NJU-China-background.html

humanpractice

What are drugs? Technically speaking, drugs are chemical substances that affect the normal functioning of the body and/or brain. In fact, a distinction between legal and illegal drugs does not exist; only the use of drugs is recognized as legal or illegal. Here, the term “illegal drugs” is used to describe drugs that are under international control but that are produced, trafficked and/or consumed illicitly. Illegal drug types are described in various ways, depending on their origin and effect. These drugs can be naturally occurring, semi-synthetic (chemical manipulations of substances extracted from natural materials) or synthetic (created entirely by laboratory manipulation). The primary illegal drugs are opiates (primarily heroin), cocaine, cannabis and ATS (amphetamine-type stimulants), such as amphetamines, methamphetamine and ecstasy.

Figure 1. Different types of illegal drugs

Drug addiction is a chronic, relapsing brain disorder characterized by compulsive drug seeking and taking despite the negative consequences that may ensue. Addictions are caused by the impact of the drug itself on the brain (direct effects and neuroadaptations) and modified by various environmental factors. These factors include epigenetic changes, addict mindset, and social influences, including peer pressure, family environment, and, in particular, stress and stressor responses. Currently, drug addiction is commonly accepted as a disease of the brain, and most people who suffer from drug addiction cannot recover without medical help. The United Nations World Drug Report (2014) estimates that approximately 324 million people use illegal drugs annually [1]. Drug abuse and related addiction continue to be a serious public health concern worldwide.

Figure 2. The main problem drugs in different areas.

Illegal drugs are so harmful that countries across the world have decided to control them. However, the illegal drug trade (also called drug trafficking) remains one of the largest global businesses. Although estimating the value of the illegal drug trade conducted in dozens of currencies around the world is extremely difficult, the United Nations Office for Drug Control and Crime Prevention generally describes the production, trafficking and sales of illegal drugs as a $435 billion a year industry [2]. However, unlike the international arms trade, which largely flows from developed nations that produce arms to less developed nations that use arms, the international drug trade has traditionally flowed from developing to developed nations. The illegal drug trade attracts criminal organizations because the potential profits are significantly more than those from other criminal commodities. As noted in the United Nations World Drug Report (2007), the high value of illegal drugs is understandable because “unlike human beings, diamonds or firearms, the drug supply is consumed each year and in need of continuous renewal” [3].

Figure 3. The major trafficking routes of illegal drugs. There are three major producing areas of illicit drugs, Latin America and “the golden crescent” and “the golden triangle” in Asia.

Figure 4. The estimated global value of illegal drug trades compared with normal trades.

Illegal drugs ruin human lives. All illegal drugs have immediate physical effects. While some of the physical effects of drugs may sound nice, these effects do not last long. Drugs can severely hinder psychological and emotional development, particularly among young people. Drugs can also take away potential that users can never reclaim as drugs substitute the development of other natural coping mechanisms. Many people get depressed and lonely after using drugs and start feeling sick. Additionally, people who use drugs commonly seem confused, have red eyes, sweat copiously and lack concern regarding their physical appearance.

Illegal drugs cause health problems. Drug abuse poses massive personal and public health costs. Drugs cloud the judgment of users; thus, drug users often take more risks. Drug abusers often share syringes that may be contaminated by someone else’s blood, which can lead to infections caused by HIV, hepatitis, syphilis or other infectious diseases.

Illegal drugs threaten social stability and national security. In many countries worldwide, the illegal drug trade is thought to be directly linked to violent crimes such as murder. This situation is particularly true in developing countries but is also an issue for many developed countries worldwide. The Mexican government estimates that 90% of the killings in Mexico are drug related [4]. A report by the UK government’s Drug Strategy Unit stated that drug use was responsible for the great majority of crime, including 85% of shoplifting, 70-80% of burglaries and 54% of robberies [5]. The primary beneficiaries of the international drug trade may be a relatively small number of sophisticated trafficking organizations; however, the victims include countless drug addicts worldwide and innocent victims of crimes committed to support drug habits. Moreover, increasing evidence has indicated that the illegal drug trade has a substantial negative impact on all aspects of development. As the former Colombian Minister of Justice Rodrigo Lara Bonilla noted, “countries that begin by producing and trafficking in drugs end up by consuming them”.

The United Nations World Drug Report (2014) stated that “Opiates and opioids top the list of problem drugs that cause the most burden of disease and drug-related deaths worldwide” [1].

Opiates are natural narcotic alkaloids derived from the poppy plant or semi-synthetic derivatives with narcotic properties. Common opiates include morphine, opium and heroin. Opioids are either fully synthetic or semi-synthetic alkaloids formulated to mimic the action of a natural opiate alkaloid. Examples of opioids are hydrocodone and oxycodone. Opiates are more common in the recreational drug world but are also utilized in the medical field, whereas opioids are more common in the medical and pharmaceutical fields but are also abused in the recreational drug world.Currently, many researchers are using the term “opioid” to refer to all opiate/opioid drugs and limiting the use of “opiates” to only natural opium poppy-derived drugs such as morphine. For this reason, the term “opioid” is used here as the common parlance to refer to all opiate/opioid drugs.

