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Contingency Medical Countermeasures for Mass Nerve-Agent Exposure: Use of Pharmaceutical Alternatives to Community Stockpiled Antidotes
Abstract
Having sufficient medical countermeasures (MCMs) available for the treatment of acetylcholinesterase-inhibiting nerve agent poisoned patients following a mass chemical exposure is a challenge for communities. After stockpiles containing auto-injectors are exhausted, communities need to be aware of alternative pharmaceutical options. The Department of Homeland Security Chemical Defense Program convened a federal interagency working group consisting of first responders, clinicians, and experts from the fields of medical toxicology, pharmacology, and emergency management. A literature review of pharmaceutical alternatives for treating nerve agent toxicity was performed. Pharmaceuticals that met the federal Public Health Emergency Medical Countermeasures Enterprise Product Specific Requirements were prioritized. Food and Drug Administration approval for one indication, market availability, and alignment to government procurement strategy were considered. This article summarizes the literature on comparative pharmacokinetics and efficacy against nerve agents (where available) of Food and Drug Administration approved drugs with muscarinic acetylcholine receptor antagonist and gamma-aminobutyric acid receptor agonist effects. This work is intended to serve as a resource of pharmaceutical options that may be available to communities (ie, emergency managers, planners, clinicians, and poison centers) when faced with a mass human exposure to a nerve agent and inadequate supplies of MCMs. ( Disaster Med Public Health Preparedness . 2018;page 1 of 8)
... Ce troisième maillon a pour objectif d'administrer les traitements et les antidotes au PRV dès les premiers symptômes afin de limiter le risque de forme grave et d'éviter les morts évitables en appliquant la stratégie du damage control en cas de lésions associées [35][36][37]. Contrairement aux deux premiers, ce troisième maillon relève d'une prise en charge médicale. Les victimes sont « médicalisées » dans le but de les stabiliser en attendant leur décontamination approfondie, si elle est nécessaire. ...
Les risques terroristes nucléaires, radiologiques, biologiques et chimiques (NRBC) constituent une menace permanente. Les primo-intervenants seront probablement des personnels non spécialisés face à un événement de cette nature. À l’extérieur ou à l’accueil des hôpitaux, leur rôle sera pourtant décisif sur le plan tactique afin de mettre en œuvre les premières mesures et minimiser les effets sur la population. Acquérir et entretenir un niveau de formation suffisant pour un risque d’occurrence rare, pour agir efficacement en tenue de protection dans un contexte aussi stressant sont des défis pédagogiques et organisationnels pour nos services. En 2019, la brigade de sapeurs-pompiers de Paris conceptualise la « chaîne de survie NRBC » regroupant les cinq actions essentielles à mener par les primointervenants en cas d’événements NRBC. Ces tâches, indissociables, sont représentées sous la forme d’une chaîne constituée de cinq maillons : 1) Décontamination d’urgence pour limiter l’intoxication et la contamination ; 2) Recherche de symptômes pour identifier l’agent et alerter les secours ; 3) Administration précoce des traitements pour réduire la morbi mortalité ; 4) Décontamination approfondie pour protéger le système de santé ; 5) Évacuation vers l’hôpital. En 2020, l’acronyme « DUST DAHO » est ajouté pour optimiser la mémorisation et la restitution des cinq maillons de cette chaîne. Cet outil cognitif s’adresse à tous les acteurs, soignants ou non, à l’extérieur ou à l’accueil de l’hôpital, quel que soit l’agent NRBC en cause. Il pourrait également être un outil de communication précieux pour le grand public en cas de crise.
... The identification, even if supposed and unconfirmed, of an agent makes it possible to immediately address the emergency situation and to specify the nature of the risk to hospitals that will probably already be confronted with the spontaneous arrival of victims. Logistical (volume and nature of antidote), tactical (adaptation of protective clothing, persistence or not of the agent in question), and strategic (evacuation of areas) provisions depend on this link, for example, in a "powder envelop" situation [11,12]. For chemical agents, this may involve searching for several symptoms in the same patient or for the same symptom in several patients. ...
In the field of Chemical Defense toward Nerve Agents, the development of analytical methodologies for analysis of different sample matrices, training of human resources in handling, detection of such toxic chemicals, and design of more effective medical countermeasures may be hampered by the lack of infrastructure and well-prepared human resources. Therefore Nerve Agents Surrogates may be an invaluable alternative to accomplish such tasks, as these compounds present similar behavior and are easier to handle in comparison to actual nerve agents, being useful analytical and toxicological tools for technical purposes.
Introduction:
Atropine sulfate is an FDA-approved medical countermeasure (MCM) for the treatment of organophosphorus nerve agent and organophosphate pesticide toxicity. Sufficient MCM supplies must be available in an incident involving a mass human exposure either from an accidental chemical release or a terrorist attack.
Methods:
We performed a randomized, 3-sequence, 3-period phase I crossover study to assess the bioavailability and pharmacokinetics (PK) of a single dose (0.5 mg and 1.0 mg) of 1% ophthalmic atropine sulfate solution administered sublingually to 15 healthy adult volunteers. The primary endpoint was evaluation of the bioavailability of each of the two sublingual doses against a 1.0 mg reference intravenous (IV) atropine dose. Secondary endpoints included the safety and tolerability (xerostomia scale) of atropine sulfate administered sublingually.
Results:
Sublingual atropine was safe (no severe AEs or SAEs were reported with either dose) and well tolerated, with a single subject reaching maximum xerostomia on a single dosing day. The geometric mean AUC∞ was 286.40, 493.81, and 816.47 min*ng/mL for the 0.5 mg and 1.0 mg sublingual doses, and the 1.0 mg IV dose, respectively. Compared to IV administration, the 1.0 mg sublingual dose produced 0.60 (90% CI: 0.55-0.66) of the overall concentration of atropine over time (AUC∞).
