Post-exposure Therapy Research Articles

Diabetogenic potential of dexamethasone and effect Annona muricata methanolic bark extract as post-exposure therapy in albino rats

Diabetes mellitus (DM) is a metabolic disorder leading to high level of morbidity and mortality in human population and it has been identified as the leading cause of death from non-infectious diseases. The use of dexamethasone has been on the increase due to wide array of therapeutic effects it has and the use has mostly been without prescription, since it is a non- prescription drug. Therefore, the potential of dexamethasone to induce DM was studied. Some of the drugs currently used in the treatment of diabetes have their own problematic effects and also expensive, Annona muricata methanolic bark extract(AMMBE) was used in the treatment of dexamethasone-induced diabetes in rats. The research was carried out on albino rats in Federal College of Animal Health and Production Technology, Ibadan and lasted for twenty-eight (28) days. The rats were allotted into four groups (A, B, C and D). Group B, C and D were induced with glucocorticoid (Dexamethasone) (2mgkg-1) daily for seven (7) days intraperitoneally, while group A which was the positive control were given distilled water throughout without induction with glucocorticoid. Group B (the negative control) was induced with glucocorticoid with noAMMBE administration. Group C, was induced and treated with AMMBE at 400 mgkg-1for 14 days. While Group D, was induced with glucocorticoid and were treated with the standard drug (glibenclamide) at 2.5mgkg-1body weight of the rats daily for 14 days. Organ samples of liver, kidney and pancreas were collected for histopathological lesions evaluation. The result showed that dexamethasone induced diabetes after seven (7) days of intraperitoneal administration of 2 mgkg-1 body weights with the glucometer readings in most of the albino rats up to and above 129 mgdL-1. The average blood sugar levels in induced groups (B, C and D) were 132.0±4.05, 129.0±1.41 and130.0±2.93, respectively which were not statistically significant (P>0.05). After administration of AMMBE, the average blood sugar level for group B (126.0±1.41) was significantly different (P<0.05) from C (91.0±1.72) and D (87.0±2.97). Clinical signs of alopecia, dehydration, writhing, paw-licking were observed. There were massive losses of pancreatic cell mass grossly afterinduction with dexamethasone. Histopathological lesions observed ranges from no visible lesion in the control and glibenclamide treated groups to accentuation of hepatocytes in the AMMBE treated rats, and marked vacuolar degeneration of hepatocytes in periportal areas to centrilobular area with Kidney degeneration and multifocal coagulation necrosis of tubular epithelium in group induced with dexamethasone but untreated (group B)Diabetogenic potential of dexamethasone and effect Annona muricata methanolic bark extract degeneration, multifoci coagulation and necrosis. The blood sugar levels post exposure to AMMBE and Glibenclamide showed reduction in the sugar levels. It could be concluded that dexamethasone has the potential of inducing diabetes when its use is prolonged and AMMBE has antidiabetic effect which could be fully explored.

A Cluster-Randomized Trial of Hydroxychloroquine for Prevention of Covid-19

BackgroundCurrent strategies for preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are limited to nonpharmacologic interventions. Hydroxychloroquine has been proposed as a postexposure therapy to prevent coronavirus disease 2019 (Covid-19), but definitive evidence is lacking.MethodsWe conducted an open-label, cluster-randomized trial involving asymptomatic contacts of patients with polymerase-chain-reaction (PCR)–confirmed Covid-19 in Catalonia, Spain. We randomly assigned clusters of contacts to the hydroxychloroquine group (which received the drug at a dose of 800 mg once, followed by 400 mg daily for 6 days) or to the usual-care group (which received no specific therapy). The primary outcome was PCR-confirmed, symptomatic Covid-19 within 14 days. The secondary outcome was SARS-CoV-2 infection, defined by symptoms compatible with Covid-19 or a positive PCR test regardless of symptoms. Adverse events were assessed for up to 28 days.ResultsThe analysis included 2314 healthy contacts of 672 index case patients with Covid-19 who were identified between March 17 and April 28, 2020. A total of 1116 contacts were randomly assigned to receive hydroxychloroquine and 1198 to receive usual care. Results were similar in the hydroxychloroquine and usual-care groups with respect to the incidence of PCR-confirmed, symptomatic Covid-19 (5.7% and 6.2%, respectively; risk ratio, 0.86 [95% confidence interval, 0.52 to 1.42]). In addition, hydroxychloroquine was not associated with a lower incidence of SARS-CoV-2 transmission than usual care (18.7% and 17.8%, respectively). The incidence of adverse events was higher in the hydroxychloroquine group than in the usual-care group (56.1% vs. 5.9%), but no treatment-related serious adverse events were reported.ConclusionsPostexposure therapy with hydroxychloroquine did not prevent SARS-CoV-2 infection or symptomatic Covid-19 in healthy persons exposed to a PCR-positive case patient. (Funded by the crowdfunding campaign YoMeCorono and others; BCN-PEP-CoV2 ClinicalTrials.gov number, NCT04304053.)