Figure 5. Difference between opiates and opioids. Opiates and opioids are commonly confused with each other because they both target opioid receptors in the brain, can be addictive, and can be used in the medical field.

Opioids have the potential to cause substance dependence that is characterized by a strong desire to take opioids, impaired control over opioid use, persistent opioid use despite harmful consequences, a higher priority given to opioid use than to other activities and obligations, increased tolerance, and a physical withdrawal reaction when opioids are discontinued.

The number of people who used opioids, including heroin and prescription painkillers, within the past year is estimated at between 28.6 and 38 million people globally [1]. The majority of people dependent on opioids use illicitly cultivated and manufactured heroin, but an increasing proportion use prescription opioids. Compared to the global average prevalence of 0.7%, opioid use remains high in North America and Oceania, with prevalence rates of 4.3% and 3%, respectively. While opioid use has increased globally over the past year, the primary increase has been observed in the United States. In contrast, opioids have remained the most prevalent primary drug of abuse among those seeking treatment in Asia [1]. According to the data offered by China National Drug Abuse Monitoring Center, in China, the population abusing heroin and other opioids was estimated at 1.458 million by the end of 2014; drug abusers account for 49.3% of registered drug addicts;, and this number has increased 6.4% compared with last year; the rate of heroin abusers infected with HIV is 3.5% [6]. In 2006, the estimated total cost in the United States of nonmedical use of prescription opioids was $53.4 billion, of which $42 billion (79%) was attributable to lost productivity, $8.2 billion (15%) to criminal justice costs, $2.2 billion (4%) to drug abuse treatment, and $944 million to medical complications (2%) [7].

At the heart of opioid addiction is the powerful rewarding effect that occurs when the opioids bind to the opioid receptors, triggering a cascade of intense pleasurable responses related to dopamine release in the brain. Dopamine is a neurotransmitter present in regions of the brain that regulate movement, emotion, cognition, motivation and pleasure. The overstimulation of this system, which rewards our natural behaviors, produces euphoric effects. Users describe an initial rush followed by feelings of warmth, pleasure and sedation. Once regular use is established, vulnerable individuals develop an uncontrollable compulsive behavior that is the primary characteristic of opioid dependence, seeking to obtain the substance in spite of any negative consequence.

Due to the effect of opioids on the portion of the brain that regulates breathing, high doses of opioids can cause respiratory depression and death. Thus, opioids are responsible for a high proportion of fatal drug overdoses around the world. Worldwide, an estimated 69000 people die from opioid overdose each year [8]. The consequences of intravenous opioid drugs are also serious, with the spread of HIV being the worst. Unclean syringes also lead to various infectious diseases such as hepatitis B, hepatitis C, bacterial endocarditis, tetanus and septicemia. Furthermore, those individuals who abuse opioids also account for a greater likelihood of crime, accidents and suicide.

Opioid dependence is a complex health condition that often requires long-term treatment and care. The treatment of opioid dependence is important to reduce its health and social consequences and to improve the well-being and social functioning of the people affected. The primary objectives of treating and rehabilitating persons with opioid dependence are to reduce dependence on illegal drugs, to reduce the morbidity and mortality caused by the use of illicit opioids, to improve physical and psychological health, to reduce criminal behavior, to facilitate reintegration into the workforce and education system and to improve social functioning. The achievement of a drug-free state is the ideal and ultimate objective; however, this objective is unfortunately extremely difficult to obtain, particularly in the short term.

The primary drugs used in treatments of opioid dependence are methadone and naltrexone. Methadone, an opioid receptor agonist, is widely used in the maintenance treatment of opiate addiction, primarily heroin. Methadone reduces adverse drug reactions and takes control of withdrawal symptoms effectively. However, methadone can become a new addiction when abused. Naltrexone, an opioid receptor antagonist, can prevent relapse following detoxification because it can take away the pleasure and has fewer poisonous side effects. Unfortunately, these treatment approaches have their limitations, and the majority of addicts relapse repeatedly following detoxification. According to the data of a prospective follow-up study, the relapse rate of opioid addicts following detoxification is 91%, and the initial relapse occurred within one week in 59% of opioid addicts [9]. This relapse is not because the opioid addicts are “weak” or “morally lax” or are “not trying hard enough”. Instead, this relapse is because opioids change the chemical balance in the brain.

Because opioid drugs are extremely harmful and because the associated relapse following detoxification is very common, this project selected opioid drugs as a target with the aim of developing a new therapeutic strategy to treat opioid addiction and to reduce relapse. The goal was to increase and optimize early interventions for the therapy of addictive opioid abuse that is extraordinarily costly in terms of human life, productivity and expense to society.

To this end, we need a target,a medicine and an agent.