Conclusion:
Sublingual atropine sulfate 1% ophthalmic solution may be an alternative formulation and route of administration combination which expands the capacity and dosing options of atropine as a nerve agent MCM.
Human exposure to weaponized organophosphates (e.g. nerve agents) occurs in the context of military and terrorist attacks, assassinations, laboratory accidents, and suicide attempts. Increasing global tensions have led to renewed scrutiny of nerve agents and their deliberate use to poison political enemies. Poisoning from these highly potent agents present several challenges. Toxicitiy from these agents may persist untreated if clinicians do not recognize the resultant cholinergic toxidrome. Despite clinicians lack of familiarity with nerve agent toxicity, large scale exposures due to chemical munitions may significantly stress healthcare systems and deplete antidote availability. Finally, recent history suggests that environmental persistence of some nerve agents may pose additional threat due to delayed exposure and injury to innocent bystanders. This chapter reviews important advances in the clinical management of individuals exposed to nerve agents. It discusses contingency management and alternate antidotes in the setting of mass depletion of existing antidote stock.
Background: Drooling can be a severe disability and have high impact on daily life. Reversible treatment is preferable.
Aim: To analyse if sublingual administration of atropine eye drops is a useful reversible treatment option for severe drooling in children with disabilities.
Design: The study had a prospective, single-system research design. The participants served as their own controls. The study period was three weeks without treatment, four weeks with atropine eye drop solution 10mg/ml one drop a day followed by four weeks of one drop twice a day. Parents’ rating of their child’s drooling assessed on a 100mm VAS scale and unstimulated salivary secretion rate measurement was performed together with notations about side effects and practicality.
Results: Parents’ VAS assessment of drooling decreased from a median (range) of 74 (40-98) at baseline to 48 (18-88) (P=0.05) and 32 (12-85) (P=0.004) after four weeks of atropine once a day and another four weeks of atropine twice a day, respectively (n=11). Unstimulated salivary secretion rates decreased from baseline to end of study (P=0.032). Several parents complained about difficult administration. No irreversible side effects were noted.
Conclusions: Sublingual atropine eye-drops is an alternative for treatment of severe drooling in children with disabilities.
The drug midazolam has been recommended to replace diazepam as the immediate anticonvulsant treatment for nerve agent-induced seizures. This recommendation marks the latest decision in an ongoing program to improve medical countermeasures to treat nerve agent poisoning. Extensive rodent screening studies first identified midazolam as the most promising compound to focus on for advanced testing. Midazolam was then evaluated directly with diazepam for the ability to terminate nerve agent seizures in a nonhuman primate model. In all animal tests midazolam was twice as potent and more rapidly acting than diazepam, thus minimizing the possibility of seizure-induced brain damage.
Receptor binding studies were performed on 24 soft anticholinergic agents and 5 conventional anticholinergic agents using
4 cloned human muscarinic receptor subtypes. The measured pK
i values of the soft anticholinergic agents ranged from 6.5 to 9.5, with the majority being in the range of 7.5 to 8.5. Strong
correlation was observed between the pK
is determined here and the pA
2 values measured earlier in guinea pig ileum contraction assays. The corresponding correlation coefficients (r
2) were 0.80, 0.73, 0.81, and 0.78 for pK
i(m1), pK
i(m2), pK
i(m3), and pK
i(m4), respectively. Quantitative structure-activity relationship (QSAR) studies were also performed, and good characterization
could be obtained for the soft anticholinergics containing at least 1 tropine moiety in their structure. For these compounds,
the potency as measured by the pK
i values was found to be related to geometric, electronic, and lipophilicity descriptors. A linear regression equation using
ovality (O
e), dipole moment (D), and a calculated log octanol-water partition coefficient (QLogP) gave reasonably good descriptions (r=0.88) for the pK
i(m3) values.
Keywordsdrug design–soft drugs–receptor binding–metabolism–drug evaluation–muscarinic antagonists
Early termination of prolonged seizures with intravenous administration of benzodiazepines improves outcomes. For faster and more reliable administration, paramedics increasingly use an intramuscular route.
This double-blind, randomized, noninferiority trial compared the efficacy of intramuscular midazolam with that of intravenous lorazepam for children and adults in status epilepticus treated by paramedics. Subjects whose convulsions had persisted for more than 5 minutes and who were still convulsing after paramedics arrived were given the study medication by either intramuscular autoinjector or intravenous infusion. The primary outcome was absence of seizures at the time of arrival in the emergency department without the need for rescue therapy. Secondary outcomes included endotracheal intubation, recurrent seizures, and timing of treatment relative to the cessation of convulsive seizures. This trial tested the hypothesis that intramuscular midazolam was noninferior to intravenous lorazepam by a margin of 10 percentage points.
At the time of arrival in the emergency department, seizures were absent without rescue therapy in 329 of 448 subjects (73.4%) in the intramuscular-midazolam group and in 282 of 445 (63.4%) in the intravenous-lorazepam group (absolute difference, 10 percentage points; 95% confidence interval, 4.0 to 16.1; P<0.001 for both noninferiority and superiority). The two treatment groups were similar with respect to need for endotracheal intubation (14.1% of subjects with intramuscular midazolam and 14.4% with intravenous lorazepam) and recurrence of seizures (11.4% and 10.6%, respectively). Among subjects whose seizures ceased before arrival in the emergency department, the median times to active treatment were 1.2 minutes in the intramuscular-midazolam group and 4.8 minutes in the intravenous-lorazepam group, with corresponding median times from active treatment to cessation of convulsions of 3.3 minutes and 1.6 minutes. Adverse-event rates were similar in the two groups.
