for clinical use. Male Wistar rats (292 +/- 24 g) were administered single subcutaneous injections of 20 mmol kg(-1) of each agent. Myocyte apoptosis (caspase-3 and annexin-V) and necrosis (anti-myosin antibody) were detected immunohistochemically on cryosections of the heart and soleus muscle. All of the cardiotonic agents except dopamine produced significant amounts of cardiomyocyte death compared with the vehicle controls, with necrosis (range 2-8%, p < 0.01) approximately one order of magnitude greater in extent than apoptosis (range 0.06-0.5%, p < 0.05). The incidence of necrosis induced by norepinephrine (8%) was approximately twice that of epinephrine and isoproterenol (4 %) and four times that of dobutamine and milrinone (2%). All agents were also toxic to the soleus muscle (range 0.1-8%), but isoproterenol (8%, p < 0.05) and epinephrine (4%, p < 0.05) were the most significant. No cell death was detected in control animals treated with only the vehicle. A majority of cardiotonic agents currently in clinical use are toxic to cardiac and skeletal myocytes. These observations suggest that judicious clinical use of such agents requires careful weighing of potential benefits against the harm via accelerated cumulative loss of myocytes.

Further, here are some excerpts studying the effects of several milrinone derivatives:

European Journal of Medicinal Chemistry 40 (2005) 1405–1413

Novel milrinone analogs of pyridine-3-carbonitrile derivatives as promising cardiotonic agents
Adnan A. Bekhit a,*, Azza M. Baraka b

Abstract
In an attempt to design new inotropic drugs for congestive heart failure (CHF) with less proarrhythmic potential, three series of compounds analogous to milrinone were prepared, namely, 4-aryl-6-(4-pyridyl)-2-oxo-1,2-dihydropyridine-3-carbonitriles 2a–g, 4-aryl-6-(4-pyridyl)-2-thioxo-1,2-dihydropyridine-3-carbonitriles 3a–g and 2-amino-4-aryl-6-(4-pyridyl)-pyridine-3-carbonitriles 4a–g. The first series was prepared by reacting 4-acetyl pyridine with the appropriate aldehyde, ethyl cyanoacetate and ammonium acetate in ethanol. Reaction of 2a–g with phosphorus pentasulfide afforded the second series 3a–g. The third target compounds 4a–g were prepared applying the same procedure used to synthesize 2a–g using malononitrile instead of ethyl cyanoacetate. All the newly synthesized compounds were evaluated for their cardiotonic activity and their in vivo cardiovascular effects. In addition, their oral and parentral acute toxicity were determined. Compounds 2a, 2b, 2c, 4c and 4f proved to exert cardiotonic activity comparable to that of milrinone using spontaneously beating atria model from reserpine-treated guinea pigs. In addition these compounds proved to be non-toxic and well tolerated by mice up to 250 mg kg–1 orally and up to 125 mg kg–1 through parenteral route.

This means that milrinone, the PDE Inhibitor people are worrying about, also has derivatives that are cardiotonic, meaning they strengthen the heart. They are also non-toxic and well-tolerated.

So, if PDE3A inhibition itself was sufficient for cardiotoxic effects, these analogues would have demonstrated that toxicity to a degree similar to milrinone. The fact that they did not, despite being potent cAMP-specific PDE inhibitors, indicates that another mechanism is responsible for the acute toxicity of milrinone.

As a final important note, you must also remember that these cardiotoxic studies are done on subjects with congenital heart disease – which the typical healthy athlete like yourself does not have. If you do have heart disease, then you should consult a doctor when taking ANY supplement or medication.

In summary, this all means that the PDE3A inhibition caused by Rhamnus Nakaharai in Pink Magic is not toxic, or at least not as damaging as simple stimulants like caffeine, ephedrine, yohimbine, theophylline, theomobrine, 1,3-dimethylamylamine, and the like – something which most people consume far greater amounts of every day.