Evidence to Practice

Transcription

1 Evidence to Practice

2 Images courtesy of NASA. Materials are derived from previous editions as well as this edition of Space Physiology and Medicine - Evidence and Practice, 4th Edition. Reproduction for purposes other than personal use or teaching will require the Editors' and the Publisher's approval. The Editors reserve the right to change this materials as new information arises.

3 Learning Objectives 1. Review the principles of space pharmacology and 2. Address the use and efficacy of medications in the unique environment of space.

4 Outline Learning Objectives Introduction History of Therapeutics In Space Medications in Space Medical Kits Patterns of Medication Use During Flight Stability of Drug Preparations in Space Missions (Space Shuttle and ISS) Pharmacotherapeutics and Drug Development for Space Missions Test Beds for the Study of Space Pharmacokinetics Gastrointestinal (GI) Absorption Hepatic and Renal Clearance Therapeutic Response Monitoring Microgravity Analogs In-Flight Pharmacokinetics Future Directions Radioprotection, Infection and Immunity Shelf Life and Packaging of Drugs for Space Missions Factors Unique to the Space Environment that May Influence Stability of On-board Medications

5 Introduction Pharmacokinetics (PK) characterizes the absorption, distribution, metabolism, and excretion (ADME) of drugs. Pharmacodynamics (PD) describes the time course of drug action as it relates to its therapeutic effect. Pharmacotherapeutics is combined PK & PD knowledge that assures best therapeutic outcome within clinical settings. Pharmacovigilance (PV) deals with the science and activities related to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problems.

6 Introduction Need for on board medications Efficacy of medications in-flight Absorption, distribution, metabolism, and excretion (ADME) affected by space flight induced changes in blood flow and function of the GI tract, liver, kidneys Mission duration

7 History of Therapeutics in Space Growing formulary SMS (40% of STS crews experienced) Rx for common colds, insomnia Digestive disturbances (9%) Infectious disease (respiratory and urinary tract) Antibiotics Emergency cardiac events

8 History of Therapeutics in Space Minor illnesses on STS missions (STS-1 through STS-94)

9 History of Therapeutics in Space Medications use by indication aboard ISS (PMCs)

10 Medications in the Space Medical Kits Mercury Cyclizine (45 mg 0.9 ml injector) - SMS Meperdine hydrochloride (90 mg 0.9 ml injector) pain Epinephrine (1:1000) Dextroamphetamine* Evolution from injectables to tablets *First medication take in space 6 th and last mission Gordon Cooper Courtesy of NASA

11 Medications in the Space Medical Kits Gemini Crew member testing before flight Dextroamphetamine sulfate with a decongestant before reentry Lomotil (diphenoxylate) GI motility inhibitor (induced constipation) Oral medications deemed not problematic 1 1 NASA. Gemini Summary Conference. Washington, DC: NASA Office of Scientific and Technical Information; NASA SP-138

12 Medications in the Space Medical Kits Apollo Two kits available one in the command module and the other in lunar module Tablet formulations Cardiovascular drugs (quinidine sulfate and dipyridamole added for ASTP Apollo 10 meds most frequently used Aspirin Acetaminophen Triprolidine (Actifed) Secobarbital Lotomil Oxymetazonline (Afrin) Cyclizine (Marezine) 1 NASA. Gemini Summary Conference. Washington, DC: NASA Office of Scientific and Technical Information; NASA SP-138

