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Lupine publishers | Salisbury, Novichok and the OPCW

Lupine Publishers | LOJ Pharmacology & Clinical Research

Abstract

The poisoning of a former russian spy in Salisbury, England, in march 2018, led to the Discovery of several chemical weapons not included in the Chemical Weapons Convention, allegedly developed by the URSS and not declared by Russia. This, in some way, has made diplomatic pressure to modify the lists of chemicals forbbiden or controle by the CWC, with some reluctancia by the russian government and some of their alias. The Organización for the Prohibition of Chemical Weapons (OPCW) has started actions to include novichok agents in the lists of prohibited agents. This is the story.

Keywords: Novichok; Nerve Agents; Poisons; OPCW; Skripal; Salisbury

The Beggining

In the spring of 2018, Sergei Skripal (former russian spy) and his daughter Yulia, started to feel ill. It was found that they were poisoned with a chemical hard to identify; however, an excellent chemical analysis let the analytical team to say that the chemical(s) employed were some nerve agents that were not included in the control lists establishers in the Chemical Weapons Convention (CWC), however, this compounds are chemical weapons of a new class, never declared by any state party member of the CWC. The scientists arrived at the conclusión that the chemicals employed belong to a group of nerve agents known as Novichok. These chemicals act as acetylcholinesterase inhibitors, same as VX or Sarin, but more tonics (it is said that eight times as poisonous as VX, and with effects as rapid as 30 seconds [1-4].

According to Al Jazeera, Skripal and his daughter were found unconscious on a bench outside a mall in Salisbury on March 4, 2018, poisoned. Skripal is a former Russian military intelligence officer accused of spying for the United Kingdom. He was imprisoned in 2006, and later was part of an exchange program for Russian citizens accused of espionage in the United States. He was granted asylum in the United Kingdom. It is considered that the poisoning was made through the knob of the main door of his house, since that was the place where the highest concentration of nerve agent was found. The first actions of the british government included that 23 undeclared Russian intelligence officers were expelled from the UK. Before the analysis of the evidence gave a confirmation of the agent employed, a police officer who visited the Skripal’s home was admited in a hospital with symptoms characteristic with a nerve agent poisoning [5]. In the end, these three victims were capable of recovery. Several weeks later some civilians were found with similar medical condition in Amesbury, a town about 11 km from Salisbury. Charlie Rowley found a fake Premier Jour (Nina Ricci) parfume bottle that he recovered and gave to his wife, Dawn Sturges’. They assambled the atomizer and she applied the liquid in her wrists. And so, they were contaminated. The bottle contained not parfume but a nerve agent. This case was tested as terrorism by the british authorities [6]. Dawn went into ICU at Salisbury Hospital and died a week later. Charlie survived and was released from the hospital, but several days later he was admitted again with an acute case of meningitis and blindness, and unable to move his left arm. On March 12 Theresa May declared: “Either this was a direct action of the Russian State towards our country, or the russian government lost control over the substance with the potential for catastrophic destruction and allowed it to fall into the hands of others. On april 2018, scientists from the Organization for the Prohibition of Chemical Weapons (OPCW) confirmed the presence of Novichok in biological sampling from the Skripals as well as from the site of the presumed contamination. On september of the same year, a couple of suspects were identified, two russian citizens members of the russian intelligence body (GRU), that flew from Moscow to London just two days prior to the Skripal poisoning and were in Salisbury for only 30 minutes. They were identified as Alexander Mishkin, and Anatoly Chepiga Both were honored for their actions in Ukraine [7].

International Reacticos

This situation led to a series of diplomatic actions from several countries: USA expelled 60 russians from its territorial, including 12 officials from the Russia UN misión; UK made the same with 34 russian diplomats. Other EU countries expelled 34 diplomats, Ukraine did the same with 13 diplomats, the OTAN expelled 7 and other countries around the world added for 13 more expelled diplomats [8,9]. On its side, Russia retaliated by expelling 23 british diplomats and 60 from USA. And something bizarre: the russian government conducted a Twitter poll to let the russian people determine which USA consulate was to be closed. The winner was the St. Peterburg one.

