Comparative Absorption of Atropine from a Metered-Dose Inhaler and an Intramuscular Injection

Kehe, Colin R.; Lasseter, Kenneth C.; Miller, Norman N.; Wick, Karen A.; Shamblen, E. Cooper; Ekholm, Bruce P.; Sandahl, Jane H.; Chang, Shaw F.; Goldlust, Marvin B.; Kvam, Donald C.; Harrison, Lester I.

doi:10.1097/00007691-199204000-00009

Cited by 17 publications

(10 citation statements)

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“…Human scintigraphy studies further highlighted the advantage of submicronic test formulation with lung scintigrams showing nearly 80% of the inhaled drug reaching the pulmonary vasculature, which is much more in comparison to that reported for micronized drugs, where nearly two-third of the drug is deposited in the oropharyngeal region and is not available to the lungs (Bhavna et al, 2009). The blood bioavailability curve with respect to AS post nebulization in humans was favorable by way of a much earlier bioavailability of the antidote in the therapeutic range (6-8 ng/ml) as compared to known values of AS given through intramuscular route, where the therapeutic concentration is achieved at 30 min (Kehe et al, 1992;Ali et al, 2009). The therapeutic concentration was reached within 5 min and two peaks were observed.…”

Section: Discussionmentioning

confidence: 76%

“…Thereafter, the curve followed a slow falling pattern and at 120 min, only 4 ng/ml of the drug was present in blood. The bioavailability of the drug was much more favorable in comparison to that of the known standard intramuscular dose of atropine sulphate (Kehe et al, 1992) in terms of amplitude as well as early peaking of the drug concentration curve in blood.…”

Section: Atropinization Signs and Symptomsmentioning

confidence: 90%

“…Figure 1 shows the plasma concentrations of 3% nano-AS respiratory fluid in human volunteers (n ¼ 6) in ng/ml at different time intervals after nebulization. The first blood sample drawn within 5 min of inhalation showed the drug concentration of 12.7 ng/ml, suggesting a much earlier bioavailability of the antidote in therapeutic range (6-8 ng/ml) as compared to known values of atropine sulphate given through intramuscular route, where the therapeutic concentration is achieved at 30 min (Kehe et al, 1992;Ali et al, 2009). At 15 and 30 min interval post inhalation, the concentration of atropine in blood was 11 and 6.1 ng/ml respectively.…”

Section: Atropinization Signs and Symptomsmentioning

confidence: 90%

“…This provided additional evidence that nano-AS nebulization was able to deliver therapeutic dose through the lungs quickly. In comparison, it is reported that peak effect by intramuscular route occurs after 30 min (Kehe et al, 1992), while that with oral route occurs only after 60-120 min (Dollery, 1999). Figure 1 shows the plasma concentrations of 3% nano-AS respiratory fluid in human volunteers (n ¼ 6) in ng/ml at different time intervals after nebulization.…”

Section: Atropinization Signs and Symptomsmentioning

confidence: 99%

“…Members of the rescue team are presently provided with a 2 mg intramuscular injection of AS alone or in combination with pralidoxime chloride to be taken as a prophylactic measure before entering the 'hot' zone (Dunn et al, 1997;Bentur et al, 2006). However, the peak plasma concentration (6-8 ng/mL) after giving a standard dose of 2 mg AS intramuscular injection does not occur until 30 min have elapsed, limiting its use as a therapeutic option, more so in case of mass casualty (Kehe et al, 1992;Ali et al, 2009). In a hospital setting, assuming the patient can be transported there, the intravenous bolus route is the fastest way to introduce and maintain a state of atropinization, with the peak pharmacological concentration occurring within 5-10 min (Berghem et al, 1980;Ali-Melkkilä et al, 1993;Ali et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Development and clinical study of submicronic-atropine sulphate respiratory fluid as a novel organophosphorous poisoning antidote