13 Medications in the Space Medical Kits Contents of the Apollo Command-Module Medical Kit 1 Items a Indication Formulation Quantity Actifed (tripolidine and psuedoephedrine) Decongestant Tablets 60 Afrin (oxymetazoline) Decongestant Nose drops 3 Ampicillin Antibiotic Tablets 60 Aspirin Analgesic Tablets 72 Atropine Cardiac arrhythmias Injectable solution 12 b Bacitracin Antibotic Eye ointment 1 Benadryl (diphenhydramine) Antihistaimine Tablets 8 c Darvon (propoxyphene) Analgesic Tablets 18 Demerol (meperdine) Analgesic Injectable solution 6 b Dexedrine (d-amphetamine) Stimulant Tablets 12 Lidocaine Cardiac arrhythmias Injectable solution 12 b Lomotil (diphenyoxylate) Diarrhea Tablets 24 d Marezine (cyclizine) Antihistamine Injectable solution 3 Marezine (cyclizine) Antihistamine Tablets 24 e Methylcelluose Laxative Capsules 2 Multivitamins Tablets 20 Mylanta (simethicone) Antiflatulent Tablets 40 Neosporin (polmyxin B) Antibiotic Ointment 1 or 2 Ophthaine Topical anesthetic Eye drops 1 Pronestyl (procainamide) Cardiac arrhythmias Tablets 80 b Scopolamine-Dexedrine Motion sickness Tablets 12 Seconal (secobarbital) Sleep aid Tablets (100 mg) 21 Seconal (secobarbital) Sleep aid Tablets (50 mg) 12 c Skin cream Tetracycline Antibiotic Tablets Varied Tetrahydrozoline HCL Eye drops 1 f Tylenol (acetaminophen) Analgesic Tablets 14 c Bandaids 12 Compress bandages 2 a Not all medications were carried in the amounts not on all flights b Carried on Apollo 16 and 17 only c Carried on Apollo 8 only d Increased to 48 on Apollo 17 e Carried on first 4 missions only f Carried on Apollo 17 only 1 Hawkins WR, Ziegleschmid JF. Clinical aspects of crew health. In: Johnston RL, Dietlein LF, Berry CA, eds. Biomedical Results of Apollo. Washington, DC: US Government Printing Office; 1975: NASA SP-368.

14 Medications in the Space Medical Kits Contents of the Apollo Lunar-Module Medical Kit 1 Items Indication Formulation Quantity Actifed Decongestant Tablets 8 Afrin Decongestant Nose drops 1 Aspirin Analgesic Tablets 12 Atropine Cardiac arrhythmias Injectable solution 4 Darvon Analgesic Tablets 4 Demerol Analgesic Injectable solution 2 Dexedrine Stimulant Tablets 4 Lidocaine Cardiac arrhythmias Injectable solution 8 Lomotil Diarrhea Tablets 12 Methylcelluose Eye drops 1 Neosporin Antibiotic Ointment 1 Pronestyl Cardiac arrhythmias Tablets 12 Seconal Sleep aid Tablets 6 Bandaids 6 Compress bandages 2 Urine collection and transfer device 6 1 Hawkins WR, Ziegleschmid JF. Clinical aspects of crew health. In: Johnston RL, Dietlein LF, Berry CA, eds. Biomedical Results of Apollo. Washington, DC: US Government Printing Office; 1975: NASA SP-368.

15 Medications in the Space Medical Kits Space Shuttle Shuttle Orbiter Medical System (SOMS) Courtesy of NASA

16 Medications in the Space Medical Kits Space Shuttle Six sub packs (each pack 6.7kg or 15 lbs) 1. Drug 2. Trauma 3. Eyes, ears, nose and throat 4. Airway 5. Intravenous 6. Saline Supply bag Developed from Gemini Minor ambulatory care, first aid and BLS Early versions contained injectable / intravenous, oral, and topical medications Ziploc bags incorporated Pre-filled syringes Stowage system continues into the ISS Program Courtesy of NASA 1 NASA. Gemini Summary Conference. Washington, DC: NASA Office of Scientific and Technical Information; NASA SP-138

17 Medications in the Space Medical Kits ISS Nine sub packs 1. Convenience Medication 2. IV Supply 3. Medical Supply 4. Minor Treatment 5. Medical Diagnostic 6. Oral Medication 7. Topical and Injectable Medications 8. Physician Equipment 9. Emergency Medical Treatment Courtesy of NASA

18 Medications in the Space Medical Kits Types of medication in the Shuttle SOMS Kit and ISS Med Kit Type of Mission Space Shuttle ISS Medication Sub-packs 5 9 Analgesics 6 5 Anti-infectives Antimotion sickness 3 4 Stimulants 1 2 Antihistamines 3 6 Decongestants 2 3 Sedatives 2 3 Courtesy of NASA

19 Medications in the Space Medical Kits Concerns Shelf life considerations Pharmacovigilance Stability 1 Potential adverse effects Formation of toxic degradation products Change in bioavailabilty 2 Changes in integrity of packaging 1 Meyer JH, Elashoff J, Porter-Fink V, Dressman J, Amidon GL. Human postprandial gastric emptying of 1- to 3- mm spheres. Gastroenterology 1988; 94: Levine RR. Factors affecting gastrointestinal absorption of drugs. Am J Dig Dis 1970; 15:

20 Patterns of Medication Use during Flight Apollo flights Medication during the 10 Apollo flights 1 Aspirin (tab) Acetaminophen (tab) Triprolidine (tab) Secobarbital (tab) Diphenoxylate (tab) Oxymetazoline (nasal spray) Cyclizine (tab) 1 Hawkins WR, Ziegleschmid JF. Clinical aspects of crew health. In: Johnston RL, Dietlein LF, Berry CA, eds. Biomedical Results of Apollo. Washington, DC: US Government Printing Office; 1975: NASA SP-368.