In The 1970 Decade, the Soviets had a Nerve Agents Development Program Known as Folinate, that Intended to have Chemicals that were:

a) Non detected by conventional detection OTAN instrumentos;

b) Capable of penétrate the soldares’ body, even with full protecting clothes;

c) Safer to preparation, handling and storage.

By the end of the 1990 decade, the russian government was looking that this chemicals or their precursors were not mentioned by the CWC.

What we know and what we don’t:

Most of what we understood as of 2018 of Novichok agents comes from testimony and memoirs of Dr. Vil S. Mirzayanov, the Chief of the Department of Counteraction against Foreign Technical Intelligence at the Russian State Union Scientific Research Institute for Organic Chemistry and Technology (Gonio) [10]. In 1995, The Stimson Center published a document: Chemical weapons disarmament in Russia: Problems and prospects. 1995, The Stimson Center, consisting of several essays written by various specialists in chemical weapons and in Russia. Particularly, Mirzayanov wrote a paper: Dismantling the Soviet/Russian Chemical Weapons Complex: An Insider’s View. This can be read in this paper, Mirzayanov wrote that the soviets in 1978 finished the construction of a large facility for nerve agent’s production, with capacity to make 20,000 tons annually, and that they produced 15,000 tons of a chemical called Substance 33, similar to the nerve agent VX. He mentions a group of chemicals with the names A-230, A-232, and the series of chemicals called Novichok, intended to be handled as binary weapons, in response to the US Big Eye project, to produce Sarin in a binary way [11,12]. These Novichok chemicals (basically Substance 33, A-230 and A-232, as well as others named Novichok-5, Novichok-7 and a no-name Novichok, tested 1988-19989) were never mentioned in bilateral Memorandums of Understanding designed to promote mutual transparency among URSS/Russia and USA about chemical weapons programs.

Jonathan Tucker informed in 2000, that Russia denied any production of Novichok, but also signed an agreement with the Syria government to create a syrian center for chemical weapons defense, under the cover of a Syrian Center of Ecological Protection, and reports that three russian scientists working in that center were involved on the novichok program; Tucker also says that in 1999 a London based arabic newspaper reported that some Syrian missile warheads were loaded with VX and a novel agent called novichok [13]. So, for as long as 24 years the name novichok has been in the chemical weapons universe, but for over 20 of those years it was some kind of urban legend, untill 2018 when it surfaced publicly and with a lot of noise [14]. We now know that it is another chemical that interferes with the metabolism of the neuro transmitter acetylcholine, binding to the acetylcholinesterase enzyme, and that can result in death. And a recent technical report informs that it is much more toxic than VX because novichok (in a theoretical computer simulation) has fewer conformers than VX; while VX shows 6561 conformers, the novichok A-234 shows 486 and A-230 shows only 54, which leads to a faster binding among the neurotoxic agent and the acetylcholinesterase enzyme that governs the metabolic transformation of acetylcholinesterase.

Novichok and the OPCW

In the sixteenth session of the Scientific Advisory Board (SAB) of the OPCW, 4-6 April 2011, on the agenda item elevenNovel toxic compounds, two of the points discussed were related to novichok. I will reproduce them completelly, according to the published report. 11.1 The Chairperson introduced the topic of new toxic compounds that are not included in the schedules of chemicals. This has been attracting increasing attention in recent years, particularly among non-governmental organizations (NGOs). Although very little information has appeared in the public domain, there have been claims that a new class of nerve agents, known as “Novichoks”, has been developed. In December 2008, a former defence scientist published a book, which included information on structures reported to be those of the new agents. Some of these structures meet the criteria for Schedule 2 B4 (S2 B4); however, all others are non-scheduled chemicals [15]. The author claimed that the toxicity of certain “Novichok” agents may exceed that of VX. 11.2 In a discussion of the issue, SAB members emphasised that, to date, there has been no confirmation of the author’s claims, nor has any peer review been undertaken in regard to the information on these chemicals in the scientific literature on this subject. The SAB noted that those chemicals containing a phosphorus atom to which is bonded one methyl, ethyl or propyl (normal or iso) group but not further carbon atoms would be declarable as S2 B4 chemicals above a threshold of one tone [11]. The SAB asked the Secretariat if such chemicals had ever been declared. The Secretariat replied that it has no record of any such declarations. With respect to nonscheduled chemicals relevant to “Novichoks”, it was noted that for declarations under the other chemical production facility (OCPF) regime, the name of the chemical is not required, and therefore, the Secretariat would not be able to determine (from declarations received) if there are facilities producing “Novichok” agents that are also non-scheduled chemicals. So, as can be seen, the OPCW had an early information, but the internal procedures stablished by the CWC did not permit the organization to go further. However, the SAB understood that it was a serious danger and started working in two areas intended to prevent the resurgement of the chemical weapons, that is, education and outreach.

