There are three main therapeutic mechanisms: first, as a substitute for cocaine, it plays a role by producing dopamine-like effects; Second, as an antagonist of cocaine, it hinders the combination of cocaine and dopamine transporter; The third is to regulate the cocaine effect by acting on other cocaine binding sites. What needs to be particularly emphasized is that the relapse rate of drug addicts after detoxification is as high as over 90%. Because the neural mechanism of relapse is not clear, no effective drugs or means to prevent relapse have been developed internationally. Some studies show that most smokers will relapse or have similar reactions within three months. The root of substitutes lies in the reward effect, which is the direct cause of drug addiction. The commonly used methods to evaluate the reward effect of drugs mainly include conditioned place preference (CPP) experiment and self-administration experiment. The known treatment methods of cocaine addiction can't play a fundamental role, and most of them are in the laboratory stage, especially cocaine catalytic antibodies and cocaine vaccines.

Catalytic antibody

Catalytic antibody, also known as antibody enzyme, is an artificial mimic enzyme, which endows antibody with catalytic activity. Cocaine catalytic antibody, developed in the United States, is a kind of catalytic monoclonal antibody induced by phosphate (a transitional analog of cocaine), which can catalyze the degradation of cocaine to benzyl and make it a non-addictive metabolite, repeatedly participate in the process of catalyzing the degradation of cocaine to a non-irritating active product, and prevent cocaine from entering the brain and combining with its receptor. Cocaine catalytic antibody can stay in the body for several weeks or longer after injection, which can ensure that cocaine can be prevented from directly entering the brain within one month.

Monoclonal antibodies hydrolyze cocaine and then remain free, thus restoring its catalytic effect. In animal experiments, four-fifths of the experimental rats were still alive after intravenous drip of lethal dose of cocaine, and all the surviving rats recovered to the reaction level before treatment after 48 hours. The experimental results of bupropion and non-pharmaceutical emulsion enhancer, which are not similar to cocaine in structure, show that the antibody has pharmacological and behavioral specificity in inhibiting cocaine addiction. However, catalytic antibodies can only be effective for low-dose addiction, but not for high-dose repeated cocaine addiction. It is expected that only the development of polyclonal catalytic antibodies or humanized monoclonal catalytic antibodies can overcome these shortcomings.

Butyrylcholinesterase is the most representative catalytic antibody, and some materials even list it as a substitute for cocaine. Butyrylcholinesterase can hydrolyze cocaine into benzoic acid and basionyl formyl, but this process is very slow in human body. The researchers adjusted the amino acids in the near-active region of the enzyme, thus increasing the rate of this reaction by 2500 times. In vitro experiments show that it can shorten the half-life of cocaine.

vaccine

Cocaine vaccine consists of a small amount of drugs, which are chemically attached to inactive protein. It is a high protein (mainly toxin) derivative, which produces antibodies by stimulating the immune system. Anti-cocaine antibodies can lock cocaine molecules in the blood stream, form drug-antibody complexes, reduce the quantity and speed of cocaine entering the brain, and thus reduce the stimulation of cocaine to the brain. If the vaccinated person produces enough antibodies to capture and control most of the cocaine molecules in the blood circulation, cocaine will not produce euphoria or other mental effects that strengthen drug use and addiction.

The vaccine against cocaine was not successful at first. One problem is that cocaine molecules are very small and generally do not stimulate the immune system to respond. However, in 1992, Bagasra et al. used a hemoglobin (KLH) as a carrier to induce anti-cocaine antibodies in rats, and the circulating antibody level was inversely proportional to the analgesic effect. Although the circulating antibody titer is low, it is still difficult to fight against large doses and repeated intake of cocaine. The cocaine vaccine prepared by this idea is equivalent to "drawing a big bull's eye" on the derivative.

Since 1997, Immune Pharmaceutical Company has immunized mice with a combined vaccine of synthetic norcocaine derivatives and bovine serum albumin. The antibody binds to cocaine and norcocaine in a concentration-dependent manner, but the inactive products of cocaine and local anesthetics procaine and lidocaine (different from cocaine in structure) do not bind to it. The titer after active immunization exceeded the peak arterial plasma concentration after repeated cocaine intake. The antibody significantly changed the distribution of cocaine after intravenous injection (increased in plasma and decreased in brain and heart), which was beneficial to its therapeutic use. When cocaine is eliminated by human metabolism, antibodies can still bind cocaine.