For subjects in status epilepticus, intramuscular midazolam is at least as safe and effective as intravenous lorazepam for prehospital seizure cessation. (Funded by the National Institute of Neurological Disorders and Stroke and others; ClinicalTrials.gov number, ClinicalTrials.gov NCT00809146.).
Atropine and glycopyrronium are frequently used for premedication to reduce oral and respiratory secretions and prevent bradycardia.
Glycopyrronium is said to have similar antisialagogue effects, but is less likely to cause significant tachycardia than atropine.
Different antimuscarinic receptor selectivity patterns could explain the differences. The aim of this investigation was to
determine the possible selectivity of glyco pyrronium for M2 and M3 muscarinic receptor subtypes. Muscarinic receptor subtypes in Wistar rat ventricle and submandibular gland homogenates were
characterized with [3H]-N-methylscopolamine ([3H]-NMS) by ligand binding studies. Inhibition of [3H]-NMS binding by non-labelled compounds showed the following order: in rat ventricle: glycopyrronium > atropine ≫ otenzepad
> hexahydrosiladiphenidol (HHSiD) ≫ pirenzepine; in rat submandibular gland: glycopyrronium > atropine ≫ HHSiD ≫ pirenzepine
> otenzepad. These were similar to the expected order of frequency of M2 and M3 subtypes, respectively. Glycopyrronium showed similarly high affinities for both M2 (ki = 1.889 (SEM 0.049) nmol litre−1 and M (Ki = 1.686 (0.184) nmol litre−1 subtypes. Glycopyrronium bound to a homogeneous population of binding sites in both tissues and showed no selectivity for
M2 or M3 muscarinic receptor subtypes. (Br. J. Anaesth. 1995; 74: 549–552)
This study investigates the rate and extent of absorption following intramuscular injection of midazolam and diazepam.
Four healthy male volunteers were recruited in this randomized three-way cross-over study. On one occasion each subject received simultaneous im injections of 5 mg midazolam and 10 mg diazepam in separate deltoid muscles. On two other separate occasions each subject received an iv infusion of 7.5 mg midazolam and 30 mg diazepam over five minutes. Frequent arterial blood samples were collected for up to two hours and venous blood samples were collected for up to 24 hours for midazolam and ten days for diazepam. A gas chromatography assay was used to determine the plasma concentrations of midazolam and diazepam. The im absorption profiles were estimated using constrained least-squares deconvolution.
There were substantial intersubject variabilities in the estimated pharmacokinetic parameters (volume and clearances) of intravenous midazolam and diazepam. The mean (+/-sd) time to peak plasma concentration (Cmax) was shorter for im midazolam (17.5 +/- 6.5 min) relative to diazepam (33.8 +/- 7.5 min). The mean (+sd) time to peak absorption rate was also shorter for midazolam (9 +/- 2 vs 13.8 +/- 7.5 min). The peak rate of absorption was identical (0.18 mg. min-1) and bioavailability was 1.0 for both drugs.
We conclude that midazolam has more rapid absorption than diazepam following im administration.
The purpose of this study was to evaluate the pharmacokinetic profile of intranasal lorazepam in comparison to currently established administration routes. Eleven healthy volunteers completed this randomized crossover study. On three occasions, each separated by a 1-week washout, subjects received a 2 mg dose of lorazepam via the intranasal, intravenous, or intramuscular route. Blood samples were collected serially from 0 to 36 hours. Noncompartmental methods were used to determine pharmacokinetic parameters. Lorazepam was well absorbed following intranasal administration with a mean (% CV) bioavailability of 77.7 (11.1). Intranasal administration resulted in a faster absorption rate than intramuscular administration, Elimination profiles were comparable between all three routes, The concentration-time profile for intranasal delivery demonstrated evidence of a double peak in several subjects, suggesting partial oral absorption. Females were found to have significantly higher AUC values than males for all three delivery routes. Overall, this study demonstrated favorable pharmacokinetics of intranasal lorazepam in relation to standard administration methods. Intranasal delivery could provide an alternative, noninvasive delivery route for lorazepam.
Purpose
The safety and efficacy of medications that may be administered via the intranasal route in adult patients in the prehospital and emergency department (ED) settings are reviewed.
Summary
When medications of appropriate molecular character and concentration are delivered intranasally, they are quickly transported across this capillary network and delivered to the systemic circulation, thereby avoiding the absorption-limiting effects of first-pass metabolism. Therapeutic drug concentrations are rapidly attained in the cerebrospinal fluid, making intranasal administration a very effective mode of delivery. To optimize the bioavailability of intranasally administered drugs, providers must minimize the barriers to absorption, minimize the volume by maximizing the concentration, maximize the absorptive surface of the nasal mucosa, and use a delivery system that maximizes drug dispersion and minimizes drug runoff. Medications can be instilled into the nasal cavity with syringes or droppers by applying a few drops at a time or via atomization. The intranasal route of administration may be advantageous for patients who require analgesia, sedation, anxiolysis, termination of seizures, hypoglycemia management, narcotic reversal, and benzodiazepine reversal in the ED or prehospital settings. Medications that have been studied in the adult population include fentanyl, sufentanil, hydromorphone, ketamine, midazolam, haloperidol, naloxone, flumazenil, and glucagon. The available data do indicate, however, that intranasal administration may be a safe, effective, and well tolerated route of administration.
