AOD-9604, 5mg

AOD-9604

History

AOD-9604 was initially developed by Professor Frank Ng in 1997 at Monash University, Australia. Professor Frank, a biochemist, had been carrying out studies on human growth hormone since the 1960s. AOD-9604 was synthesized as a result of studies that were seeking to develop a drug that could produce the fat-burning (catabolic) effects produced by the natural human growth hormone but one that did not have its anabolic (muscle building) effects. Therefore, AOD-9604 is merely a modification of a fragment of the human growth hormone.

After AOD-9604 was proven to be safe, effective, and did not possess the unwanted properties of HGH, an application for a patent was made in 1997 by Metabolic Pharmaceuticals, an Australian company. The company was granted the patent in 2003 and it consists of the peptide itself.

Fat Burning

In studies performed by researchers at Monash University, it was established that the fat burning properties of GH seem to be regulated by a small area at one end of the GH molecule. The area is mostly made up of amino acids 176-191 and seems not to have effects on insulin or growth resistance. In its mechanism of action, this peptide replicates the manner in which natural GH controls fat metabolism, but it does not lead to any harmful effects on growth or blood sugar unlike with unmodified GH. This amino acid 176-191 inhibits lipogenesis and stimulates liposys as observed in scientific studies conducted on both animals and humans. Liposys is the process by which fat is broken down while lipogenesis is the process by which non-fat food compounds are transformed into body fat. In recent studies, it has been demonstrated that apart from fat reducing properties, AOD-9604 has more regenerative properties linked to GH. Clinical trials are being performed to confirm the potential application of AOD-9604 in bone and cartilage repair, osteoarthritis, and hypercholesterolemia.

In tests that were carried out on fat cells obtained from humans, researchers noted that AOD-9604 led to a release of fat particularly from obese fat cells with no effects on fat levels in the lean cells, improved the burning of fat, and lowered the accumulation of new fat in all fat cells. The researchers also noted that AOD-9604 lowered body fat in obese individuals and improved the burning of fat without inducing growth (mainly because it has no effects on IGF levels), or altering food consumption, or any other undesired GH effect. Based on these results, scientists have concluded that AOD-9604 is highly potent and effective as a fat burner.

In an animal-based study carried out by Ng FM1 and colleagues, AOD-9604 was evaluated for its metabolic effects in obese Zucker rats. When the rodents were orally administered with a dose of 500microg/kg AOD-9604 on a daily basis for 19 days, they showed a reduction in body weight of over 50% in comparison to the control group. The researchers observed an increase in lipolytic activity in the adipose tissues of the AOD-9604 treated group. When compared to chronic treatment with natural hGH, the euglycemic clamp techniques did not demonstrate any harmful effects on the sensitivity of the animals to insulin following chronic administration of AOD-9604. In this study, the researchers concluded that AOD-9604 had a high potential to be developed into a safe and orally usable therapeutic agent against obesity.

AOD-9604 has been shown to play a key role in the increase of muscle mass, in the removal of excessive adipose tissues including those in the abdomen region, and boosts the lipid composition of the body. In vivo tests have been performed to test the effects of AOD-9604 in muscles of laboratory mice. Results from these studies have demonstrated that AOD-9604 leads to a short-term rise in levels of blood glucose and prolonged rise in levels of plasma insulin, and other fragments including 172-191, 177-191, and 178-191.

In an animal-based study carried out by Ng et al. (2002), it was established that 500mcg of AOD-9604 led to an increase in the lipolytic activities of the adipose tissues, and it did not indicate any adverse effects on blood glucose level. Also, despite mimicking the behavior of human growth hormone (hGH), it does not lead to hyperglycemia since it is not engaged in competition with hGH receptors. Based on these properties, scientists have proposed that it has potential uses in eliminating excess abdominal fat (a major characteristic of HIV-related lipodystrophy).

Muscle and Bone Cell Growth Promotion

Currently, there are a number of studies being conducted at Mt. Sinai Hospital in Toronto, Canada by Professor Rita Kandel and Professor Marc Grynpas through their partnership with Metabolic. This proof of principle studies are focused on showing that AOD-9604 has: ex vivo anabolic effects on native tissues; in vitro enhancement of myoblast differentiation into muscle cells; and in vitro anabolic effects on chondrocytes and has the potential to boost the formation of cartilage tissue. In animal-based studies, Metabolic has established that AOD-9604 can initiate osteogenesis (the formation of new bone) in cell culture and that in animal models of osteoporosis, it can enhance the mechanical properties of bone. Considering AOD-9604’s encouraging safety profile based on toxicity studies and its promising efficacy data from human clinical studies, there is a strong basis for the use of AOD-9604 in situations whereby bone repair is compromised. Some potential occasions whereby it is applicable include prevention of fractures (e.g. osteoporosis), signs that bone growth needs stimulation (e.g. in dental bone grafts or in spinal fusion), and nonunion fractures. In contrast with other products meant to help in bone repair, it may present better benefits since it can be administered orally, is highly safe to use and it promotes bone repair.

