By inventing dynamite, Alfred Nobel only wanted to ease the hardest work of miners. He could not have imagined the terrible destructive consequences of his invention. And quite often scientists, who direct their efforts to help people, create another "tank", and at the modern level of technology the weapon, which became wittingly or unwittingly a result of such developments, can cause truly terrible troubles: the consequences of dynamite use and even the tragedy in Hiroshima pale before them.
The history of chemical weapons did not begin yesterday. At first, their developers aimed at just killing people, and, as the history of the First World War shows, they have achieved serious success in this. But the further on - the more it became clear that it is possible to kill by more simple and mass methods.
The history of chemical weapons did not begin yesterday. At first, their developers aimed at just killing people, and, as the history of the First World War shows, they have achieved serious success in this. But the further on - the more it became clear that it is possible to kill by more simple and mass methods.
Chemical, biochemical, and biological weapons are far more subtle, effective, and terrifying tools, especially when used with substances whose effects have not yet been adequately studied.
In his article in Nature, Malcolm Dando, a researcher at Bradford University's Bioethics Center, examines the impact of advances in science on the creation of weapons of mass destruction. The paper begins by recalling the terrorist attack on the Nord-Ost theater in 2002. At that time, a tranquilizing chemical (presumably fentanyl, but exact details have not yet been made public) was sprayed into the hall where the hostages were being held when the building was stormed. About a hundred people died as a result of this substance, and the justification for such a step is still highly questionable.
A simple example of such a weapon is pathogens. Not so long ago the world was shaken by the news of white powder in the mail - anthrax spores. It is true that disease-carriers that are used for military purposes must either have spores that are very stable and do not degrade over time (like anthrax) or have the ability to be transmitted very easily from person to person (like smallpox or pneumonic plague).
In his article in Nature, Malcolm Dando, a researcher at Bradford University's Bioethics Center, examines the impact of advances in science on the creation of weapons of mass destruction. The paper begins by recalling the terrorist attack on the Nord-Ost theater in 2002. At that time, a tranquilizing chemical (presumably fentanyl, but exact details have not yet been made public) was sprayed into the hall where the hostages were being held when the building was stormed. About a hundred people died as a result of this substance, and the justification for such a step is still highly questionable.
A simple example of such a weapon is pathogens. Not so long ago the world was shaken by the news of white powder in the mail - anthrax spores. It is true that disease-carriers that are used for military purposes must either have spores that are very stable and do not degrade over time (like anthrax) or have the ability to be transmitted very easily from person to person (like smallpox or pneumonic plague).
In addition, such weapons can be fought with antibiotics, although at this stage it is possible to develop genetically modified pathogens that are resistant to known drugs.
However, modern science no longer deals with such "simple" things as massacres or put downs. As Dando notes, there has been a paradigm shift in research in this area.
A number of drugs exist and are being actively developed (Valium and its new analogues, the composition of which has not been disclosed), the administration of which to a person causes a sharp drop in aggression. Some companies already advertise the commercially available oxytocin, which causes a sudden explosion of confidence in the person they are talking to. There are substances, the introduction of which causes stupor in a person: it becomes difficult to speak, coordination of movements deteriorates, thought processes are slowed down.
Even anesthetics and sedatives known and successfully used for medical purposes, in large doses or when administered to a healthy person who does not need treatment, can become a weapon. Although the efficacy of such available drugs is questionable, such research opens the way to mechanisms for manipulating people's emotions for military purposes.
However, modern science no longer deals with such "simple" things as massacres or put downs. As Dando notes, there has been a paradigm shift in research in this area.
A number of drugs exist and are being actively developed (Valium and its new analogues, the composition of which has not been disclosed), the administration of which to a person causes a sharp drop in aggression. Some companies already advertise the commercially available oxytocin, which causes a sudden explosion of confidence in the person they are talking to. There are substances, the introduction of which causes stupor in a person: it becomes difficult to speak, coordination of movements deteriorates, thought processes are slowed down.
Even anesthetics and sedatives known and successfully used for medical purposes, in large doses or when administered to a healthy person who does not need treatment, can become a weapon. Although the efficacy of such available drugs is questionable, such research opens the way to mechanisms for manipulating people's emotions for military purposes.
The current dynamics of mind control tools are quite alarming, even though much of the research in this area is not made public.
Fentanyl derivatives with a substituent in the 4-position of the piperidine nucleus are identified as a separate group of incapacitants. These analgesics were synthesized much later than fentanyl and have a more attractive pharmacological profile, and three of them: sufentanil, alfentanil and remifentanil have found use in medicine. Carfentanil, which by its chemical structure is 4-carbomethoxy-fentanyl, is used in veterinary medicine to immobilize large animals.