Conclusion
Based on the published literature, intranasal administration of fentanyl, sufentanil, ketamine, hydromorphone, midazolam, haloperidol, naloxone, glucagon, and, in limited cases, flumazenil may be a safe, effective, and well-tolerated alternative to intramuscular or intravenous administration in the prehospital and ED settings.
Organophosphate poisoning occurs worldwide and often requires admission to an ICU. Grading of patients may be of value to identify high-risk cases but this has never been prospectively evaluated. Conventional treatment with atropine may lead to CNS toxicity, although control of secretions may still be inadequate. We conducted a randomized, controlled trial in 44 patients to compare atropine with glycopyrrolate, a drug that may provide better control of secretions and does not cross the blood-brain barrier. Grading was performed prospectively and compared to outcome. Thirty-nine cases were evaluated (atropine 22, glycopyrrolate 17); the treatment groups were comparable at baseline. No differences could be detected in outcome except for a trend to fewer respiratory infections in the glycopyrrolate group. Thus, treatment with atropine and glycopyrrolate was equally effective. A grading of serious was associated with ventilation, complications, and a prolonged ICU stay. A revised simplified grading is proposed. (Crit Care Med 1990; 18:956)
Respiratory toxicity, injury and treatment following vapor inhalational exposure to the chemical warfare nerve agent (CWNA) soman (GD) were examined in non-anesthetized rats. This study exposed male Sprague-Dawley rats (250-300 g) to 520, 560, 600, 825 or 1410 mg×min/m(3) of soman in a customized head-out inhalation system. Signs of CWNA-induced cholinergic crises were observed in all soman-exposed animals. The LCt50 of vaporized soman as determined by probit analysis was 593.1 mg×min/m(3). All animals exposed to 825 and 1410 mg×min/m(3) developed severe convulsions and died within 4-8 min post-exposure. Edema measured by wet/dry weight ratio of the left lung lobe increased in a dose-dependent manner in all soman-exposed animals. Bronchoalveolar lavage (BAL) fluid and blood acetylcholinesterase (AChE) activities were inhibited dose-dependently in soman-exposed groups at 24 hours. A significant increase in total BAL protein was observed in soman-exposed animals at all doses. AChE activity was inhibited in lung and whole brain tissues in all soman-exposed animals. Histopathological analysis of the lungs of animals exposed to 600 mg×min/m(3) of soman revealed prominent morphological changes including alveolar histiocytosis, hemorrhage and inflammation consisting of neutrophilic exudate. Exposure of animals to 600 mg×min/m(3) of soman followed by treatment with two actuations for 10 seconds of Combivent (21 μg of ipratropium bromide and 120 μg of albuterol sulfate) and Symbicort (80 μg budesonide and 4.5 μg formoterol) by inhalation into a modified metered dose inhaler (MDI)10 minutes post-exposure resulted in increased minute volume, but did not decrease mortality. These results indicate that inhalation exposure to soman vapor causes acute respiratory toxicity and injury in untreated, un-anesthetized rats and that inhalation treatment with Combivent or Symbicort did not influence the outcome.
Introduction:
The increased use of organophosphate (OP) insecticides and the ever increasing possibility of terror groups using nerve agents underscore the need to develop effective and safe antidotes against OP poisoning. While intramuscular administration of nerve gas antidotes like atropine sulphate has certain lacunae, intravenous route is neither practical nor feasible in the field conditions for mass casualties. The objective was to develop a novel atropine sulphate nasal drop formulation, evaluate and characterize it using scintigraphy and to carry out safety-efficacy study in human volunteers with a view to obtain early pharmacological effects in comparison to the existing options, particularly the conventional intramuscular route.
Methods:
Permeability studies were done using atropine sulphate solution containing variable amount of chitosan. Radiometric method was developed for scintigraphy studies while standard spectroscopy was used for the quantification of atropine sulphate in fluids. Concentration of atropine sulphate in nasal drops to produce therapeutic concentration in blood was calculated. Six volunteers (age range 18-53 years) were administered the formulation delivering 6mg of atropine sulphate each. Bioavailability and atropinization were noted serially.
Results:
Based on the results of in vitro, human scintigraphy and analytical data, 1% atropine sulphate-0.5% chitosan was chosen as the final nasal formulation. Human bioavailability curve was created which showed that the therapeutic concentration of the drug in blood was reached within 5min with nasal drops suggesting that drug delivery through the nasal route is significantly better than the intramuscular route. Unpaired t-test between the means of baseline value of heart rate and that of each time interval showed that increase in heart rate of all the volunteers became significant at 15min (P<0.01) and extremely significant at 30min (P<0.001). Correlation was evident from 5min (c>0.7). Pupil diameter showed maximal increase at 30min (P<0.01).
Conclusions:
This novel product, 1% atropine sulphate-0.5% chitosan nasal drops might be a safe and efficacious emergency treatment of organophosphorous poisoning with several advantages over the present management, including early atropinization and capability of mass treatment in least amount of time.
The increased use of organophosphorus (OP) pesticides and the ever increasing possibility of terror groups using nerve agents underscore a need to develop effective and safe antidotes against OP poisoning. The objectives of the present study were to develop a novel atropine sulfate (AS) sublingual injection formulation, to create its bioavailability data in humans and to evaluate its suitability for field use with a view to obtain early therapeutic drug concentration in comparison to the conventional intramuscular route that provides a therapeutic peak of 6 to 8 ng/mL in blood at 30 minutes.
Two milligrams per 0.1 mL of AS was sublingually injected in 6 volunteers, and bioavailability and atropinization signs (blood pressure, pupil diameter, and heart rate) were noted.
