Potential risk of poisoning by nerve agent Injury, Occupational Diseases, Poisoning
Conditions
Interventions
Subject numbers were allocated to treatments according to a randomisation schedule prepared by an independent statistician.
Doses of the study drug physostigmine salicylate and hyoscine hydrobromide
physostigmine and placebo
hyoscine and placebo
or 2 doses of placebo.
Description of follow up of all treatment arms:
Trial procedures in Parts A, B2, and C (4-h infusion). Vital signs were recorded at -1 days, pre-dose, 1, 2, 4, 8, 12, and 24
Sponsors
Defence Science and Technology Laboratory
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Parts A and B: caucasian man. Part C: caucasian woman. Women of childbearing potential agreed to use adequate contraception and had a negative serum pregnancy test at screening and before each dose of Investigational Medicinal Product (IMP). Women were considered to be of non-childbearing potential if they were surgically sterile (had undergone removal of both ovaries and/or uterus, or had undergone bilateral tubal ligation at least 6 months before the trial). 2. Aged 18–40 years 3. Body mass index (BMI) in the range 18.9–29.0 4. Weight =60 kg 5. Normal vision (spherical error between +1.00 D and –1.00 D, and cylindrical error less than or equal to 1.00 D) 6. Part B, C: normal intraocular pressure and anterior chamber angle assessment 7. Sufficient intelligence to understand the nature of the trial and any hazards of participating in it. Ability to communicate satisfactorily with the investigator and to participate in, and comply with the requirements of, the entire trial. 8. Willingness to give written consent to participate after reading the Informed Consent Form, and having had the opportunity to discuss the trial with the investigator or his delegate 9. Willingness to give written consent to have data entered into The Overvolunteering Prevention System
Exclusion criteria
Exclusion criteria: 1. Pregnant or lactating 2. Pre-menopausal, sexually active, and not using a reliable method of contraception 3. Clinically relevant abnormal history, physical findings, ECG, or laboratory values at the pre-trial screening assessment that could have interfered with the objectives of the trial or the safety of the volunteer 4. Presence of acute or chronic illness or history of chronic illness sufficient to have invalidated the volunteer’s participation in the trial or have made it unnecessarily hazardous 5. Impaired endocrine, thyroid, hepatic, respiratory, or renal function (including mechanical obstruction of the urinary system), diabetes mellitus, coronary heart disease or arrhythmias, or history of any psychotic mental illness 6. Current or past history of asthma (within the last 10 years) 7. History or family history of glaucoma 8. Dibucaine number 450 msec at screening (an average of 3 readings after 10 min rest) 19. Possibility that the volunteer would not cooperate with the requirements of the protocol 20. Evidence of drug abuse on urine testing 21. Positive test for hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) 1 or 2 22. Loss of more than 450 ml blood during the 3 months before the trial, e.g. as a blood donor 23. Objection by General Practitioner to volunteer entering trial
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 1. Definition of the optimal dose ratio of the active ingredients physostigmine salicylate: hyoscine hydrobromide, to achieve maximum potential therapeutic benefit without significant side effects when given concomitantly by intravenous infusion, measured by vital signs recorded at -1 days, pre-dose, 1, 2, 4, 8, 12, and 24 h, and at follow up 2. Hyoscine blood levels measured using liquid chromatography with tandem mass spectrometry (LC-MS-MS) at pre-dose, 15 and 30 min, and 1, 2, 2.5, 3, 3.5, 3.83, 5, 6, 7, 8, 9, 10, and 12 h 3. Physostigmine blood levels measured using liquid chromatography with tandem mass spectrometry at pre-dose, 15 and 30 min, and 1, 2, 3, 3.5, 4, 4.5, 5, 5.5, 6, and 8 h | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. To assess the pharmacokinetics (PK) and pharmacodynamics of increasing dosing regimens of physostigmine/hyoscine administered by intravenous infusion in healthy men and women measured using: 1.1. Hyoscine blood levels measured using liquid chromatography with tandem mass spectrometry (LC-MS-MS) at pre-dose, 15 and 30 min, and 1, 2, 2.5, 3, 3.5, 3.83, 5, 6, 7, 8, 9, 10, and 12 h 1.2. Physostigmine blood levels measured using liquid chromatography with tandem mass spectrometry (LC-MS-MS) at pre-dose, 15 and 30 min, and 1, 2, 3, 3.5, 4, 4.5, 5, 5.5, 6, and 8 h 1.3. Red blood cell acetylcholinesterase blood levels measured using colorimetrical assay at -1 days, pre-dose, 1, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 h | — |
Countries
England, United Kingdom
Outcome results
None listed