Incapacitants of this group have been studied in the United States, China, and Russia. The majority of the military gives high marks to the military chemical potential of fentanyl derivatives: «When used suddenly, when the enemy is taken by surprise, the effect of narcotic analgesics and emetics can be overwhelming. The effect of analgesics is knockout - the live force of the attacked troops loses the ability to stay on their feet, much less to move, within minutes of the onset of the chemical attack. In severe cases people fall into unconsciousness.»
Fentanyl derivatives with a substituent in the 4-position of the piperidine nucleus are identified as a separate group of incapacitants. These analgesics were synthesized much later than fentanyl and have a more attractive pharmacological profile, and three of them: sufentanil, alfentanil and remifentanil have found use in medicine. Carfentanil, which by its chemical structure is 4-carbomethoxy-fentanyl, is used in veterinary medicine to immobilize large animals.
Incapacitants of this group have been studied in the United States, China, and Russia. The majority of the military gives high marks to the military chemical potential of fentanyl derivatives: «When used suddenly, when the enemy is taken by surprise, the effect of narcotic analgesics and emetics can be overwhelming. The effect of analgesics is knockout - the live force of the attacked troops loses the ability to stay on their feet, much less to move, within minutes of the onset of the chemical attack. In severe cases people fall into unconsciousness.»
However, the tragic experience of using fentanyl during the liberation of hostages in 2002, which ended in the death of 130 people, and numerous experiments on animals do not allow us to classify substances of this group as incapacitants. Thus, according to scientists from the Defense Science and Technology Research Laboratory (DSTL), carfentanil and remifentanil have close therapeutic and lethal doses, which will lead to high lethality in humans in the absence of timely and specialized medical care.
Is Carfentanil the most powerful opioid?
Carfentanil is considered the strongest of the commercially available narcotic analgesics, being 40 times more effective than fentanyl and 8,000 to 10,000 times more effective than morphine. Other than an extremely low effective dose, it has no advantage over other analgesics and is therefore only used in veterinary practice to temporarily immobilize large animals such as bears, rhinos, and elephants.
Carfentanil is used to equip special cartridges - "flying syringes" or in food baits, where it has replaced the etorphine previously used for this purpose.
Synthesis: synthesized in 1976 by Janssen Pharmaceutica. The first versions of the synthesis were so imperfect that in some steps the yield of the intermediate product did not exceed 1%.
In the early 90's for the needs of the U.S. Army were developed much more productive schemes for obtaining carfentanil, which increased the yield of the final product by 7 times compared to the original method.
A simple and fast UGI-4CC reaction proposed in 2010 has simplified carfentanil production even more, allowing to obtain remifentanil and carfentanil in two stages with the yield of 67-70%. Modern methods of carfentanil synthesis do not require expensive reagents and are relatively cheap.
Carfentanil is considered the strongest of the commercially available narcotic analgesics, being 40 times more effective than fentanyl and 8,000 to 10,000 times more effective than morphine. Other than an extremely low effective dose, it has no advantage over other analgesics and is therefore only used in veterinary practice to temporarily immobilize large animals such as bears, rhinos, and elephants.
Carfentanil is used to equip special cartridges - "flying syringes" or in food baits, where it has replaced the etorphine previously used for this purpose.
Synthesis: synthesized in 1976 by Janssen Pharmaceutica. The first versions of the synthesis were so imperfect that in some steps the yield of the intermediate product did not exceed 1%.
In the early 90's for the needs of the U.S. Army were developed much more productive schemes for obtaining carfentanil, which increased the yield of the final product by 7 times compared to the original method.
A simple and fast UGI-4CC reaction proposed in 2010 has simplified carfentanil production even more, allowing to obtain remifentanil and carfentanil in two stages with the yield of 67-70%. Modern methods of carfentanil synthesis do not require expensive reagents and are relatively cheap.
In 2008, Imam Khomeini University in Iran, known for its work on the synthesis of incapacitants and irritants, proposed an efficient method to obtain phenethylpiperidone, the main precursor in the synthesis of fentanyls, from the available and inexpensive phenylethylamine and methylacrylate. Interestingly, this unique method was developed by underground Russian chemists from a Kazan criminal group for the synthesis of "white Chinese" back in 1992.
