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Wednesday, May 6, 2015

Optimoterol - The debut of superior β2 receptor agonist/cardioselective β1 receptor antagonist Proprietary Blend-OA

Move over Clenbuterol and Welcome OptimoterolTM
The debut of superior β2 receptor agonist/cardioselective β1 receptor antagonist
proprietary ratio combination as an Optimized Agent format.

Potent and highly efficacious combination of Formoterol and Nebivolol in an optimized ratio format for research into the benefits of the potent β2 agonist Formoterol while using an optimum correlative dose of Nebivolol to promote minimized adverse effect potentials via cardioselective antagonism of β1 receptors.

Optimoterol
Optimized Agent design to provide the most superior efficacy and therapeutic index for the spectrum of benefits.

Research Indications:  Anti-Obesity/Lipolytic Research, Anabolic/Myotrophic Research, Neurogenic/Dendritogenic Research, Anti-Aging Research, Mitochondrial Research
Formoterol is a long-acting β2 agonist (LABA) that has an extended duration of action (up to 12 hours) compared to short-acting β2 agonists such as salbutamol, which are effective for 4–6 hours.
Nebivolol is a cardioselective β1 receptor antagonist with a mean half-life of about 12 hours.
Enhanced Muscular Hypertrophy and Anti-Obesity Potentials: Potent Lipolytic Effects with Concurrent Anabolic-Myotrophic Effects
β2 agonists increase energy utilization and fat metabolism, however, therepeutic use for obesity has been limited by the concomitant activation of β1 receptors resulting in excessive increases in heart rate. A recent 2012 dose-finding study (in healthy men) demonstrated significantly increased resting energy expenditure, and fat oxidation at a dose of 160 μg of formoterol per day without significantly increased heart rate. Formoterol's specificity for the β2 receptor (relative to β1 receptors) may facilitate its use for this purpose. A combination of a highly selective β2 agonist like formeterol with a low dose highly selective β1 blocker may further improve the differential therapeutic ability to selectively agonize β2 receptors for metabolic benefits in treating obesity without adverse β1 agonist effects.[1] The selective β1 blocker (β1 antagonist) Nebivolol at low doses results in fully cardioselective effects and demonstrates efficacy to abolish potential adverse effects of formoterol at higher doses. Nebivolol demonstrates antihypertensive vasodilatory effects as well.

As with other beta(2)-adrenoceptor agonist (beta(2)-agonist), formoterol, has been shown to cause muscle hypertrophy in rats even when administered at the micromolar dose of 25 micro g/kg/day. A similar low dose of formoterol as well improves muscle function in the dystrophic mdx mouse. The findings indicate formoterol has considerably more powerful anabolic effects on skeletal muscle than older generation beta(2)-agonists (like clenbuterol and albuterol), and has considerable therapeutic potential for muscular dystrophies and other neuromuscular disorders where muscle wasting is indicated. [2]

::  MECHANISM OF ACTION :: 

Beta-adrenergic agonists may help build muscle through two mechanisms.

1.) They may increase androgen signaling through induction of histone demethylase (!) (!) which leads to increases in androgen receptor signaling (!). When androgen receptor signaling is increased, protein synthesis, utilization and delivery is dramatically enhanced. Additionally, the anabolic benefits of androgen receptor activation may be furthered when glycogen uptake is improved, which also occurs with beta agonists.(!) 

2.) They inhibit myostatin, ESPECIALLY formoterol(!), have you seen the rats, swine, and cows who have myostatin genes deleted? They are hunormous! (!)
By inhibiting this enzyme, muscle growth is DISINHIBITED and other anabolic hormones are also then disinhibited. Thus, everything else you do will result in higher results and strength will be improved dramatically as muscle growth is accelerated. You see, because myostatin is an enzyme/protein complex that is almost solely around to control** muscle growth(!).

ANABOLIC EFFECTS ON BONE
Formoterol - may also have anabolic effects on bone and thus lead to expansion / growth of cortical bone , it may also , with long-term use - lead to increases bone mass and density(BMD/BDD).  (!) (!) (!)
The PKA/cAMP pathway leads to increases in osteocytes and osteoclasts and also increases enzymatic growth factors including IGF-1, Transforming Growth Factor and Bone Morphogenic Proteins. The complex alteration in signal transduction leads to widespread beneficial enhancement in growth factors both in bone and in some cartilage.