Because the Salisbury incident, the OPCW made an investigation and concluded (12 april 2018) that it was a toxic agent the chemical employed against Skripal and his daughter, that the identity of this toxic chemical coincided with the one obtained in UK analysis, and that it was of high purity. The name and stucture of the identified toxic chemical are contained in a classified report of the Technical Secretariat of the OPCW, available only to CWC States Parties. On 2 May 2018, the OPCW Director General made a request for information from States Parties on new types of nerve agents, supported by the 12 april report; in the same date, the Director General made an equal request from the SAB [16]. Later, on 4 september 2018, a report from the OPCW Technical Secretariat the findings were that the analysis of a simple of the small bottle found by Charles Rowley and Dawn Sturgess showed that the simple consisted of the same toxic chemical found in the Skripal’s simple, with a concentration of 97-98%. Once again, the name and chemical structure of the toxic chemicals identified are contained in the full confidential report that the Technocal Secretariat of the OPCW made available to all State Parties. The Russian position was that, since novichok was not listed in the prohibited substances, there was no violation of the CWC.

On october 2018, Russia’s military intelligence service (GRU) was accused of a hacking intent against OPCW headquarters, which led to four russians being expelled from The Netherlands after this alleged cyber strike. This came after UK government accused the GRU of some other cyber-attacks across the whole globe. A proposal made jointly by Canada, The Netherlands and the United States was revised in a OPCW Executive Council and in January of 2019 was adopted by the council, so was informed by Sabine Nolde, Canada’s representative, and confirmed the Dutch foreign ministry. This opened a 90 days period to object or make observations to this adopted proposal. In april of 2019 it was expected that the majority of the OPCW members would vote supporting the addition of novichok in the annex of the CWC forbidding some substances.

Conclusion

This kind of poisoning actions by Russia is not new, just remember the Alexander Litvinenko’s murder. This whole case shows that no matter the compromise of an international agreement to ban weapons of mass destruction, there will always be rogué states or groups of non-state actors willing to produce and use them; so, the OPCW must be fiercely supported by all nations and all people concerned with global peace and understanding.

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Lupine Publishers | Pharmacist-Led Antimicrobial Stewardship

Lupine Publishers | LOJ Pharmacology & Clinical Research

 

 

Short Communication

The value of critical care pharmacists has been well documented. Various studies have shown that critical care pharmacists reduce medication errors, improve patient outcomes, reduce costs and waste, and decrease mortality rates among patients with thromboembolic diseases or infections [1,2]. Antimicrobial resistance (AMR) causes prolonged illness, greater risk of infection spread, increased morbidity, and higher mortality rates, which result in increased expenses to the government, healthcare services, and individuals. It is estimated that around 700,000 people die annually from drug-resistant infections, with experts predicting an alarming possible increase to 10 million deaths each year by 2050 and major future challenges to the way we practice medicine and surgery. Resistance has been associated with increasing mortality, treatment failure and healthcare costs [3,4]. This alarming rate exceeds the annual number of deaths caused by cancer (8.2 million) and is almost ten times that of motor vehicle accidents (1.2 million) [5]. In the United States, in addition to significant mortality, antimicrobial resistance adds $20 billion in excess direct health care costs and up to $35 billion in annual societal costs as a result of lost productivity [6]. Antibiotic stewardship was established to combat this trend and was recognized in 1996 to draw attention to the rising incidents in mortality and morbidity associated with inappropriate use of antibiotics [7]. Antibiotic stewardship is a core part of critical care, and many times, the physician will rely on the pharmacist’s recommendations and expertise. Antibiotic Stewardship Recommendations include constituting a team, close coordination between teams, audit, formulary restriction, deescalation, optimizing dosing, active use of information technology among other measure [8].