Use: It is no longer a secret that fentanyl was part of the chemical arsenal of the former Soviet Union. The first references to the Soviet narcotic gas date back to 1969, which was allegedly used during the Sino-Soviet border conflict on Damansky Island. Later, the CIA claimed that a fast-acting narcotic chemical agent, referred to in publications under the unofficial name of "Blue-X" or "Black Rain," was used by the Soviet Army in Afghanistan and by the Vietnamese Army in Cambodia.
Use: It is no longer a secret that fentanyl was part of the chemical arsenal of the former Soviet Union. The first references to the Soviet narcotic gas date back to 1969, which was allegedly used during the Sino-Soviet border conflict on Damansky Island. Later, the CIA claimed that a fast-acting narcotic chemical agent, referred to in publications under the unofficial name of "Blue-X" or "Black Rain," was used by the Soviet Army in Afghanistan and by the Vietnamese Army in Cambodia.
The substance had such a lightning effect that a person would fall asleep almost instantly and when they woke up they were still in the same position as they had been seconds before exposure to the gas. U.S. intelligence believed that under this name was already known at the time as fentanyl. Later, it was replaced by the more active incapacitants of this group - carfentanil and remifentanil.
Little is known about Blue-X: supposedly it was synthesized in the USSR in the 1980s, effective by inhalation, odorless. It was used by spraying from aircraft and in mortar shells. The first symptoms of poisoning occur after 10 minutes and are manifested by loss of consciousness, respiratory and cardiac depression. Average duration of action is 2-8 hours.
Given the extremely high toxicity of fentanyls, their effects are more similar to those of the lethal poisonous substances described in sources under various names - "Instant Death", "Sleeping Death" and "The Flash". These toxic substances were colorless and odorless, and acted so quickly that victims were found in combat positions, holding rifles in their hands, with their eyes open and their fingers on the triggers.
Little is known about Blue-X: supposedly it was synthesized in the USSR in the 1980s, effective by inhalation, odorless. It was used by spraying from aircraft and in mortar shells. The first symptoms of poisoning occur after 10 minutes and are manifested by loss of consciousness, respiratory and cardiac depression. Average duration of action is 2-8 hours.
Given the extremely high toxicity of fentanyls, their effects are more similar to those of the lethal poisonous substances described in sources under various names - "Instant Death", "Sleeping Death" and "The Flash". These toxic substances were colorless and odorless, and acted so quickly that victims were found in combat positions, holding rifles in their hands, with their eyes open and their fingers on the triggers.
According to a spokesman for the U.S. State Representative: deaths occurred because they "just forgot to breathe." There were scattered reports of the use of such a poisonous substance from Yemen (1963-1967) and even Eritrea.
In 2002, during the hostage rescue operation at Dubrovka, an unknown narcotic gas was used to put the terrorists to sleep, killing 130 people.
According to the official statement of the federal services, a "special recipe based on fentanyl derivatives" was used. Thomas Zilker, a German toxicologist, confirmed that a US laboratory had found traces of two fentanyl derivatives in the samples of German victims of the unknown gas. At the insistence of the U.S. side, however, he refused at the time to provide the exact names of the opioids used.
Exactly 10 years after the seizure of the Dubrovka theater complex, in 2012 the British Defense Science and Technology Laboratory (DSTL) published a report on the results of blood, urine and clothing samples obtained from the three British victims of the attack. Carfentanil, remifentanil and their metabolites were detected in the tests.
Toxicity: the high therapeutic index of carfentanil in rodents and dogs led to the erroneous conclusion that in humans, too, the lethal dose would be hundreds or even thousands of times higher than the anesthetic dose. But, as it turned out, carfentanil, even in doses that do not cause complete unconsciousness, leads to deadly respiratory depression.
Toxicity: the high therapeutic index of carfentanil in rodents and dogs led to the erroneous conclusion that in humans, too, the lethal dose would be hundreds or even thousands of times higher than the anesthetic dose. But, as it turned out, carfentanil, even in doses that do not cause complete unconsciousness, leads to deadly respiratory depression.
Carfentanil is the most toxic substance synthesized by humans, even more potent than such chemical warfare agents (including the Novichok agent). Considering the results of chemotoxicological tests of victims of fatal overdoses, the lethal dose of carfentanil is about 50 mcg, and according to Peter Stout, chief executive director of Houston Forensic Center, death can occur after taking 20 mcg of analgesic. For comparison, the estimated average lethal dose (LD50) of VX is about 600 micrograms per person.
In humans, the average incapacitating concentration of carfentanil analgesics is estimated to be 0.07-0.35 mg-min/m3. According to calculations, during the operation to free the hostages in the Dubrovka theater complex (2002), it was sufficient to spray only 650 grams of the drug in the hall.