Our strategy

Reference

1. UN World Drug Report, 2014. United Nations Office on Drugs and Crime
2. http://www.cnbc.com/id/100957882
3. UN World Drug Report, 2007. United Nations Office on Drugs and Crime
4. Traci Carl (November 3, 2009). "Progress in Mexico drug war is drenched in blood". Associated Press. Retrieved May 4, 2010.
5. Central America: Out of control March 9th 2013 The Economist
6. 2014 China's drug situation report
7. Hansen RN1, Oster G, Edelsberg J, Woody GE, Sullivan SD. Economic costs of nonmedical use of prescription opioids. Clin J Pain. 2011 Mar-Apr;27(3):194-202.
8. World Health Organization < Information sheet on opioid overdose >
9. Smyth BP1, Barry J, Keenan E, Ducray K. Lapse and relapse following inpatient treatment of opiate dependence. Ir Med J. 2010 Jun;103(6):176-9.
10. Al-Hasani R, Bruchas MR. Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology. 2011 Dec;115(6):1363-81.
11. Kreek MJ, Levran O, Reed B, Schlussman SD, Zhou Y, Butelman ER. Opiate addiction and cocaine addiction: underlying molecular neurobiology and genetics. J Clin Invest. 2012 Oct;122(10):3387-93.
12. Pasternak GW, Pan YX. Mu opioids and their receptors: evolution of a concept. Pharmacol Rev. 2013 Sep 27;65(4):1257-317.
13. Traynor J. μ-Opioid receptors and regulators of G protein signaling (RGS) proteins: from a symposium on new concepts in mu-opioid pharmacology. Drug Alcohol Depend. 2012 Mar 1;121(3):173-80.
14. Matthes HW, Maldonado R, Simonin F et al. Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the µ-opioid-receptor gene. Nature383(6603),819–823 (1996). [CrossRef] [Medline] [CAS]
15. Sora I, Takahashi N, Funada M et al. Opiate receptor knockout mice define µ receptor roles in endogenous nociceptive responses and morphine-induced analgesia. Proc. Natl Acad. Sci. USA94(4),1544–1549 (1997). [CrossRef] [Medline]
16. Loh HH, Liu HC, Cavalli A, Yang W, Chen YF, Wei LN. MOP knockout in mice: effects on ligand-induced analgesia and morphine lethality. Brain Res. Mol. Brain Res.54(2),321–326 (1998). [CrossRef] [Medline]
17. Zhang Y, Landthaler M, Schlussman SD, Yuferov V, Ho A, Tuschl T, Kreek MJ. Mu opioid receptor knockdown in the substantia nigra/ventral tegmental area by synthetic small interfering RNA blocks the rewarding and locomotor effects of heroin. Neuroscience. 2008
18. Mihue Jang, Jong Hwan Kim, Hae Yun Nam, Ick Chan Kwon & Hyung Jun Ahn. Design of a platform technology for systemic delivery of siRNA to tumours using rolling circle transcription, Nature Communications.
19. R. Jorgensen, Altered gene expression in plants due to transinteractions between homologous genes, Trends Biotechnol. 8 (12) (1990) 340–344.
20. A. Fire, S. Xu, M.K. Montgomery, S.A. Kostas, S.E. Driver, C.C. Mello, Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans, Nature 391 (1998) 806–811.
21. S.M. Elbashir, J. Harborth, W. Lendeckel, A. Yalcin, K. Weber, T. Tuschl, Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells, Nature 24 (411) (2001) 494–498.
22. Gulnihal Ozcan, Bulent Ozpolat, Robert L. Coleman, Anil K. Sood , Gabriel Lopez-Berestein , Preclinical and clinical development of siRNA-based therapeutics, Advanced Drug Delivery Reviews 87 (2015) 108–119
23. Ken Howard, Unlocking the money-making potential of RNAi, Nature Biotechnology 21(2008)1441-1446.
24. Joa ˜o Conde, Natalie Artzi, Are RNAi and miRNA therapeutics truly dead, Trends in Biotechnology 33(2015)141-144.
25. Alvarez-Erviti, L. et al. Nat. Biotechnol. 29, 341–345 (2011).
26.Hagiwara K, Ochiya T, Kosaka N. A paradigm shift for extracellular vesicles as small RNA carriers: from cellular waste elimination to therapeutic applications[J]. Drug delivery and translational research. 2014,4(1):31-7.
27. El Andaloussi S, Lakhal S, Mager I, Wood MJ. Exosomes for targeted siRNA delivery across biological barriers[J]. Advanced drug delivery reviews. 2013,65(3):391-7.
28.Stoorvogel W. Functional transfer of microRNA by exosomes[J]. Blood. 2012,119(3):646-8.
29. Jasper G van den Boorn, Martin Schlee, Christoph Coch & Gunther Hartmann. SiRNA delivery with exosome nanoparticles
30. Kaplitt MG, Leone P, Samulski RJ, Xiao X, Pfaff DW, O'Malley KL, et al. Long-term gene expression and phenotypic correction using adeno-associated virus vectors in the mammalian brain[J]. Nature genetics. 1994,8(2):148-54.