Human bioavailability curve was created, which was equivalent to 2 mg IM injection in amplitude within 10 minutes and describing a better curve thereafter. Peak plasma concentration of AS occurred at 15 minutes and was 21 ng/mL. Increase in heart rate became extremely significant at 5 minutes (P < .0001) with maximum increase of 62% + or - 6% at 10 minutes after administration. Pupil diameter showed maximal increase of 58% + or - 21% at 15 minutes (P < .01).
Sublingual AS appears to have several advantages over conventional IM route including better bioavailability, rapid onset of action, and early atropinization. It is a safe and efficacious procedure with the potential to become an alternative to conventional IM injection, particularly in case of chemical terrorism scenario where hundreds of victims may require immediate atropinization simultaneously.
Anticholinergics are the mainstay of the pharmacological management of organophosphate poisoning (OPP). Atropine has the potential to cause central toxicity which may complicate the management of this life-threatening condition. A combination of atropine and glycopyrrolate in equivalent dosages titrated to the peripheral muscarinic signs, theoretically reduces the central effect of the anticholinergics by 50% and thereby the risk of central toxicity, while it provides effective control of the peripheral manifestations of OPP. This study reports the clinical morbidity and mortality associated with the management of OP with this anticholinergic combination over a 4-year period, 2003 to 2006, at Tygerberg Academic Hospital (TAH). Two of the 53 patients treated for OPP died, with this mortality lower than that previously reported at TAH. Atropine toxicity was evident in 12 (22.5%) patients and responded to a temporary cessation of the combination infusion. The demographic profile, presenting symptoms, duration of stay and complications encountered were similar to previous reports from TAH. Patients treated with the infusion of a combination of atropine and glycopyrrolate had a lower mortality rate compared with earlier reports from the same unit, but the occurrence of atropine toxicity was unchanged despite the hypothesized theoretical advantage.
We determine the efficacy of parenteral ophthalmic antimuscarinic agents (tropicamide ophthalmic 1% and cyclopentolate hydrochloride ophthalmic 1%) on survivability in a rat model of acute, lethal organophosphate pesticide (OP) poisoning. After obtaining an appropriate dose-response for study comparison, rodents were randomized to receive 1 of 4 intraperitoneal antidotes; (1) 0.3 mL normal saline, (2) atropine 10 mg/kg, (3) ophthalmic tropicamide 20 mg/kg, or (4) ophthalmic cyclopentolate 20 mg/kg. Five minutes after pretreatment, 15 mg/kg of dichlorvos was administered subcutaneously. Mortality rates and time to death were compared using Fisher exact test and the Kaplan-Meier method with log-rank test, respectively. If alive at 120 minutes, survival was assumed and the study was terminated. Survival in rats pretreated with atropine (10 mg/kg) was 90%. Survival in rats pretreated with tropicamide (20 mg/kg) and cyclopentolate (20 mg/kg) were 90% [P < 0.01; 95% confidence interval (CI) 0.71-1.09] and 90% (P < 0.01; 95% CI 0.71-1.09), respectively, compared with controls (10% survival; 95% CI 0.04-0.45). Time of death ranged between 6 and 13 minutes in nonsurvivors. Overall comparison of survival time revealed a statistically significant improvement in experimental groups compared with controls (P < 0.0001). Pretreatment with parenteral ophthalmic solutions (tropicamide or cyclopentolate) was equivalent to standard atropine in preventing lethality in this rat model of acute, lethal OP poisoning.
A sensitive radioreceptor assay for the determination of glycopyrrolate concentrations in human plasma, urine and cerebrospinal fluid (CSF) is described. The applicability of the assay for kinetic studies in human was studied by determining the plasma concentrations and the renal excretion in three gynaecological surgical patients, who received 8 micrograms/kg of glycopyrrolate as a premedication intramuscularly. Tritiated N-methyl scopolamine was used to label the muscarinic cholinergic receptors in the membrane preparation obtained from the rat brain. The limit of detection of the assay was 70 ng/l in plasma, 2 micrograms/l in urine and 140 ng/l in CSF. There was no evidence of cross-reactivity of glycopyrrolate derivatives in clinical concentrations. A very rapid absorption was found with a mean maximum plasma concentration (Cmax) of 14.26 (range 12.02-16.97) micrograms/l and mean Tmax (time to Cmax) of 13.3 (range 10-15) min. and almost 50% of the dose administered was excreted into the urine within 3 hr. The CSF levels of glycopyrrolate were under detection limit. It is concluded that the sensitivity of the method is sufficient for pharmacokinetic studies of glycopyrrolate after therapeutic dosing.
In the present study, a sensitive and reproducible radioreceptor assay (RRA) was used to evaluate the basic pharmacokinetic properties of glycopyrrolate, a quaternary amine with peripheral antimuscarinic activity. Based on the plasma levels after a single intravenous injection, 6 micrograms/kg (n = 6), the distribution phase half-life (2.22 +/- 1.26 s.d. min) and the elimination phase half-life (0.83 +/- 0.29 h) of glycopyrrolate were short due to the low distribution volume during the elimination phase (0.64 +/- 0.29 l/kg) and to the respectively high total plasma clearance value (0.54 +/- 0.14 l/kg/h). An intramuscular injection, 8 micrograms/kg (n = 6), was followed by a fast and predictable systemic drug absorption and clinical effects (heart rate increase, dry mouth). In this group the time to maximum plasma concentration (tmax) was 27.48 +/- 6.12 min and the maximum plasma concentration (Cmax) was 3.47 +/- 1.48 micrograms/l. After oral drug intake, 4 mg (n = 6), an apparently low and variable gastrointestinal absorption was found (tmax = 300.0 +/- 197.2 min, Cmax = 0.76 +/- 0.35 microgram/l), thus indicating that the oral route of drug administration is of no value as a routine premedication. The correlation between the plasma concentration of glycopyrrolate and the drug effects appears to be variable. Because of its sensitivity, the RRA method proved to be quite useful in evaluating the kinetics of glycopyrrolate and its relationship to various clinical effects.