Carfentanil and other powerful opioids are able to penetrate through the intact skin, with this method of administration anesthesia in experimental animals came in 15-20 minutes.
In humans, the average incapacitating concentration of carfentanil analgesics is estimated to be 0.07-0.35 mg-min/m3. According to calculations, during the operation to free the hostages in the Dubrovka theater complex (2002), it was sufficient to spray only 650 grams of the drug in the hall.
Carfentanil and other powerful opioids are able to penetrate through the intact skin, with this method of administration anesthesia in experimental animals came in 15-20 minutes.
Alfentanil is a fast but dangerous opioid
In 1989, the National Institute of Justice (NIJ) decided to spend half a million dollars to find and research substances capable of immobilizing criminals without harming them.
The research was conducted at Lawrence National Laboratory in Livermore, California, under the direction of Ray Finucane. According to the developers, a precisely calculated dose of the drug was to be delivered to the target in a dart fired from a special weapon. Unlike an aerosol, this method of delivery significantly reduced the risk of overdose and side effects.
Taking into account that the main requirement was a quick unconsciousness, the first candidate for this role was a synthetic analgesic used in anesthesiology - alfentanil (Alfentanil, Alfenta). This analgesic was well enough studied, its effect was four times faster than that of fentanyl, and it was widely used in anesthesiology, which should have reassured the public opinion. The first results of experiments with alfentanil were very encouraging, and in 1990 580 thousand dollars had already been spent on this research.
In 1989, the National Institute of Justice (NIJ) decided to spend half a million dollars to find and research substances capable of immobilizing criminals without harming them.
The research was conducted at Lawrence National Laboratory in Livermore, California, under the direction of Ray Finucane. According to the developers, a precisely calculated dose of the drug was to be delivered to the target in a dart fired from a special weapon. Unlike an aerosol, this method of delivery significantly reduced the risk of overdose and side effects.
Taking into account that the main requirement was a quick unconsciousness, the first candidate for this role was a synthetic analgesic used in anesthesiology - alfentanil (Alfentanil, Alfenta). This analgesic was well enough studied, its effect was four times faster than that of fentanyl, and it was widely used in anesthesiology, which should have reassured the public opinion. The first results of experiments with alfentanil were very encouraging, and in 1990 580 thousand dollars had already been spent on this research.
In those years, alfentanil was considered the fastest-acting of all known opioids, its effects were felt as early as 20 seconds after injection. It is weaker than fentanyl, but its effect is much shorter - about 15 minutes. The dosage usually used for anesthesia, 5-11 mcg/kg, does not cause serious complications.
However, if you exceed the therapeutic dose by only 4 times, as there is a danger of fatal respiratory arrest. For this reason, the researchers had to abandon further experiments with alfentanil and search for a safer alternative.
Disappointed with alfentanil, scientists at the Livermore laboratory decided to switch to Lofentanil, which, although inferior to its predecessor in speed of action, was much safer.
Lofentanil is chemically a 3-methyl derivative of carfentanil and is just as active as the latter - doses of less than 1 microgram cause analgesia and a sedative effect.
However, the project manager was dissatisfied with the results of these tests. In his opinion, the use of opioids as incapacitants required much greater safety and speed than that of lofentanil. It was also unsuitable as an incapacitant or a drug because it was not well treated with the antidote naloxone.
However, if you exceed the therapeutic dose by only 4 times, as there is a danger of fatal respiratory arrest. For this reason, the researchers had to abandon further experiments with alfentanil and search for a safer alternative.
Disappointed with alfentanil, scientists at the Livermore laboratory decided to switch to Lofentanil, which, although inferior to its predecessor in speed of action, was much safer.
Lofentanil is chemically a 3-methyl derivative of carfentanil and is just as active as the latter - doses of less than 1 microgram cause analgesia and a sedative effect.
However, the project manager was dissatisfied with the results of these tests. In his opinion, the use of opioids as incapacitants required much greater safety and speed than that of lofentanil. It was also unsuitable as an incapacitant or a drug because it was not well treated with the antidote naloxone.
Ohlofentanil (Ohmecarfentanil)
Also, as in the case of Ohmecarfentanil, the 3-methyl group in the piperidine and the 2-hydroxyl group in the phenylethyl chain increase the activity by 20-33%. Ohmecarfentanil and its oxyethyl homologue, NIH 10792, are considered the strongest opioids tested on primates - these compounds outperform morphine by 30,000 times in the monkey withdrawal suppression test.
