Clen Study: Interesting

Clen study

My main concern with CLEN is the effect on the heart (build up of collagen and scar tissue, irregular heart beat) and I have seen a couple of studies showing this with even low (human sized) doses.
However, I believe this study shows no collagen build up or long term heart risk. Is that what this study is saying?

I'm trying to decide if it's worth the risk.

Clenbuterol induces cardiac hypertrophy with normal functional, morphological and molecular features.
Wong K, Boheler KR, Bishop J, Petrou M, Yacoub MH.

Division of Cardiothoracic Surgery, National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, London, UK.

OBJECTIVE: Several pharmacological agents have been shown to produce 'physiological' or 'pathological' hypertrophy based on their functional characteristics. The aim of this study was to examine the features of cardiac hypertrophy induced by the selective beta 2-adrenergic agonist, clenbuterol. METHODS: Cardiac hypertrophy was induced in 7-week-old Sprague-Dawley rats by daily injections of clenbuterol for 3 weeks. Thyroxine and isoproterenol were also used to produce cardiac hypertrophy to serve as positive controls for physiological and pathological hypertrophy, respectively. Left ventricular function was determined using an isolated rat heart preparation. Ventricular samples were used for morphological examination while interstitial collagen was measured using high-pressure liquid chromatography. Expression of sarcoplasmic reticulum Ca(2+)-ATPase2a (SERCA2a) and phospholamban (PLB) were measured by dot blot analysis. RESULTS: Clenbuterol treatment induced 26% left ventricular hypertrophy. These hearts demonstrated normal systolic isovolumic parameters and diastolic (active relaxation and passive stiffness) function. In addition, left ventricular concentration of collagen and morphology was normal as were the expression of SERCA2a and PLB mRNA. CONCLUSION: These results suggest that clenbuterol-induced hypertrophy is 'physiological' in terms of its function, extracellular structure and gene expression.

Thoughts?

Personally, even if long term cardiovascular damage could be seen in rats, I wouldn't use this study to make my decision to run it. I have never based any decision on those that involve animal test subjects.

good point, but does anyone know of any heart related side effects in humans from moderate clen usage....I guess that's really what I'm looking for.

http://www.ncbi.nlm.nih.gov/entrez/q...m_uid=12600052
Try this, ok, now that it works, there are many studies. It is hard to research the effects on humans because you must pass your research through a "Human Subjects Review Board" which protects participants.

Some more interesteding Clen stuff on Taurine and human sized doseages

Taurine
The finding that clenbuterol induces myocyte-specific necrosis in the heart is novel. It may be speculated that, in the absence of a functional satellite cell system, all necrosis in the heart will lead to reparative fibrosis. Our acute data may therefore provide etiological support to those of Duncan et al. (11), who showed an increase in collagen infiltration (possibly reparative fibrosis) in the heart after chronic clenbuterol administration. A possible mechanism for clenbuterol's cardiotoxicity is its adverse effect on taurine levels in the heart (9, 36). This amino acid is known to have a protective role in some tissues, particularly in the heart and lungs, with one of its possible roles being the modulation of calcium levels (16). Doheny et al. (9) showed that taurine levels in the heart are depressed in response to a single subcutaneous administration of clenbuterol. Furthermore, the dose of clenbuterol (125 µg/kg body wt) used and the time point (5 h) after clenbuterol administration at which the taurine levels in the heart become significantly depressed almost exactly match those found for the onset of necrosis in the heart in our investigation (Figs. 2A and 3A). Doheny et al. (9) did not investigate taurine levels in the soleus but only in the gastrocnemius muscle, where taurine levels increased 6 h after clenbuterol administration. In light of the present findings, it may also be of interest to investigate changes in the levels of taurine in the soleus after controlled administration of clenbuterol.

Human sized Doseage:
The present investigation has provided important information on the effects of acutely administered clenbuterol in the rat. In humans, a single dose of clenbuterol is generally self-administered as a 20-µg tablet. This is equivalent to 0.3 µg/kg body wt in a 70-kg male and is comparable to the dose administered in the only clenbuterol investigation using human subjects (23). To compare this with our 300-g rats, the dose needs to be scaled for differences in body weight and metabolic rate between the two species (Kleiber's Law, 0.75 exponent). The relative dose per kilogram in the rat is 60 times that of the human dose, i.e., 17.9 µg clenbuterol/kg body wt. As demonstrated in Fig. 2, this dose is sufficient to induce 3.8 ± 0.49% necrosis in the fibers of the soleus. Such a level of necrosis may appear small, but this is in response to a single administration, and this level of necrosis may underestimate the level induced by enteral administration (Fig. 5B). Individuals abusing clenbuterol often take several tablets and use the side effects of muscle tremors and tachycardia to judge their maximum dose. By using the above calculations, a daily dose of five to six tablets would be sufficient to reach the threshold (100 µg/kg body wt) for inducing damage in the heart and to induce 6.8 ± 1.9% necrosis in the soleus. An important additional factor to be considered is clenbuterol's long half-life within the body (38). Abusers of this substance often administer it by using an "on-off" cycle over several days. An accumulation of nonmetabolized clenbuterol during the on stage of the cycle may lead to chronically elevated plasma levels, which would further impact myocyte loss in both striated muscles. Although the present investigation has not investigated the compound effects of chronic clenbuterol administration, it does demonstrate that, at the very least, damage will be induced at the onset of each cycle of administration.