As pointed out by Swenson,1 there can be drug-induced systemic effects from topical ophthalmic application of a β-adrenergic antagonist. Over the past eight years, the National Registry of Drug-Induced Ocular Side Effects in the Department of Ophthalmology at the Oregon Health Sciences University, Portland, has been monitoring this medication.It is evident that some patients who receive topical ocular timolol maleate obtain therapeutic plasma timolol levels.2,3 Of the 1,900 cases of possible adverse reactions secondary to ophthalmic timolol reported to the Registry, 63% are systemic side effects. One reason why systemic blood levels of this drug may occur is the "first order pass" effect. Essentially, this means that when timolol is administered orally, the drug first passes through the liver where most of it is metabolized before being exposed to the target organs. However, timolol eyedrops drain through the nasolacrimal system rapidly, and an estimated 80% of the drug may
The clinical and laboratory features of moderate to severe organophosphate and carbamate toxicity in 37 infants and children are presented. Ingestion of an improperly stored liquid pesticide was the most common route of intoxication (76% of patients); five (14%) children became intoxicated after playing on carpets and floors of homes that had been sprayed or fogged by unlicensed exterminators. The transfer diagnoses were incorrect for 16 or 20 patients who were transferred to our center from another institution. Miosis (73%), excessive salivation (70%), muscle weakness (68%), and lethargy (54%) were the most common abnormal signs; 49% and 22% of patients had tachycardia and seizures, respectively, and 38% of children had respiratory insufficiency that required endotracheal intubation and mechanical ventilation. The results of erythrocyte and serum cholinesterase activity assays were concordant in 83% of patients. Thirty-four (92%) patients were treated with atropine and/or pralidoxime; three patients required only supportive care. Most patients had a prompt response to therapy; however, two patients with organophosphate toxicity required multiple doses of atropine during a 24-hour period; in both instances, the doses of atropine were subtherapeutic. There were no deaths. Pneumonitis and/or atelectasis developed in ten patients, including six who had ingested a petroleum distillate-containing insecticide.
1. Six young male volunteers were exposed to sarin vapour (isopropyl methyl phosphonofluoridate) at a concentration of 0.5 mg/m(3) for 30 min (concentration time (Ct) 15 (mg min)/m(3)).2. The resulting clinical syndrome was treated by instilling 0.06 ml of a 1% solution of cyclopentolate into the conjunctival sac.3. Visual acuity, retinoscopy, objective and subjective refraction and pupil sizes were noted before the trial, after exposure to sarin and after treatment with cyclopentolate.4. No appreciable difference was demonstrated between the control objective retinoscopy values and those obtained after cyclopentolate treatment of the clinical syndrome induced by sarin. Reduced near visual acuity was observed in some subjects treated with cyclopentolate as compared with acuity after exposure to sarin alone, considered to be due to the partial cycloplegia produced by treatment. Visual acuity after exposure to sarin alone was improved in some instances by the miosis produced.5. It is suggested that unless full dark adaptation is a consideration, treatment of the ophthalmic condition resulting from exposure to this dosage of sarin should be reserved for those experiencing distressing ocular symptoms.
Twenty-two healthy volunteers aged 20-78 years received single 5-mg doses of diazepam by intravenous injection, by mouth in the fasting state, and by a deltoid intramuscular injection. The kinetic profile of diazepam by each route was determined from multiple plasma diazepam concentrations measured 7-14 days after each dose. After intravenous injection, diazepam volume of distribution (Vd) was larger in women than in men, but increased with age regardless of sex. Elimination half-life was longer in elderly than in young men (101 v 32 h, P less than 0.025), partly due to the increased Vd as well as to a significant reduction in total metabolic clearance (0.24 v 0.46 ml/min/kg, P less than 0.05). However, the prolonged half-life in elderly as opposed to young women (99 v 44 h; P less than .01) was due mainly to increased Vd because clearance was not significantly changed (0.29 v 0.35 ml/min/kg). In all subjects, oral diazepam was rapidly absorbed; peak plasma levels were reached an average of 0.9 h after dosage. Absolute bioavailability averaged 94%, indicating essentially complete absorption. Neither age nor sex significantly influenced oral absorption. In all male subjects, and in 8 of 12 women, absorption of diazepam after deltoid intramuscular injection was rapid and essentially complete. However, in three young and one elderly women, absorption was slower and apparently incomplete. Age as such did not significantly influence absorption of intramuscular diazepam.
Eye disease and cardiovascular disease frequently coexist. As a result, cardiologists and ophthalmologists often treat the same patients. Among ophthalmologists it is well known that topical ophthalmic medications are capable of producing serious cardiovascular effects, including congestive heart failure, arrhythmias, and death. However, cardiologists may not be aware of these potential complications. This article reviews the cardiovascular effects of commonly prescribed topical ocular medications and describes important contraindications to their use in patients with cardiovascular disease. Cardiologists, by making themselves and their patients more aware of the cardiovascular effects of topical ocular medications, may be able to avoid the adverse and potentially fatal complications of these agents.
To investigate the pharmacological basis of systemic effects of atropine eyedrops, we estimated the bioavailability of ophthalmic 1% atropine solution in healthy volunteers.
In a randomized crossover study we administered 0.3 mg atropine either intravenously or ocularly to six healthy volunteers. The plasma concentrations of the biologically active atropine enantiomer, 1-hyoscyamine, were determined using a muscarinic cholinoceptor binding assay.