A compound called 4''-Iodo-Ohmecarfentanil is mentioned in forums devoted to the synthesis of designer drugs. A case is described where the injection of just 3 micrograms (0.000003 mg) of this substance almost caused an overdose in an addict with a high tolerance to heroin.
Also, as in the case of Ohmecarfentanil, the 3-methyl group in the piperidine and the 2-hydroxyl group in the phenylethyl chain increase the activity by 20-33%. Ohmecarfentanil and its oxyethyl homologue, NIH 10792, are considered the strongest opioids tested on primates - these compounds outperform morphine by 30,000 times in the monkey withdrawal suppression test.
A compound called 4''-Iodo-Ohmecarfentanil is mentioned in forums devoted to the synthesis of designer drugs. A case is described where the injection of just 3 micrograms (0.000003 mg) of this substance almost caused an overdose in an addict with a high tolerance to heroin.
Sufentanil - safe, but slow
Sufentanil was first obtained in 1974. Prior to the discovery of remifentanil, it was considered the safest analgesic among fentanyl derivatives and one of the few to find medical use.
Sufentanil has less depressant effect on the cardiovascular system than fentanyl and is considered a safer analgesic. In surgery it is used, for example, in open heart surgery. Sufentanil is 7-10 times stronger than fentanyl and about 1000 times stronger than morphine. Sufentanil is slow in action - complete loss of consciousness in a person only 3 minutes after intravenous injection.
The first references to the possibility of using sufentanil as an incapacitant date back to 1980, when the Advanced Riot Control Device development program discussed the possibility of using carfentanil and sufentanil for temporary human immobilization.
The next phase of this program planned to study a combination of these fentanyls and the antidote naloxone, which reduces the risk of respiratory arrest in opioid poisoning. Details of this work were not disclosed.
Sufentanil was first obtained in 1974. Prior to the discovery of remifentanil, it was considered the safest analgesic among fentanyl derivatives and one of the few to find medical use.
Sufentanil has less depressant effect on the cardiovascular system than fentanyl and is considered a safer analgesic. In surgery it is used, for example, in open heart surgery. Sufentanil is 7-10 times stronger than fentanyl and about 1000 times stronger than morphine. Sufentanil is slow in action - complete loss of consciousness in a person only 3 minutes after intravenous injection.
The first references to the possibility of using sufentanil as an incapacitant date back to 1980, when the Advanced Riot Control Device development program discussed the possibility of using carfentanil and sufentanil for temporary human immobilization.
The next phase of this program planned to study a combination of these fentanyls and the antidote naloxone, which reduces the risk of respiratory arrest in opioid poisoning. Details of this work were not disclosed.
In 1995, T.H. Stanley of Salt Lake City University (USA) conducted an interesting experiment, the purpose of which was to study the possibility of using sufentanil for temporary immobilization of humans. After intramuscular injection of sufentanil, participants were asked to walk uninterruptedly to determine the time of effect.
It was found that sufentanil caused impaired coordination and loss of mobility after 15 min. Increasing the dose allowed to reduce the time of effect to 10 minutes, but there were signs of respiratory depression, and the volunteers had to be given the antidote - naloxone.
In the future it was planned to continue experiments with the combination sufentanil/nalmefen, which, according to T. Stanley, would increase the dose of the drug, and therefore achieve even more rapid immobilization, while the opioid antagonist - nalmefen would not allow the development of deadly respiratory depression.
In order to speed up the onset of immobilization in animals, veterinarians add a certain enzyme to the composition - hyaluronidase. With its help they manage to reduce the time to complete immobilization of the animal by 50%. This is despite the fact that such a common analgesic in veterinary medicine as tiafentanil is fast-acting for 2-3 minutes.
It was found that sufentanil caused impaired coordination and loss of mobility after 15 min. Increasing the dose allowed to reduce the time of effect to 10 minutes, but there were signs of respiratory depression, and the volunteers had to be given the antidote - naloxone.
In the future it was planned to continue experiments with the combination sufentanil/nalmefen, which, according to T. Stanley, would increase the dose of the drug, and therefore achieve even more rapid immobilization, while the opioid antagonist - nalmefen would not allow the development of deadly respiratory depression.
In order to speed up the onset of immobilization in animals, veterinarians add a certain enzyme to the composition - hyaluronidase. With its help they manage to reduce the time to complete immobilization of the animal by 50%. This is despite the fact that such a common analgesic in veterinary medicine as tiafentanil is fast-acting for 2-3 minutes.