Post-exposure prophylaxis for Blood-Borne Viral (BBV) Infections

Viral infections, such as human immunodeficiency virus (HIV), hepatitis B (HBV) and hepatitis C (HCV), are transmitted either sexually or through blood-borne contamination. The later causes enormous concern within health establishments and health care-workers.Post-exposure management of HIV rests on the use of triple Anti-Retroviral Therapy (ART), but special care must be taken to choose the right combination for particular circumstances, especially when the subject is pregnant or likely to get pregnant from the event.New-borns of mothers living with HIV require special attention, as maternal viral load plays a central role in their management. When viral load is not detectable, there is a good argument to avoid ART in these infants. Continued maternal ART is encouraged more so in women who intend to breastfeed.The management of exposure to Hepatitis B requires a detailed risk assessment of the source. In high-risk cases, Hep B immunoglobulin will be necessary otherwise passive immunisation with HBV vaccine will suffice.The use of anti-viral treatment for exposure to Hepatitis C remains controversial. New and potent drugs have been introduced but are quite expensive, and the cost-effectiveness of post-exposure therapy should be considered. Curative treatment now exists for HCV, and an option might be to follow exposed subjects up and give them definitive treatment if seroconversion occurs.This review discusses in details the practical steps in the management of sexual and occupational exposure to HIV and other blood-borne viruses with emphasis on preventing infections. Healthcare facilities should have tightly managed protocols for the management of exposure and the ability to start medication as early as possible when indicated.

A panel of human neutralizing mAbs targeting SARS-CoV-2 spike at multiple epitopes

The novel highly transmissible human coronavirus SARS-CoV-2 is the causative agent of the COVID-19 pandemic. Thus far, there is no approved therapeutic drug specifically targeting this emerging virus. Here we report the isolation and characterization of a panel of human neutralizing monoclonal antibodies targeting the SARS-CoV-2 receptor binding domain (RBD). These antibodies were selected from a phage display library constructed using peripheral circulatory lymphocytes collected from patients at the acute phase of the disease. These neutralizing antibodies are shown to recognize distinct epitopes on the viral spike RBD. A subset of the antibodies exert their inhibitory activity by abrogating binding of the RBD to the human ACE2 receptor. The human monoclonal antibodies described here represent a promising basis for the design of efficient combined post-exposure therapy for SARS-CoV-2 infection.

Intramuscular Delivery of Replicon RNA Encoding ZIKV-117 Human Monoclonal Antibody Protects against Zika Virus Infection

Monoclonal antibody (mAb) therapeutics are an effective modality for the treatment of infectious, autoimmune, and cancer-related diseases. However, the discovery, development, and manufacturing processes are complex, resource-consuming activities that preclude the rapid deployment of mAbs in outbreaks of emerging infectious diseases. Given recent advances in nucleic acid delivery technology, it is now possible to deliver exogenous mRNA encoding mAbs for in situ expression following intravenous (i.v.) infusion of lipid nanoparticle-encapsulated mRNA. However, the requirement for i.v. administration limits the application to settings where infusion is an option, increasing the cost of treatment. As an alternative strategy, and to enable intramuscular (IM) administration of mRNA-encoded mAbs, we describe a nanostructured lipid carrier for delivery of an alphavirus replicon encoding a previously described highly neutralizing human mAb, ZIKV-117. Using a lethal Zika virus challenge model in mice, our studies show robust protection following alphavirus-driven expression of ZIKV-117 mRNA when given by IM administration as pre-exposure prophylaxis or post-exposure therapy.

Inhibitors of SARS-CoV-2 Entry: Current and Future Opportunities.