The mean area under the curve from zero to infinitum (AUC0-infinity) for 1-hyoscyamine was 1.862+/-0.580 microg/L x hr after intravenous, and 1.092+/-0.381 microl/L x hr after ocular administration (mean+/-sd, n=6), respectively. The mean bioavailability was 63.5+/-28.6% (mean+/-SD, n=6; min 19%, max 95%). Large interindividual differences characterized the absorption and elimination phases of 1-hyoscyamine kinetics. The terminal half-life (t1/2beta) of 1-hyoscyamine in plasma was not affected by the route of drug administration.
The systemic bioavailability of 1-hyoscyamine was considerable and may explain the systemic anticholinergic side effects reported in association with the clinical use of atropine eyedrops.
All benzodiazepines enter cerebral tissue rapidly. However, the duration of action is short for diazepam ( The physicochemical properties of benzodiazepines (lipid solubility and protein binding) regulate their rate and extent of entry into the brain and cerebrospinal fluid. However, the duration of the pharmacological activity of benzodiazepines may be in part related to the affinity of these compounds for the benzodiazepine receptors in the brain: midazolam, clonazepam and lorazepam have higher affinities than diazepam. In the emergency setting, the intravenous route is the most suitable, delivering adequate quantities of benzodiazepines as fast as possible. However, when intravenous administration is not available, rectal administration of a solution is a convenient method for diazepam, midazolam being the only one of these drugs that should be given intramuscularly. The assessment of the efficacy of benzodiazepines in the management of acute seizures and status epilepticus is mainly based on nonrandomised uncontrolled trials. According to the route of administration, the efficacy was 28.6 to 100% (intrarectal) and 54 to 100% (intravenous) for diazepam, 82 to 100% (intravenous) for lorazepam, and 79% (intranasal), 93 to 100% (intramuscular) and 100% (intravenous) for midazolam. Although diazepam was initially chosen for the management of refractory status epilepticus, the longer duration of action of lorazepam and clonazepam may favour the use of these 2 drugs. However, double-blind evaluations are necessary to determine which drug is best.
This study evaluated the ability of six benzodiazepines to stop seizures produced by exposure to the nerve agent soman. Guinea pigs, previously prepared with electrodes to record electroencephalographic (EEG) activity, were pretreated with pyridostigmine (0.026 mg/kg, i.m.) 30 min before challenge with soman (56 microg/kg, s.c.) and then treated 1 min after soman exposure with atropine (2.0 mg/kg, i.m.) and pralidoxime chloride (2-PAM Cl; 25 mg/kg, i.m.). All animals developed seizures following this treatment. Benzodiazepines (avizafone, clonazepam, diazepam, loprazolam, lorazepam, and midazolam) were given i.m. 5 or 40 min after seizure onset. All benzodiazepines were effective in stopping soman-induced seizures, but there were marked differences between drugs in the rapidity of seizure control. The 50% effective dose (ED50) values and latencies for anticonvulsant effect for a given benzodiazepine were the same at the two times of treatment delay. Midazolam was the most potent and rapidly acting compound at both treatment times. Since rapid seizure control minimizes the chance of brain damage, use of midazolam as an anticonvulsant may lead to improved clinical outcome in the treatment of nerve agent seizures.
Tiotropium is a long-acting anticholinergic drug. Studies with cloned human muscarinic receptors show that tiotropium binds equally well to M(1), M(2), and M(3) receptors. However, it dissociates very slowly from M(1) and M(3) receptors compared with ipratropium, and more rapidly from M(2) receptors. Binding studies with [(3)H]tiotropium in human lung show that it is approximately 10-fold more potent than ipratropium. In vitro, tiotropium has a potent inhibitory effect against cholinergic nerve-induced contraction of airways. It dissociates extremely slowly, compared with the dissociation of atropine and ipratropium. Clinical studies with single doses of inhaled tiotropium confirm that it is a potent and long-lasting bronchodilator. Furthermore, it protects against cholinergic bronchoconstriction for > 24 h. Pharmacokinetic studies show that little of the inhaled drug is absorbed, thus predicting a high margin of safety.
Atropine is the drug of choice for treatment of organophosphate nerve agent and insecticide intoxication and has been used for this indication for several decades. Adverse reactions to atropine may occur, and are of two types: toxic and allergic. Toxic reaction, the most common form, results from the anti-muscarinic effects of the drug. Since it is most probably related to interpersonal variation in sensitivity to atropine, toxic effects may appear at the usual therapeutic doses. The second type, allergic reaction, includes local manifestations, usually after the administration of eyedrops, and systemic reaction in the form of anaphylaxis. Since most patients manifest only a mild reaction, allergy testing is not performed and the prevalence of allergy to atropine is therefore not known. Severe allergic reaction to atropine is rare, as evidenced by the small number of case reports in the literature despite the drug's extensive use. Alternative anti-muscarinic drugs recommended for OP poisoning include glycopyrrolate and scopolamine. Glycopyrrolate is a peripheral anti-muscarinic drug that has been studied in comparison to atropine for many clinical indications, while scopolamine is an anti-muscarinic drug with both peripheral and central effects. An acceptable alternative regimen for patients with proven allergy to atropine is a combination of glycopyrrolate with centrally active drugs such as benzodiazepines or scopolamine.
