A New Strategy for Obesity Treatment

[madman]

A New Strategy for Obesity Treatment: Revealing the Frontiers of Anti-obesity Medications

Obesity dramatically increases the risk of type 2 diabetes, fatty liver, hypertension, cardiovascular disease, and cancer, causing both declines in quality of life and life expectancy, which is a serious worldwide epidemic. At present, more and more patients with obesity are choosing drug...

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Abstract

Obesity dramatically increases the risk of type 2 diabetes, fatty liver, hypertension, cardiovascular disease, and cancer, causing both declines in quality of life and life expectancy, which is a serious worldwide epidemic. At present, more and more patients with obesity are choosing drug therapy. However, given the high failure rate, high cost, and long design and testing process for discovering and developing new anti-obesity drugs, drug repurposing could be an innovative method and opportunity to broaden and improve pharmacological tools in this context. Because different diseases share molecular pathways and targets in the cells, anti-obesity drugs discovered in other fields are a viable option for treating obesity. Recently, some drugs initially developed for other diseases, such as treating diabetes, tumors, depression, alcoholism, erectile dysfunction, and Parkinson's disease, have been found to exert potential anti-obesity effects, which provides another treatment prospect. In this review, we will discuss the potential benefits and barriers associated with these drugs being used as obesity medications by focusing on their mechanisms of action when treating obesity. This could be a viable strategy for treating obesity as a significant advance in human health.




1.1. Therapy for Obesity


2. DRUG REPURPOSING TO FIGHT OBESITY AND ITS POTENTIAL MECHANISM
2.1. Drug Repurposing


3. CLINICAL STUDY ON DRUG REPURPOSING TO COMBAT OBESITY
3.1. Metformin
3.2. Fenretinide
3.3. Fluoxetine
3.4. Disulfiram
3.5. Sildenafil


4. PRECLINICAL STUDY ON DRUG REPURPOSING TO COMBAT OBESITY(FOCUS ON THE MECHANISM)
4.1. Metformin
4.2. Fenretinide
4.3. Fluoxetine
4.4. Disulfiram
4.5. Sildenafil
4.6. Imatinib
4.7. Entacapone


5. OBSTACLES TO DRUG REPURPOSING FOR OBESITY
5.1. Efficacy Problem
5.2. Safety Problem




FUTURE PERSPECTIVE AND CONCLUSION

Many pharmaceutical personnel and biotechnology companies have gained interest in drug repositioning in the last few years. There are also many examples of repositioned drugs leading to new indications. This review mainly describes drugs used in other fields that could have anti-obesity effects. These drugs have been found to reduce the weight of animals or patients. Furthermore, the drugs have been approved by the FDA, with clear pharmacokinetic and pharmacodynamic characteristics and an acceptable safety profile. Phase I clinical trials can be omitted in drug repurposing, saving significant time and money. Therefore, drug repurposing becomes an interesting strategy in the search for safe and effective anti-obesity drugs. On the other hand, combination therapy is a promising treatment strategy for this disease, and combination therapy may provide prolonged weight loss effects with fewer side effects. There are also examples of drug combinations among FDA-approved anti-obesity drugs for the long-term treatment of patients with obesity. Thus, the combination of drugs also provides us with novel insight.

Although drug reuse significantly reduces the time and money required to develop new anti-obesity drugs, the process of repurposing still encounters multiple barriers. Efficacy and safety issues are of utmost concern, so dose and toxicity should be reduced without compromising effectiveness and to resolve the above-discussed limitations to achieve cost-effective and more efficient drug development. While it remains to be seen whether these drugs will be translated into clinical practice, if they do not succeed, we predict that the relevant chemical structures or targets may prove useful in developing new anti-obesity drugs. Developing a new molecule with unknown biological effects is risky compared to testing the efficacy of an established drug with known molecular targets and biological effects. James Black Pharmacology, a Nobel Laureate in Medicine and Physiology in 1988, once said, "The most effective basis for discovering a new drug is to start with an old one." While there are still significant challenges to drug repurposing to treat obesity, each of these challenges deserves to be examined in-depth in the field of drug discovery. As long as a breakthrough exists, it will be crucial to improving human obesity and other metabolic health.

 

[madman]

Table 1. Current Know anti-obesity drugs approved by the FDA with their molecular targets and side-effect.

 

[madman]

Fig. (1). Major steps and estimated time involved in the conventional drug development process. New drug discovery and design take one to two years, after three to five years of in vitro trials to evaluate whether it can be used in vivo, after five to seven years of a total of three clinical trials to ensure safety and practicality. Finally, after one to two years of FDA certification, it is used in the market. (A higher resolution/color version of this figure is available in the electronic copy of the article).

 

[madman]

Table 2. New anti-obesity potential of old drugs.

 

[madman]

Table 3. Advantages and disadvantages of anti-obesity medications.

 

[madman]

Fig. (2). Summary of weight loss mechanisms of metformin. Metformin may improve obesity by reducing appetite, increasing energy metabolism, and regulating the gut microbiome. (A higher resolution/color version of this figure is available in the electronic copy of the article).

 

[Nelson Vergel]

Great review article, @madman !

 

[madman]

Fig. (3). Entacapone inhibits gluconeogenesis in the liver and increases thermogenesis in adipocytes by reducing the expression of FOXO1. Entacapone is an effective chemical inhibitor of FTO, FOXO1 is the direct substrate of FTO, so entacapone can inhibit FOXO1 and promote the expression of UCP1 to promote thermogenesis. Meanwhile, inhibiting the expression of FOXO1 can inhibit the level of G6Pase, thus inhibiting gluconeogenesis (dotted arrows: inhibition, solid arrow: activation). (A higher resolution/color version of this figure is available in the electronic copy of the article).