Good read, but I'm still a little confused. Can you break that down to me a little more? Especially this part,..."Although the present investigation has not investigated the compound effects of chronic clenbuterol administration, it does demonstrate that, at the very least, damage will be induced at the onset of each cycle of administration."

From my reading, I think the cycle they refer to is the 2 day on, 2 day off method, but I could be wrong.

I'm no scientist but I believe they're saying that they can show damage from one administration of clenbuterol but cannot tell whether chronic use has additional compounding effects (because it builds up in the blood). Takeaway would be - bad to use once, maybe worse to use chronically.

By the way, do you play hockey (you've got a goalie avatar)? Does anyone you know who plays use clenbuterol?

If those studies didnt scare you, this may

http://www.thebullmagazine.com/magma...=12&pageID=126

by Karl Hoffman
Every organism requires a means to rid itself of cells that are no longer required, are damaged, or that may be harmful to the organism. Cell death is a tightly controlled process and may occur by apoptotic or non-apoptotic means (necrosis). Apoptosis is the regulated destruction of a cell and may be triggered by either external or internal signals. Unlike necrosis, apoptosis does not result in an inflammatory response from the surrounding cells and the morphological features are quite distinct. Apoptosis, or programmed cell death, involves complex signaling that results in a molecular cascade triggering a series of proteases known as caspases. Caspases are central to the process of apoptosis and are activated specifically in apoptotic cells. Caspases cleave a limited set of proteins within the cell which are critical for cell survival, resulting in cell death.

In rats, doses of clenbuterol on the order of 100 mcg (micrograms) per kg of body weight have been shown to induce necrosis of cardiac myocytes (muscle cells) (1). The same research group that examined necrosis recently showed that much smaller doses of clenbuterol, as low as 1 mcg/kg of body weight, could induce apoptosis in cardiac myocytes (2). Before looking at the mechanisms and implications of this, we must convert these figures to Human Equivalent Doses (HED) to see if there is any relevance to humans here. In some cases, when extrapolating animal doses to human doses a direct mg/kg to mg/kg conversion is adequate. Considering necrosis, using this conversion 100 mcg/kg would translate into 10,000 mcg for a 100 kg bodybuilder. It’s unlikely that anyone routinely consumes this much clenbuterol, so necrosis would not be an issue in humans. Apoptosis is a different story however. The 1 mcg/kg figure would amount to 100 mcg in a human. People routinely consume between 100 and 200 mcg of clenbuterol daily so apoptosis is a distinct possibility in humans.

For some drugs and routes of administration extrapolating from animals to humans works better if one takes body surface area into account:

http://www.fda.gov/cber/gdlns/dose.htm

In the case of rats in this study with an average weight of 289 grams, one multiplies the toxic dose in mg/kg by 0.15 to arrive at the HED in mg/kg. Using this algorithm for necrosis we arrive at an HED of 1500 mcg for the 100 kg bodybuilder. This is still far outside the range of clenbuterol doses used by people, so again necrosis is not relevant in the human heart. However, scaling this way for apoptosis gives us an HED of 16 mcg for or 100 kg subject. So regardless of how we calculate HED, clen doses commonly used by humans are well within the apoptotic range.

Clenbuterol is a relatively specific beta 2 receptor agonist, but it does show some degree of beta 1 binding at high doses. In addition to acting directly on beta receptors, clenbuterol facilitates release of norepinephrine (NE) from sympathetic nerve terminals by stimulating pre-synaptic beta 2 adrenoreceptors. (Ephedrine acts in a similar manner, both directly and indirectly by inducing NE release.) To test the mechanism of clenbuterol’s apoptotic action, the authors administered reserpine to deplete the NE releasing capacity of the sympathetic nerve terminals. This resulted in a 68% reduction in apoptosis. Similarly, prior administration of bisoprolol, a selective beta 1 antagonist resulted in a 98% reduction in apoptosis. Based on the above observations the authors concluded that NE is primarily responsible for cardiac apoptosis due to clenbuterol. Note that after administrtion of a single dose of clenbuterol the authors observed apoptosis at 4 hours. The long elimination time of clenbuterol allows for the buildup of high concentrations in the heart (3).