Recently, a novel coronavirus initially designated 2019-nCoV but now termed SARS-CoV-2 has emerged and raised global concerns due to its virulence. SARS-CoV-2 is the etiological agent of “coronavirus disease 2019”, abbreviated to COVID-19, which despite only being identified at the very end of 2019, has now been classified as a pandemic by the World Health Organization (WHO). At this time, no specific prophylactic or postexposure therapy for COVID-19 are currently available. Viral entry is the first step in the SARS-CoV-2 lifecycle and is mediated by the trimeric spike protein. Being the first stage in infection, entry of SARS-CoV-2 into host cells is an extremely attractive therapeutic intervention point. Within this review, we highlight therapeutic intervention strategies for anti-SARS-CoV, MERS-CoV, and other coronaviruses and speculate upon future directions for SARS-CoV-2 entry inhibitor designs.

Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody.

Severe acute respiratory syndrome coronavirus2 (SARS-CoV-2) is a newly emerged coronavirus that is responsible for the current pandemic of coronavirus disease 2019 (COVID-19), which has resulted in more than 3.7million infections and 260,000deaths as of 6May 20201,2. Vaccine and therapeutic discovery efforts are paramount to curb the pandemic spread of this zoonotic virus. The SARS-CoV-2 spike (S) glycoprotein promotes entry into host cells and is the main target of neutralizing antibodies. Here we describe several monoclonal antibodies that target the Sglycoprotein of SARS-CoV-2, which we identified from memory Bcells of an individual who was infected with severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003. One antibody (named S309) potently neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2, by engaging the receptor-binding domain of the Sglycoprotein. Using cryo-electron microscopy and binding assays, we show that S309 recognizes an epitope containing a glycan that is conserved within the Sarbecovirus subgenus, without competing with receptor attachment. Antibody cocktails that include S309 in combination with other antibodies that we identified further enhanced SARS-CoV-2 neutralization, and may limit the emergence of neutralization-escape mutants. These results pave the way for using S309 and antibody cocktails containing S309 for prophylaxis in individuals at a high risk of exposure or as a post-exposure therapy to limit or treat severe disease.

Mapping Immunodominant Antibody Epitopes of Abrin.

Abrin, a toxin isolated from the seeds of Abrus precatorius (jequirity pea) is considered a biological threat agent by the Center for Disease Control and Prevention. To date, there is no effective postexposure treatment for abrin poisoning, and efforts are being made to develop an efficient vaccine and measures for postexposure therapy. Epitope mapping is widely applied as an efficient tool for discovering the antigenic moieties of toxins, thus providing invaluable information needed for the development of vaccines and therapies. Aiming to identify the immunodominant epitopes of abrin, several neutralizing antiabrin polyclonal antibodies were screened using a set of 15-mer peptides spanning the amino acid sequence of either the A or B subunits of abrin. Analysis of the antibody-binding pattern revealed 11 linear epitopes for the A subunit and 14 epitopes for the B subunit that are located on the surface of the toxin and thus accessible for antibody interactions. Moreover, the spatial location of several of these epitopes suggests they may block the galactose-binding pockets or the catalytic domain, thus neutralizing the toxin. These findings provide useful information and suggest a possible strategy for the development and design of an improved abrin-based vaccine and therapeutic antibodies.

Development of an antibody cocktail for treatment of Sudan virus infection

Antibody-based therapies are a promising treatment option for managing ebolavirus infections. Several Ebola virus (EBOV)-specific and, more recently, pan-ebolavirus antibody cocktails have been described. Here, we report the development and assessment of a Sudan virus (SUDV)-specific antibody cocktail. We produced a panel of SUDV glycoprotein (GP)-specific human chimeric monoclonal antibodies (mAbs) using both plant and mammalian expression systems and completed head-to-head in vitro and in vivo evaluations. Neutralizing activity, competitive binding groups, and epitope specificity of SUDV mAbs were defined before assessing protective efficacy of individual mAbs using a mouse model of SUDV infection. Of the mAbs tested, GP base-binding mAbs were more potent neutralizers and more protective than glycan cap- or mucin-like domain-binding mAbs. No significant difference was observed between plant and mammalian mAbs in any of our in vitro or in vivo evaluations. Based on in vitro and rodent testing, a combination of two SUDV-specific mAbs, one base binding (16F6) and one glycan cap binding (X10H2), was down-selected for assessment in a macaque model of SUDV infection. This cocktail, RIID F6-H2, provided protection from SUDV infection in rhesus macaques when administered at 50 mg/kg on days 4 and 6 postinfection. RIID F6-H2 is an effective postexposure SUDV therapy and provides a potential treatment option for managing human SUDV infection.