Anticachexic Potentials -  results indicate that formoterol exerted a selective, powerful protective action on heart and skeletal muscle by antagonizing the enhanced protein degradation that characterizes cancer cachexia, and it could be revealed as a potential therapeutic tool in pathologic states wherein muscle protein hypercatabolism is a critical feature such as cancer cachexia or other wasting diseases.

Neurogenic/Dendritogenic Potentials: Strengthening of Nerve Connections in Hippocampus
Preliminary research offers hope that formoterol may be a useful treatment in Down's Syndrome. In a mouse model of the disease, the drug strengthened nerve connections in the hippocampus, a brain center used for spatial navigation, paying attention and forming new memories. [4]
Beta agonists also have the ability to increase glutamate levels (!)  (!) and activity in cerebrocortical nerve terminals which may improve memory and mental performance. They also appear to do so safely.
In the central nervous system, adenylyl cyclases regulate many cellular processes in response to extracellular and intracellular signals such as hormones, neurotransmitters, and Ca2+ (1). Inmunohistochemical studies of adenylyl cyclase in the brain have shown a selective concentration at synapses both in presynaptic axon terminals and in postsynaptic densities (2). Consistent with this localization, the activation of adenylyl cyclase with forskolin has been shown to enhance synaptic transmission in hippocampal slices from CA1 (3, 4), CA3 (5, 6), and the dentate gyrus (7) as well as in neostriatal neurons (8). Moreover, the cAMP-dependent effects on synaptic transmission have been implicated in long-term potentiation in the hippocampus both in CA1 neurons (9) and in slices from the CA3 region (6, 10). Recently, evidence has been found indicating that the extracellular signal involved in the activation of this cAMP-dependent pathway is noradrenaline, acting via a β-adrenergic receptor. Thus, the β-adrenergic agonist isoproterenol has been shown to mimic the potentiating effects of cAMP elevation in synaptic transmission (11, 12).



Stimulation of mitochondrial biogenesis
Formoterol may also help stimulate mitochondrial biogenesis. Mitochondrial dysfunction is related to many degenerative diseases — particularly neurodegenerative disorders. Formoterol thus may provide potent an anti-aging longevity-healthspan promoting mitochondrial biogenesis.[5]
Additionally, formoterol being a beta-agonist, may improve thyroid hormone ratios and thus act on a neuro-endocrine level to boost cellular metabolism as well. Specifically the increase in cyclic adenosine monophosphate results in the rise of T4 hormones...which then leads to higher metabolic output and strengthening of both neuronal growth factors and cellular metabolism. (!) (!)
References:
[1] Lee, P; Day, RO; Greenfield, JR; Ho, KKY (May 29, 2012). "Formoterol, a highly β2-selective agonist, increases energy expenditure and fat utilisation in men". International Journal of Obesity 37 (4): 593–597. doi:10.1038/ijo.2012.90. ISSN 1476-5497. PMID 22641064

[2] Harcourt LJ1, Schertzer JD, Ryall JG, Lynch GS Low dose formoterol administration improves muscle function in dystrophic mdx mice without increasing fatigue. Neuromuscul Disord. 2007 Jan;17(1):47-55. Epub 2006 Nov 28.

[3] Busquets S1, Figueras MT, Fuster G, Almendro V, Moore-Carrasco R, Ametller E, Argilés JM, López-Soriano FJ. Anticachectic effects of formoterol: a drug for potential treatment of muscle wasting. Cancer Res. 2004 Sep 15;64(18):6725-31.

[4] Dang, Van; Medina, Brian; Das, Devsmita; Moghadam, Sarah; Martin, Kara J; Lin, Bill; Naik, Priyanka; Patel, Devan; Nosheny, Rachel; Wesson Ashford, John; Salehi, Ahmad (27 June 2013). "Formoterol, a Long-Acting β2 Adrenergic Agonist, Improves Cognitive Function and Promotes Dendritic Complexity in a Mouse Model of Down Syndrome".Biological Psychiatry. doi:10.1016/j.biopsych.2013.05.024

[5] Wills, Lauren P; Trager, Richard E; Beeson, Gyda C; Lindsey, Christopher C; Peterson, Yuri K; Beeson, Craig C; Schnellmann, Rick G (April 6, 2012). "The β2-adrenoceptor agonist formoterol stimulates mitochondrial biogenesis". The Journal of Pharmacology and Experimental Therapeutics 342 (1): 106–118. doi:10.1124/jpet.112.191528.ISSN 1521-0103. PMC 3383035. PMID 22490378

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