Chemical agents have been used previously in wartime on numerous occasions, from World War I to the Gulf War. In 1994 and 1995, sarin nerve gas was used first in peacetime as a weapon of terrorism in Japan. The Tokyo subway sarin attack was the first large-scale disaster caused by nerve gas. A religious cult released sarin gas into subway commuter trains during morning rush hour. Twelve passengers died and about 5500 people were harmed. Sarin is a highly toxic nerve agent that can be fatal within minutes to hours. It causes the clinical syndrome of cholinergic hyperstimulation by inhibition of the crucial enzyme acetylcholinesterase. Therapy of nerve agent toxicity is divided into three categories, decontamination, respiratory support, and antidotes. All of these therapies may be given simultaneously. This article reviews toxicology and management of this acute chemical emergency. To help minimize the possible catastrophic impact on the public, we make several recommendations based on analysis of the Tokyo subway sarin attack and systematically review the current scientific literature.
One hundred eighty-eight seizure episodes in 46 children were randomly assigned to receive treatment with rectal diazepam and intranasal midazolam with doses of 0.3 mg/kg body weight and 0.2 mg/kg body weight, respectively. Efficacy of the drugs was assessed by drug administration time and seizure cessation time. Heart rate, blood pressure, respiratory rate, and oxygen saturation were measured before and after 5, 10, and 30 minutes following administration of the drugs in both groups. Mean time from arrival of doctor to drug administration was 68.3 +/- 55.12 seconds in the diazepam group and 50.6 +/- 14.1 seconds in the midazolam group (P = 0.002). Mean time from drug administration to cessation of seizure was significantly less in the midazolam group than the diazepam group (P = 0.005). Mean heart rate and blood pressure did not vary significantly between the two drug groups. However, mean respiratory rate and oxygen saturation differed significantly between the two drug groups at 5, 10, and 30 minutes after drug administration. Intranasal midazolam is preferable to rectal diazepam in the treatment of acute seizures in children. Its administration is easy, it has rapid onset of action, has no significant effect on respiration and oxygen saturation, and is socially acceptable.
We evaluated the pharmacokinetics and pharmacodynamics of single 5-mg doses of midazolam after administration of a novel intranasal (IN) formula, IM, and IV midazolam in an open-label, randomized, 3-way cross-over study in 12 healthy volunteers. IN doses were delivered as 0.1-mL unit-dose sprays of a novel formulation into both naris. Blood samples were taken serially from 0 to 12 h after each dose. Plasma midazolam concentrations were determined by liquid chromatography/mass spectrometry/mass spectrometry. Noncompartmental analysis was used to estimate pharmacokinetic parameters. The mean midazolam bioavailabilities and % coefficient of variation were 72.5 (12) and 93.4 (12) after the IN and IM doses, respectively. Median time to maximum concentration was 10 min for IN doses. Adverse events were minimal with all routes of administration, but nasopharyngeal irritation, eyes watering, and a bad taste were reported after IN doses. Our results support further development of this novel midazolam nasal spray.
In the event of a large scale organophosphate (OP) or nerve agent exposure that depletes a hospital's atropine stores, alternative antidotes should be considered.
To test the effects of parenteral administration of ophthalmic antimuscarinic agents on survivability in a rat model of acute, lethal OP poisoning.
After determining appropriate dosing for comparison, rodents were randomized to receive one of four intraperitoneal antidotes (n = 10 per group): 1) normal saline (0.3 mL), 2) atropine sulfate (10 mg/kg), 3) ophthalmic atropine sulfate (1%; 10 mg/kg), or 4) ophthalmic homatropine (5%; 20 mg/kg). Five minutes after pretreatment, dichlorvos (10 mg/kg) was administered subcutaneously. Mortality rates and time to death were compared by using Fisher's exact test and the Kaplan-Meier method with log rank test, respectively. If the animal was alive at 120 minutes, survival was assumed.
Survival in rats pretreated with standard atropine was 100%. Survival in rats pretreated with ophthalmic homatropine and atropine sulfate were 100% (p < 0.001; 95% CI = 0.98 to 1.02) and 90% (p < 0.01; 95% CI = 0.71 to 1.09), respectively, compared with controls (20% survival; 95% CI = 0.04 to 0.45). Time of death ranged between 7 and 19 minutes. Comparison of survival times revealed a statistically significant improvement in experimental groups compared with controls (p < 0.0001).
Parenteral pretreatment with ophthalmic preparations of homatropine or atropine sulfate was equal to standard atropine in preventing lethality in this rat model of acute, lethal OP poisoning.
Organophosphorus pesticide self-poisoning is an important clinical problem in rural regions of the developing world, and kills an estimated 200,000 people every year. Unintentional poisoning kills far fewer people but is a problem in places where highly toxic organophosphorus pesticides are available. Medical management is difficult, with case fatality generally more than 15%. We describe the limited evidence that can guide therapy and the factors that should be considered when designing further clinical studies. 50 years after first use, we still do not know how the core treatments--atropine, oximes, and diazepam--should best be given. Important constraints in the collection of useful data have included the late recognition of great variability in activity and action of the individual pesticides, and the care needed cholinesterase assays for results to be comparable between studies. However, consensus suggests that early resuscitation with atropine, oxygen, respiratory support, and fluids is needed to improve oxygen delivery to tissues. The role of oximes is not completely clear; they might benefit only patients poisoned by specific pesticides or patients with moderate poisoning. Small studies suggest benefit from new treatments such as magnesium sulphate, but much larger trials are needed. Gastric lavage could have a role but should only be undertaken once the patient is stable. Randomised controlled trials are underway in rural Asia to assess the effectiveness of these therapies. However, some organophosphorus pesticides might prove very difficult to treat with current therapies, such that bans on particular pesticides could be the only method to substantially reduce the case fatality after poisoning. Improved medical management of organophosphorus poisoning should result in a reduction in worldwide deaths from suicide.
Effects of intravenous administration of glycopyrrolate and atropine in anesthetized patients
- Mirakur