A survey investigating the current practice of French health professionals regarding infection risk after monkey bites.

International tourism is steadily increasing, with 15% of travellers reporting health problems when they come back. Animal bites represent 2% of consulting causes, of which 20% are due to monkey bites. The Monkey B virus (Macacine alphaherpesvirus 1) is an alphaherpesvirus (Herpesviridae, genus Simplexvirus) enzootic in macaques (Genus Macaca). Zoonotic infections with the Monkey B virus following exposure to macaques are exceptionally rare, but can cause fatal encephalomyelitis in humans. An observational survey was undertaken in 2018 to assess the practice of French health professionals regarding infection risk after monkey bites. French health professionals practicing in vaccination and rabies centres were specifically targeted for this study. Standardized questionnaires were sent by email to a sample of French health professionals. They were asked to participate on a voluntary and anonymous basis. The questionnaires requested epidemiological details and included multiple-choice questions about the infection management of monkey bites. The response rate was 33.5%. The frequency of monkey bites in 2017 was variable with a minority of centres managing more than 6 per year (12%), 46% managing 1-5 monkey bites and 42% none. Most of the monkey bites were described as occurring in South Asia at tourist sites, on naked upper limbs, shortly after the travellers arrived at their destination. Tetanus status verification, rabies post-exposure prophylaxis and antibiotic therapy were said to be prescribed in most cases. Knowledge about the Monkey B virus was reported as scarce for 38% of the participants. The number of monkey bites managed per year per centre varied greatly but practices regarding infectious risk after monkey bites were generally homogeneous. The risk of Monkey B virus transmission did not readily come to mind in the differential diagnosis of infection risk for many French health professionals.

An antibody against the F glycoprotein inhibits Nipah and Hendra virus infections.

Nipah virus (NiV) and Hendra virus (HeV) are zoonotic henipaviruses (HNVs) responsible for outbreaks of encephalitis and respiratory illness with fatality rates of 50–100%. No vaccines or licensed therapeutics currently exist to protect humans against NiV or HeV. HNVs enter host cells by fusing the viral and cellular membranes via the concerted action of the attachment (G) and fusion (F) glycoproteins, the main targets of the humoral immune response. Here, we describe the isolation and humanization of a potent monoclonal antibody cross-neutralizing NiV and HeV. Cryo-electron microscopy, triggering and fusion studies show the antibody binds to a prefusion-specific quaternary epitope, conserved in NiV F and HeV F glycoproteins, and prevents membrane fusion and viral entry. This work supports the importance of the HNV prefusion F conformation for eliciting a robust immune response and paves the way for using this antibody for prophylaxis and post-exposure therapy with NiV- and HeV-infected individuals.

Developing and evaluating an intervention to improve care and reduce costs of rabies postexposure therapy: an observational quality improvement initiative in selected vaccination units in Sri Lanka.

Exposure to the rabies virus is fatal unless a patient is treated with a timely, accurate and complete administration of postexposure prophylaxis (PEP). The level of adherence to PEP guidelines by health service providers is therefore critical in providing high-quality care as well as preventing unnecessary costs. We developed a simple user-friendly decision aid based on Sri Lankan national guidelines for the administration of PEP and trialed it over a 5-month period in three study settings. Pre and post levels of adherence to the national guidelines by service providers was measured in each setting. Changes to per patient cost for rabies medications and hospital admissions were also collected. A significant improvement in adherence to the guidelines was observed in two settings with a nonsignificant improvement observed in the third setting. We estimated a total cost saving of LKR 158 476 across the three sites, comprising LKR 14 418 in admissions cost savings and LKR 144 058 in medication savings. We conclude that the development of a decision aid for the administration of PEP is likely to be an effective and cost-saving intervention in the Sri Lankan setting. Further research is required to inform the generalizability of our findings.