Using a new vaccine of recombinant cholera toxin B(rCTB) instead of anti-cocaine monoclonal antibody MO240 produced by immunizing rats with bovine serum can reduce drug addiction of rats and keep their drug-seeking behavior at a low level, which will never return to the pre-immunization level. When high dose (10 times dose) of cocaine was infused, the protective effect of this anti-cocaine monoclonal antibody was not eliminated. The antibody only specifically fights cocaine addiction and does not affect the feeding behavior or food intake of rats.

The effect of cocaine vaccine remains to be seen. It is generally believed that the greatest effect can be achieved only when drug addicts have a strong addiction demand. Otherwise, people who receive treatment will still be addicted to other drugs, and anti-cocaine antibodies will still be unable to identify drugs with similar structures to cocaine. Many cocaine addicts also drink alcohol. Cocaine and ethanol form cocaine in the liver, which is more toxic than the first two. The binding capacity of cocaine and cocaine is equivalent to that of anti-cocaine antibody, so it may be more meaningful to treat this kind of people with this antibody. This immunotherapy may also play a role in the first aid of patients with overdose. The drug itself is not addictive and does not affect the self-administration behavior stimulated by cocaine itself, but it can reduce the drug abuse behavior of rats induced by cocaine-related cues in the secondary program, indicating that the drug can be used to reduce environmental relapse under the condition of minimum self-dependence potential. Alleviate the left shift of brain stimulation reward (BSR) pathway induced by cocaine in mice, but later experiments show that reducing cocaine craving behavior in mice is mainly to antagonize the function of D3 receptor, rather than some agonists. Some people interpret it as different conclusions caused by different experimental conditions and environments, but what is important is that the functions of some agonists and antagonists have not been well distinguished.

1, 2,4-triazole -3- thiopropyl-tetrahydrobenzoazepine is an antagonist with high selectivity and affinity to D3R, in which compound 1 can block the expression of CPP in mice caused by nicotine and cocaine, prevent the recurrence of craving behavior caused by nicotine, reduce the self-oral behavior of alcohol and increase the level of extracellular acetylcholine in the prefrontal cortex of mice.

Other possible treatments

Other treatments for cocaine addiction have also attracted great attention. For example, the abuse of alkyl isoborneol as a stimulant and the treatment of alcohol and nicotine addiction are being studied. Similar to cocaine, Iborn has a wide range of effects on the central nervous system, including inhibiting NMDA receptor, DAT and 5-HT, and its anti-addiction characteristics come from its complex pharmacological effects. In addition, many compounds act on the cocaine pathway indirectly or through almost unknown mechanisms, such as amantadine, which increases DA transmission through unknown mechanisms and can reduce cocaine addiction. Cardiac and cardiovascular therapy

To treat myocardial ischemia induced by cocaine abuse, oxygen inhalation, aspirin and nitrates can be given, and benzodiazepines can be injected intravenously in time to reduce heart rate and blood pressure and relieve chest pain. In addition, heparin can prevent thrombosis. Cocaine-induced coronary artery contraction is mediated by α -adrenoceptors and can be antagonized by α -adrenoceptors. Labetalol can block α and B receptors and can be used to treat cocaine-related chest pain. Compared with cocaine alone, after nasal administration of cocaine (2mg/kg body weight) and intravenous injection of labetalol (0.25mg/kg body weight), the patient's heart rate did not change, the average arterial pressure decreased, and the diameter of coronary artery did not change, which indicated that labetalol could correct the increase of blood pressure caused by cocaine, but could not eliminate the vasoconstriction caused by cocaine.

Nitroglycerin can dilate normal or diseased coronary vessels and eliminate α receptor-mediated vasoconstriction through exercise, smoking and cocaine use. Taking 0.4-0.8mg nitroglycerin sublingually can eliminate normal or pathological vasoconstriction caused by cocaine, and at the same time reduce the average arterial pressure by 10%- 15%, thus improving myocardial blood supply and reducing myocardial oxygen consumption.

If nitrate is ineffective, calcium antagonists can be used as second-line drugs. Coronary intervention should be chosen instead of thrombolysis for ST-segment elevation myocardial infarction caused by cocaine abuse. Because many studies have found that patients will have serious complications after thrombolysis. Cocaine-related myocardial infarction is often caused by vasospasm rather than thrombosis. For patients who are not qualified for coronary intervention, the indications and contraindications of thrombolytic therapy must be strictly controlled.

There is no specific treatment for heart failure caused by cocaine abuse. The Canadian Cardiovascular Association recommends that all patients with heart failure use ACEI and B-blockers, but since many patients continue to take cocaine, ARB should be considered to replace β -blockers in clinic. It is reported that after stopping cocaine for 5~9 months, the patient's heart size and systolic and diastolic function can return to normal, and LVEF is obviously improved.