The Infectious Diseases Society of America guidelines on antimicrobial stewardship recommend that the core multidisciplinary stewardship team include an infectious diseases (ID) physician and a clinical pharmacist with ID training [9]. Antibiotic prescribing in outpatient settings exceeds that of inpatient prescribing, with more than 150 million antibiotic prescriptions annually; of these prescriptions, more than 30% are either unnecessary or inappropriately prescribed [10-12]. Orally administered antimicrobials accounted for approximately 90% of total consumption: oral third generation cephalosporins, macrolides, and fluoroquinolones accounted for approximately 77% of oral consumption. Therefore, pharmacists must extend their support for the appropriate use of antimicrobials prescribed by attending physicians to not only hospitalized patients but also outpatients [13]. As the regulations for antibiotic stewardship in outpatient settings continue to evolve and optimal stewardship strategies are defined, pharmacists must be leaders in the implementation of these programs [14]. Stewardship programs can help, reduce inappropriate prescription and broad-spectrum use of antimicrobials, improve, clinical outcomes for the population as a whole, slow down the emergence of antimicrobial resistance and conserve healthcare resources [3]. The WHO Global Action Plan on Antimicrobial Resistance recommends countries work together to improve awareness and understanding of antimicrobial resistance, including through social media.

The 2018 World Antibiotic Awareness Week campaign used Twitter to tailor media messages about the Global Action Plan [15]. Social media have become important information channels but may not reach people with low knowledge and/or low interest in the subject. Within the EU, countries with low use of antibiotics, such as Sweden and The Netherlands, show a higher population knowledge level [16]. The use of community antibiotic stewardship programs (ASPs) is rising. ASPs involving pharmacists are effective in decreasing antibiotic prescribing and increasing guidelineadherent antibiotic prescribing by GPs [17]. Evidence in China and Netherlands showed that antibiotic stewardship program was associated with more less 80% and more than 25% decrease in cost of antibiotic prophylaxis per procedure respectively [18]. The issue of antimicrobial resistance is worse in low and middleincome countries (LMIC), as the incidence of infectious diseases is high compared to high-income countries. In low and middleincome countries, the mortality rates due to antimicrobialresistant bacteria are under-reported, however, available data in India, Nigeria, Pakistan, and Congo indicate that a huge number of neonatal deaths resulted from drug-resistant sepsis [19]. Annually, more than 50,000 newborns are estimated to die from sepsis due to pathogens resistant to first-line antibiotics [20]. In European countries, antimicrobial resistance is also on the rise and considered to be responsible for about 25,000 deaths annually [21]. Pharmacists are core AMS team members where there is an ongoing need to align continuing education for health professionals with realities of practice. However, antimicrobial stewardship (AMS) is not comprehensively and fully taught in medical or pharmacy curricula and little is known about the relevance of pharmacist training to meet AMS needs [22]. Critically, there is a need for establishing sustainable funding for AMS teams working beyond hospital settings that is not solely derived from cost savings through reduced drug expenditure.