Risks of HIV Infection for Medical Staff. Postexposure Prophylaxis (by the Example of the Sverdlovsk Region)

Introduction. The Sverdlovsk region is on the second place among all subjects of the Russian Federation on the level of infestation of the population is HIV. The prevalence of HIV-infected residents of the Sverdlovsk region is 1.6%. This corresponds to a generalized stage of infection. Annually in medical institutions of the Sverdlovsk region up to 4 million patients with HIV infection receive various types of medical care. In these conditions increase the risk of infection employees related to their professional activities. Aims of this study was to assess the completeness and timeliness of post-exposure antiretroviral therapy to employees in case of accidents with exposure to blood and to determine their professional the risks of infection. Materials and methods. The study was conducted on the basis of the Sverdlovsk Regional Center for Prevention and Control of AIDS and the Department of epidemiology of the Ural State Medical University. The authors analyzed 1678 strategic messages in an emergency for 2013-2016. Results. In medical organizations of Sverdlovsk region in 2013 was introduced registration of all emergencies, regardless of the HIV status of the patient. The number of registered accidents was 6.7 ± 0.3 cases per 10 thousand employees. The frequency of emergency situations doctors have1.7 times higher than the average staff and nurses. Among nurses there was a trend to increasing frequency of emergencies, with an annual growth rate of 3.0%. Changes in the frequency of emergency situations, the doctors and nurses are not installed. The authors found considerable variation in the number of accidents according to the official registration and results of the employee survey. The frequency of emergency situations is determined by the profile of the Department, business process, profession, work experience of the employee, day of week and time of day. The number of persons who received chemoprophylaxis during emergency situations, reduced annually. Reasons for the decline were later appeal for help, the failure of prevention and the absence of indications to antiretroviral therapy in low risk of infection. The proportion of doctors who are not receiving antiretroviral treatment was higher than the proportion of paramedical staff and nurses. Conclusion. The prevention of occupational infections require legal regulation. Preventive actions should be focused on the set in the process of research risks.

Therapeutic efficacy of favipiravir against Bourbon virus in mice.

Bourbon virus (BRBV) is an emerging tick-borne RNA virus in the orthomyxoviridae family that was discovered in 2014. Although fatal human cases of BRBV have been described, little is known about its pathogenesis, and no antiviral therapies or vaccines exist. We obtained serum from a fatal case in 2017 and successfully recovered the second human infectious isolate of BRBV. Next-generation sequencing of the St. Louis isolate of BRBV (BRBV-STL) showed >99% nucleotide identity to the original reference isolate. Using BRBV-STL, we developed a small animal model to study BRBV-STL tropism in vivo and evaluated the prophylactic and therapeutic efficacy of the experimental antiviral drug favipiravir against BRBV-induced disease. Infection of Ifnar1-/- mice lacking the type I interferon receptor, but not congenic wild-type animals, resulted in uniformly fatal disease 6 to 10 days after infection. RNA in situ hybridization and viral yield assays demonstrated a broad tropism of BRBV-STL with highest levels detected in liver and spleen. In vitro replication and polymerase activity of BRBV-STL were inhibited by favipiravir. Moreover, administration of favipiravir as a prophylaxis or as post-exposure therapy three days after infection prevented BRBV-STL-induced mortality in immunocompromised Ifnar1-/- mice. These results suggest that favipiravir may be a candidate treatment for humans who become infected with BRBV.

Chimeric Antibody 14D5 Protects Mice against the Far-Eastern, Siberian, and European Tick-borne Encephalitis Virus

Tick-borne encephalitis virus (TBEV), belonging to the Flaviviridae family, is the most significant pathogen transmitted by Ixodes ticks and causing one of the most severe human neuroinfections. In Russia, serum immunoglobulin produced from the donor blood is currently used for post-exposure prophylactic and therapy of tick-borne encephalitis virus. However, it is known that preparations obtained from donated blood have certain disadvantages, and therefore development of novel preparations for post exposure prophylaxis and therapy of tick-borne encephalitis is required. To develop an alternative preparation, which does not include donor blood, a chimeric antibody ch14D5 against glycoprotein E of TBEV was constructed.This study was aimed to investigate protective efficacy of the chimeric antibody ch14D5 against the Far-Eastern, Siberian, and European subtypes of TBEV in in vivo experiments.A peripheral mouse model of tick-borne encephalitis was used in this study: the chimeric antibody ch14D5 was administrated intravenously in mice one day after their intraperitoneal infection with TBEV strains Sofjin, Vasilchenko, and Absettarov. Anti-TBEV serum immunoglobulin was used as a control preparation, which was administered in the same way. Protective efficacy of the chimeric antibodies 14D5 was assessed using the log-rank test. In the study, the presence or absence of antibody-dependent enhancement of infection (ADE) was examined when mice, infected with different subtypes of the TBEV, got the antibody ch14d5.Obtained results demonstrated high efficacy of the ch14D5 antibody in post-exposure prophylaxis of the disease in mice infected with any of the used TBEV strains, as well as the absence of ADE.It was shown that protective efficacy of antibody ch14D5 is higher than that of the anti-TBEV serum immunoglobulin, and antibody ch14D5 could be used for development of a therapeutic preparation for post-exposure prophylaxis.