In the soleus muscle, 10 mcg/kg of clenbuterol was the minimum dose that induced apoptosis. In the soleus only beta 2 blockade was capable of reducing apoptosis. This latter observation implies that while NE is responsible for the cardiac toxicity of clenbuterol, the drug is acting directly on beta 2 receptors in the soleus to induce apoptosis.

An interesting possibility is that the clenbuterol induced cardiac apoptosis might be a protective response gone awry to the cardiac hypertrophy that accompanies chronic beta receptor stimulation, since both cardiac apoptosis and hypertrophy occur in humans with long term use of beta agonists :

"Accumulating evidence suggests that chronic stimulation of ß-adrenergic receptor (ß-AR) in patients causes progressive cardiac dysfunction, cell loss, and cardiac chamber remodeling. Consistent with this notion, it has been demonstrated that stimulation of the ß-AR causes hypertrophy and apoptosis in cardiac myocytes" (4).

Under physiologic conditions where the heart is exposed to normal levels of NE a balance is struck between hypertrophy and apoptosis. ICER (inducible cAMP early repressor) is upregulated by cAMP (cyclic adenosine monophosphate), which in turn is upregulated by exposure to beta agonists like NE. ICER initiates signaling that ultimately leads to apoptosis, as depicted in the diagram below, adapted from (5).



Schematic representation of ICER-mediated feedback signaling, with ICER-mediated effects italicized.

Evidently under exposure to chronic supraphysiological levels of beta agonists ICER leads to deleterious levels of apoptosis while at the same time being unable to offset beta agonist induced hypertrophy. Hence the combination of apoptosis and hypertrophy mentioned in the quote above from (4).

Paraphrasing a passage from (2), the take home message for both cardiac patients and bodybuilders based on the research discussed here might be the following:

Clenbuterol has recently been used as an adjunct to the implantation of left ventricular assist devices (The Harefield Protocol) as a bridge to recovery and has been shown to aid the reverse remodelling of the myocardium. These patients also receive 'combination therapy' that includes beta 1-AR blockade. It is likely therefore, that in this case the heart will be protected from the myotoxic effects of clenbuterol, as explained above. However, their skeletal musculature will remain vulnerable to beta 2-AR-induced myocyte death. The potential additional loss of skeletal muscle bulk in already severely ill patients, together with the effects on their protein metabolism and exercise capacity, warrants further investigation before the use of clenbuterol becomes widely accepted as a standard therapeutic intervention. With regard to the illicit use of clenbuterol the philosophy of "the more you take, the greater the benefit" must engender a cause for concern.

Perhaps a person would be wise to use alternatives to clenbuterol such as forskolin, green tea, and caffeine, at least until similar studies are carried out on these fat loss agents. At a minimum it would seem prudent to use the smallest dose of clenbuterol that one finds effective, and limit the time of exposure. The latter is the norm with most users anyway, who typically use clenbuterol for short periods of time (on the order of two weeks) due to the downregulation of beta receptors that accompanies clenbuterol use. One still wonders about the wisdom of cycling clenbuterol on a two-week on / two off schedule over long periods of time to offset receptor downregulation.

References

Burniston JG, Ng Y, Clark WA, Colyer J, Tan LB, Goldspink DF. Myotoxic effects of clenbuterol in the rat heart and soleus muscle. J Appl Physiol. 2002 Nov;93(5):1824-32.

Burniston JG, Tan LB, Goldspink DF. {beta}2-Adrenergic receptor stimulation in vivo induces apoptosis in the rat heart and soleus muscle. J Appl Physiol. 2004 Dec 10; [Epub ahead of print]

Soma LR, Uboh CE, Guan F, Luo Y, Teleis D, Runbo L, Birks EK, Tsang DS, Tissue distribution of clenbuterol in the horse. J Vet Pharmacol Therap 27: 91- 98, 2004

Tomita H, Nazmy M, Kajimoto K, Yehia G, Molina CA, Sadoshima J. Inducible cAMP early repressor (ICER) is a negative-feedback regulator of cardiac hypertrophy and an important mediator of cardiac myocyte apoptosis in response to beta-adrenergic receptor stimulation. Circ Res. 2003 Jul 11;93(1):12-22.

Sussman MA. ICER-capades: putting cardiac cyclic AMP signaling "on ice". Circ Res. 2003 Jul 11;93(1):6-8.

that stuff is scary!!