In a study that was conducted by Professor Marc Grynpas and colleagues at Mt Sinai Hospital (Canada), reports forwarded to Metabolic in 2011 indicated that in vitro tests had provided positive results in relation to AOD-9604’s potential to stimulate the formation of bones in cell culture. Professor Marc Grynpas has also provided Metabolic with results from three different in vivo studies that involved ovariectomized rat models of osteoporosis. Results from another in vivo study by MDS Pharma that was similar to those conducted by Professor Marc Grynpas were also presented to metabolic.

AOD 9604 Peptide and Cell Regeneration

Additional research was conducted to study the regenerative potential of the peptide. In 2015, 32 white rabbits were divided into four groups of eight, and each group was given a placebo,  AOD 9604, hyaluronic acid, or a combination of AOD 9604 and hyaluronic acid for 4 to 7 weeks. After the study, these rabbits were assessed morphologically and histopathologically to determine the degree of cartilage degeneration. It was concluded that rabbits given the combination of AOD 9604 with hyaluronic acid apparently exhibited the least degeneration. Thus, it was suggested by the researchers that AOD 9604 might exhibit potential to enhance cartilage regeneration and cartilage repair in some capacity.(1)

This may be due to the potential role of AOD 9604 in cellular differentiation processes and, potentially, in the synthesis of proteins important for tissue repair. According to an in vitro study, AOD 9604 may possibly enhance the differentiation of adipose mesenchymal stem cells into bone(1).

These stem cells, which are typically found within fat tissue, may have the potential to evolve into various cell types. It has been hypothesized that under the influence of AOD 9604, these stem cells may show a predisposition to differentiate into bone cells. Moreover, when the research was conducted on isolated bovine chondrocytes, it appeared that there might be an increased production of proteoglycan and collagen. Chondrocytes are cells believed to be found within cartilage tissue, and they possibly play a role in producing and maintaining the extracellular matrix, which consists of components like collagen and proteoglycans. It is posited that the presence of AOD 9604 could stimulate these chondrocytes to produce more of these vital components. The study also hints at the idea that AOD 9604 might promote the differentiation of myoblasts into C2C12 cells. Myoblasts are thought to be precursor muscle cells, and C2C12 cells are a type of murine model muscle cell line. From what the study suggests, AOD 9604 may assist in the transition of these precursor cells into a more mature form. The research seems to underline the potential role AOD 9604 might have in processes connected to the repair of bone, cartilage, and muscle tissues.

AOD 9604 and Research in Cancer Cells

The peptide may be able to bind (target) tumor-related proteins to enhance tumor drug accumulation and local cytotoxicity.(2) The hGH fragment AOD 9604 may potentially play a pivotal role in cancer cell research, as it has been observed to enhance the anticancer efficacy of doxorubicin, a commonly recognized chemotherapeutic agent. One study utilized chitosan nanoparticles, a biocompatible and biodegradable polymer, as a carrier for doxorubicin and AOD 9604.(2) The research team hypothesized that AOD 9604 possibly enhanced the doxorubicin binding to multiple breast cancer cell protein targets, thereby exhibiting greater anti-proliferative activity against the MCF-7 breast cancer cell line compared to chitosan loaded with doxorubicin alone. This suggests that AOD 9604 may potentially augment the anti-cancer potency of doxorubicin while possibly minimizing unintended actions associated with non-target tissue exposure. In conclusion, multiple clinical studies have suggested that the peptide may significantly induce lipolysis and possibly prevent lipogenesis by mimicking natural hGH.

1. 1. 1. Dong Rak Kwon and GI Young Park, Effect of Intra-articular Injection of AOD9604 with or without Hyaluronic Acid in Rabbit Osteoarthritis Model, Annals of Clinical and Laboratory Science, Volume 45, July-August 2015.
      2. Habibullah, M. M., Mohan, S., Syed, N. K., Makeen, H. A., Jamal, Q. M. S., Alothaid, H., Bantun, F., Alhazmi, A., Hakamy, A., Kaabi, Y. A., Samlan, G., Lohani, M., Thangavel, N., & Al-Kasim, M. A. (2022). Human Growth Hormone Fragment 176-191 Peptide Enhances the Toxicity of Doxorubicin-Loaded Chitosan Nanoparticles Against MCF-7 Breast Cancer Cells. Drug design, development and therapy, 16, 1963–1974. https://doi.org/10.2147/DDDT.S367586