Instead, funding for developing and supporting AMS teams should be considered within the patient safety and healthcarequality-related spending [23]. More recently, the introduction of national stewardship guidelines, and an increased focus on stewardship as part of the UK five-year antimicrobial resistance strategy, have accelerated and embedded developments. Antimicrobial pharmacists have been instrumental in effecting changes at an organizational and national level [24]. A pharmacist dispensing antimicrobials without a prescription is 83-100% of the time unaware of a patient’s allergies status [19]. Inaccurate allergy labelling results in inappropriate antimicrobial management of the patient, which may affect clinical outcome, increase the risk of adverse events and increase costs. Inappropriate use of alternative antibiotics has implications for antimicrobial stewardship programs and microbial resistance. 2019 recommended that a pharmacistled allergy management service is a safe option to promote antimicrobial stewardship and appropriate allergy labelling [25]. 2018 suggested broader adoption for the role of pharmacists in the provision of penicillin skin testing. This would help expand the service and maximize the potential benefits of penicillin skin testing [26]. Pharmacists may be tasked to lead ASP development and implementation with little or no support from an infectious diseases (ID) physician and other hospital personnel whose involvement on ASP teams is recommended (e.g., clinical microbiologists, infection control specialists, hospital epidemiologists) [27]. Pharmacists and other health care professionals should collaborate within multidisciplinary teams (MDTs) to reduce the risk of antimicrobial resistance, thereby reducing the economic burden, improving patients’ quality of life, and reducing hospitalization due to infections [19]. In a UK study, almost 60% of pharmacist’s contributions are made during the MDT round [28]. Research has shown that pharmacists play an important role in the (Emergency Department) ED, but there is a need for data supporting this in specific patient outcomes as the majority of the literature addresses adverse drug event prevention and cost-containment [29]. Critical care pharmacists are recognized in the guidelines from the Society of Critical Care Medicine (SCCM) as essential team members for the delivery of care for critically ill patients. In fact, the return on investment of an ICU pharmacist’s salary approached in multiple studies of critically ill patients with infection [30]. Including critical care pharmacists in the multidisciplinary ICU team improved patient outcomes including mortality, ICU length of stay in mixed ICUs, and preventable/nonpreventable adverse drug events [31].

Although factors, such as a lack of financial resources, may be beyond the control of the pharmacy profession, other factors, such as increased documentation in patient records and increased scholarly work demonstrating pharmacists’ contributions, can and should be addressed more consistently by all critical care pharmacists [32]. The critical care pharmacist ensures the discontinuation of these medications in patients who no longer have an indication. Unfortunately, these medications are sometimes started by the ward team and continued on discharge. Additionally, home maintenance medications are often not resumed on hospital admission and/or subsequent discharge, increasing the risk of death, emergency department visit, or hospitalization. A critical care pharmacist integrated into the ICU-Recovery Center (ICU-RC) may take attempt to identify and treat the types of medication errors found in a population of high-risk ICU [33]. In addition, pharmacists who are often the first point of care, dispense antibiotics without a physician prescription, offer alternative antibiotics even when patients present with a prescription. Within the hospitals lack of monitoring of antibiotic use is one of the major factors driving the spread of resistance [34]. The implementation of antimicrobial stewardship programs in primary health care is suboptimal. This negatively affects the global efforts to control antimicrobial resistance. There is a need to institutionalize national guidelines for AMS in primary health care [35]. Multiple randomized controlled trials (RCTs) have found that shorter courses of antibiotic therapy result in similar cure rates as traditional courses for many types of infections, including UTIs, SSTIs, and pneumonia. Unfortunately, familiarity with short-course therapy as a stewardship tool is limited. A recent study found that only one-third of infectious diseases practitioners from 58 countries recommended short-course therapies [36]. Consequently, some countries have recommended shortening the duration of antibiotic treatment of communityacquired pneumonia (CAP). No significant differences in adverse events were reported. However, none of the trials reported on the impact on the development of resistant bacteria [37]. As with the cost of climate change, estimates of total AMR costs are fraught with uncertainty and may be far too low. This cost depends on various factors: which drug and pathogen are involved, the mechanism of antibiotic resistance, the prevalence of that pathogen, the types of infections it causes and their level of transmissibility, the health burden of those infections, and whether alternative treatments are available [38]. AMS can help pharmacists improve the quality of patient care and improve patient safety through increased infection cure rates, reduced treatment failures, and increased frequency of correct prescribing for therapy and prophylaxis. The cost of employing a pharmacist at the recommended minimum staffing level is approximately £20 per patient per day. Several studies find that the role reduces overall expenditure through more efficient use of medicines and the avoidance of direct costs of iatrogenic harm, with additional savings made from avoiding payouts arising from damages claims [19,27].

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