Pertussis: The Identify, Isolate, Inform Tool Applied to a Re-emerging Respiratory Illness.

Pertussis, commonly referred to as “whooping cough,” is a highly contagious acute respiratory infection that has exhibited cyclical outbreaks throughout the last century. Although vaccines have provided some immunity, many populations, including infants and pregnant women, remain at risk for serious illness. Through the use of the novel “Identify, Isolate, Inform” (3I) tool, emergency department (ED) providers can readily recognize key symptoms of the disease and risk factors for exposure, thus curbing its transmission through early initiation of antimicrobial therapy and post-exposure prophylaxis. The three classic stages of pertussis include an initial catarrhal stage, characterized by nonspecific upper respiratory infection symptoms, which may advance to the paroxysmal stage, revealing the distinctive “whooping cough.” This cough can persist for weeks to months leading into the convalescent stage. Household contacts of patients with suspected pertussis or other asymptomatic, high-risk populations (infants, pregnant women in their third trimester, and childcare workers) may benefit from post-exposure prophylactic therapy. The Pertussis 3I tool can also alert healthcare professionals to the proper respiratory droplet precautions during contact with a symptomatic patient, as well as isolation practices until antimicrobial treatment is in progress. ED personnel should then inform local public health departments of any suspected cases. All of these actions will ultimately aid public health in controlling the incidence of pertussis cases, thus ensuring the protection of the general public from this re-emerging respiratory illness.

Role of Type I Interferons on Filovirus Pathogenesis.

Filoviruses, such as Ebola and Marburg virus, encode viral proteins with the ability to counteract the type I interferon (IFN-I) response. These IFN-I antagonist proteins are crucial to ensure virus replication, prevent an antiviral state in infected and bystander cells, and impair the ability of antigen-presenting cells to initiate adaptive immune responses. However, in recent years, a number of studies have underscored the conflicting data between in vitro studies and in vivo data obtained in animal models and clinical studies during outbreaks. This review aims to summarize these data and to discuss the relative contributions of IFN-α and IFN-β to filovirus pathogenesis in animal models and humans. Finally, we evaluate the putative utilization of IFN-I in post-exposure therapy and its implications as a biomarker of vaccine efficacy.

Prophylactic potential of memantine against soman poisoning in rats

BackgroundCarbamates physostigmine and pyridostigmine have been used as a pretreatment against poisoning with nerve agents in order to reversibly inhibit and thus protect from irreversible inhibition a portion of acetylcholinesterase (AChE) in brain and respiratory muscles that is crucial for survival. Memantine, an adamantine derivative, has emerged as a promising alternative to carbamates, since it prevented the fasciculations and skeletal muscle necrosis induced by carbamates and organophosphates, including nerve agents. AimThis experimental study was undertaken in order to investigate and compare the protective and behavioural effects of memantine and standard carbamates physostigmine and pyridostigmine in rats poisoned with soman and treated with atropine, oxime HI-6 and diazepam. Another goal was to elucidate the mechanisms of the antidotal effect of memantine and its potential synergism with standard antidotes against nerve agents. Materials and methodsMale Wistar rats were used throughout the experiments. In dose-finding experiments memantine was administered at dose interval 0–72 mg/kg sc 60 min before sc injection of soman. In time-finding experiments memantine was injected 18 mg/kg sc 0–1440 min before soman. Standard treatment antidotes - atropine 10 mg/kg, HI-6 50 mg/kg and diazepam 2.5 mg/kg – were administered im within 15 s post-exposure. Soman 0.75 LD50 was used to study its inhibitions of neuromuscular transmission on the phrenic nerve-diaphragm preparation in situ and of tissue AChE activity. Behavioural effects of the prophylactic antidotes were investigated by means of the rotarod test. Based on these data therapeutic index and therapeutic width was calculated for all three prophylactic agents. ResultsMemantine pretreatment (18 mg/kg sc) produced in rats poisoned with soman significantly better protective ratios (PRs) than the two carbamates – 1.25 when administered alone and 2.3 when combined with atropine pretreatment and 6.33 and 7.23 with atropine/HI-6 and atropine/HI-6/diazepam post-exposure therapy, respectively. The highest PR of 10.11 obtained in Atr/HI-6-treated rats was achieved after pretreatment with memantine 36 mg/kg. This additional protection lasted for 8 h. All three prophylactic regimens antagonised the soman-induced neuromuscular blockade, but the effect of memantine was fastest. Pretreatment with memantine assured higher AChE activity in brain and diaphragm than in unpretreated rats (46% vs 28% and 68% vs. 38%, respectively). All three prophylactic regimens affected the rotarod performance in rats, but the effect of memantine was relatively strongest. Memantine and pyridostigmine had lowest and highest therapeutic index and therapeutic width, respectively. ConclusionsAlthough memantine assures better and longer-lasting protection against soman poisoning in rats than the two carbamates, its small therapeutic index and narrow therapeutic width seriously limit its potential as a pretreatment agent. Despite its behavioural effects, memantine seems to be beneficial antidote when administered after soman, along with atropine/HI-6/diazepam therapy. Mechanism of the antidotal effect of memantine against soman poisoning appears to be a combination of AChE-protecting and NMDA receptor-blocking action.