et al. 2014

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Context: Increased use of organophosphate insecticides (OPI) and possibility of terror groups using stocks of nerve agents underscore the need to develop effective and safe antidotes. While intramuscular administration of antidotes like atropine sulphate (AS) has certain lacunae, intravenous route may not be always feasible in emergency field conditions. Objective: Objective was (a) to develop a novel inhalable submicronic-AS respiratory fluid as potential antidote for OPI poisoning, (b) in-vitro and in-vivo evaluation in terms of respiratory fraction, and (c) clinical study to assess drug bioavailability in blood and atropinization pattern post-inhalation. Methods: Formulation was optimized on the basis of particle size of aerosolized droplets and in-vitro nebulization rate. Anderson cascade impaction (ACI) studies were carried out to validate the advantage of test formulation in terms of respirable fraction. Six healthy volunteers were inhaled the test formulation and blood bioavailability and atropinization were noted serially. Gamma scintigraphy was used to quantify total and regional lung deposition of nebulized AS in-vivo. Results: The formulation was optimized using 30% ethanol-saline with particle size in the range of 350-500 nm. In-vitro ACI data showed high respirable fraction (82.6 ± 3.1%) for the test formulation. In-vivo scintigraphy suggested whole lung deposition of 80.2 ± 6.8% of the total inhaled dose. Early blood bioavailability and atropinization pattern confirmed that therapeutic concentration of the drug in blood was reached within 5 min. Conclusions: 3% submicronic-AS respiratory fluid might be used as potential prophylactic/ therapeutic option against OPI poisoning with several advantages over intramuscular injection, including early blood bioavailability and atropinization.

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Section: Discussionmentioning

confidence: 76%

Section: Atropinization Signs and Symptomsmentioning

confidence: 90%

Section: Atropinization Signs and Symptomsmentioning

confidence: 90%

Section: Atropinization Signs and Symptomsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Development and clinical study of submicronic-atropine sulphate respiratory fluid as a novel organophosphorous poisoning antidote

et al. 2014

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Application of an enantioselective LC‐ESI MS/MS procedure to determine R‐ and S‐hyoscyamine following intravenous atropine administration in swine

John¹,

Mikler

Worek³

et al. 2011

Drug Testing and Analysis

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S-hyoscyamine (S-hyo) is a natural plant tropane alkaloid acting as a muscarinic receptor (MR) antagonist. Its racemic mixture (atropine) is clinically used in pre-anaesthesia, ophthalmology and for the antidotal treatment of organophosphorus (OP) poisoning with nerve agents or pesticides even though R-hyo exhibits no effects on MR. Further investigative research is required to optimize treatment of OP poisoning. Swine are often the animal model utilized due to similarities in physiology and antidote response to humans. However, no studies have been reported that elucidated differences in the kinetics of R- and S-hyo. Therefore, the concentration-time profiles of total hyo as well as both enantiomers were analyzed in plasma after intravenous administration of atropine sulfate (Atr(2) SO(4) , 100 µg/kg) to anaesthetized swine. For quantification plasma samples were incubated separately with human serum (procedure A) and rabbit serum (procedure B). The rabbit serum used contained atropinesterase, which is suitable for stereoselective hydrolysis of S-hyo, while human serum does not hydrolyze either enantiomer. After incubation samples were precipitated and the supernatant was analyzed by RP-HPLC-ESI MS/MS. Procedure A allowed determination of total hyo and procedure B remaining R-hyo concentrations. S-hyo was calculated as the difference of the two procedures. Concentration data were regressed by a two-phase decay according to a two-compartment open model revealing similar kinetics for both enantiomers thus indicating distribution, metabolism and elimination without obvious stereoselective preference in tested swine.

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Atropine

French

Walter

2017

Critical Care Toxicology

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Comparative Absorption of Atropine from a Metered-Dose Inhaler and an Intramuscular Injection

Cited by 17 publications

References 0 publications

Development and clinical study of submicronic-atropine sulphate respiratory fluid as a novel organophosphorous poisoning antidote

Development and clinical study of submicronic-atropine sulphate respiratory fluid as a novel organophosphorous poisoning antidote

Application of an enantioselective LC‐ESI MS/MS procedure to determine R‐ and S‐hyoscyamine following intravenous atropine administration in swine

Atropine

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