Efficacy of equine botulism antitoxin in botulism poisoning in a guinea pig model.

BackgroundBotulism is a disease caused by neurogenic toxins that block acetylcholine release, resulting in potentially life threatening neuroparalysis. Seven distinct serotypes of botulinum neurotoxins (BoNTs) have been described and are found in nature world-wide. This, combined with ease of production, make BoNTs a significant bioweapon threat. An essential countermeasure to this threat is an antitoxin to remove circulating toxin. An antitoxin, tradename BAT (Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G)–(Equine)), has been developed and its efficacy evaluated against all seven serotypes in guinea pigs.Methods and findingsStudies were conducted to establish the lethal dose and clinical course of intoxication for all seven toxins, and post-exposure prophylactic efficacy of BAT product. Animals were monitored for signs of intoxication and mortality for 14 days. Guinea pig intramuscular LD50s (GPIMLD50) for all BoNTs ranged from 2.0 (serotype C) to 73.2 (serotype E) of mouse intraperitoneal LD50 units. A dose of 4x GPIMLD50 was identified as the appropriate toxin dose for use in subsequent efficacy and post-exposure prophylaxis studies. The main clinical signs observed included hind limb paralysis, weak limb, change in breathing rate/pattern, and forced abdominal respiration. Mean time to onset of clinical signs ranged from 12 hours (serotype E) to 39 hours (serotype G). Twelve hours post-intoxication was selected as the appropriate time point for intervention for all serotypes apart from E where 6 hours was selected because of the rapid onset and progression of clinical signs. Post-exposure treatment with BAT product resulted in a significantly (p<0.0001) higher survival at >0.008 scaled human dose for serotypes A, B, C, F and G, at >0.2x for serotype D and >0.04x for serotype E.ConclusionsThese studies confirm the efficacy of BAT as a post-exposure prophylactic therapy against all seven known BoNT serotypes.

Prophylactic efficacy of some chemoprotectants against abrin induced lethality.

Abrin is a highly toxic protein produced by Abrus precatorius. Exposure to abrin, either through accident or by act of terrorism, poses a significant risk to human health and safety. Abrin functions as a ribosome-inactivating protein by depurinating the 28S rRNA and inhibits protein synthesis. It is a potent toxin warfare agent. There are no antidotes available for abrin intoxication. Supportive care is the only option for treatment of abrin exposure. It is becoming increasingly important to develop countermeasures for abrin by developing pre- and post-exposure therapy. The aim of this study is to screen certain pharmaceutical compounds for their chemoprotective properties against abrin toxicity in vivo in BALB/c male mice. Twenty-one compounds having either antioxidant, anti-inflammatory and cyto-protective properties or combination of them, were screened and administered as 1h pre-treatment followed by exposure of lethal dose (2×LD50, intraperitoneally) of abrin. To assess the protective efficacy of the compounds, survival and body weight was monitored. Fifteen compounds extended the survival time of animals significantly, as compared to abrin. The following five of these compounds, namely: Epicatechin-3-gallate, Gallic Acid, Lipoic Acid, GSH and Indomethacin extended the life time ranging from 6 to 9 days. These compounds also attenuated the abrin induced inflammation and enzymes associated with liver function, but none of them could prevent abrin induced lethality. The compounds offering extension of life could be useful to provide a time-window for other supportive treatment and could also be used as combinatorial therapy with other medical countermeasures against abrin induced lethality.