21 Patterns of Medication Use during Flight Shuttle Utilization Medications varied flight to flight Crew member needs More crew members easy access Incidence in-flight illness increased Increased formulary inventory available Majority of formulation in tablet form Lack of significant data on pharmacokinetics and pharmacodynamics

22 Patterns of Medication Use during Flight Shuttle Utilization Utilization data difficult to obtain either written down or in the post-flight debrief with the crew surgeon Review of STS 1 STS-80 post flight debriefings 219 person flights 94% reported some medication us in-flight 88% orally administered 5% intranasal administration 4% IM 2% rectally administration 47% took SMS formulations 45% took sleep aides

23 Patterns of Medication Use during Flight Shuttle Utilization Review of STS 1 STS-94 post flight debriefings 37% of all medications were for pain medication 22% for sleep 18% for SMS 14% for decongestion 14% all others Analysis of crew debriefings indicated 150 of 317 crew members experienced SMS symptoms 90% of these crew members took medication (387 dosing episodes) Promethazine (201 doses) Scopolamine and dextroamphetamine (Scop/Dex)

24 Patterns of Medication Use during Flight Medication use profile STS-1 to STS-94 Courtesy of NASA

25 Patterns of Medication Use during Flight Anti-motion Sickness medication use STS-1 to STS-94 Medication Standard Dose Total No of Doses Men (n=117) Women (n=15) Promethazine mg Scopolamine + dextroamphetamine Promethazine + dextroamphetamine mg Scop 5-10 mg Dex mg Pro 5-10 mg Dex Metoclopramide mg Prochlorperazine 5-15 mg 4 4 Scopolamine mg 4 4 Total Courtesy of NASA

26 Patterns of Medication Use during Flight Effectiveness of drugs taken for SMS as a function of total number of doses of all drugs taken on STS-1 through STS-94 1 Courtesy of NASA 1 Putcha L, Boyd, JL, Bayuse TM, Vaksman Z, Daniels VR, Du B, Younker D. Chapter 5.2 Pharmacokinetic Operations and Research in Space. In Biomedical Results of the Space Shuttle Program, Eds:Risin D, Stepanak PC. NASA 2013

27 Patterns of Medication Use during Flight Dosage forms of promethazine and their effectiveness as a function of total number of doses taken on shuttle flights STS-1 through STS 94 Courtesy of NASA

28 Patterns of Medication Use during Flight Crew member specific carry on medications (pre-flight request) Incomplete records of carry on (not recorded / discussed in post-flight debrief) Higher dosages used for sleep aid and SMS than expected (no increase in side effects) 1 Anecdotal reports Longer duration missions more stringent pre-flight screening to minimize risk factors for disease that can t be treated effectively in flight 2 Medical unknowns for exploration class missions 1 Elfstrom J, Lindgren S. Influence of bed rest on the pharmacokinetics of phenazone. Eur J Clin Pharmacol 1978; 13: Baisden DL, Beven GE, Campbell MR, Charles JB, Dervay JP, et al. Human health and performance for long-duration spaceflight. Aviat Space Environ Med 2008;79:

29 Stability of Drug Preparations in Space Missions (STS and ISS) Post flight examination of medications flow in space 15 from STS and ISS Physical and chemical properties evaluated Some changes in physical characteristics Reduction in active pharmaceutical ingredient (API) These changes compromise the USP-recommended standards Changes observed in Amoxicillin/clavulanate Mupirocin ointment All three formulations of promethazine

30 Stability of Drug Preparations in Space Missions (STS and ISS) Medication with Reduced Active Pharmaceutical Ingredient after Space Flight Medication No of Kit Samples Received 1 No of Kits Showing Chemical Content Reduction Amoxicillin + clavulanate tablets 9 9 Mupirocin ointment 6 2 Promethazine injections Promethazine suppositories Promethazine tablets Sulfamethoxazol/trimethoprim tablets 9 6 Temazepam capsules 7 2 Notes: 1 Each sample is from a separate mission; 2 Did not meet USP standards for release of active ingredient. (Courtesy of NASA)

31 Stability of Drug Preparations in Space Missions (STS and ISS) Formulation of medications Understand impact of the space environment on the medication (i.e., radiation, vibration, and light sensitivity) Availability of data from the crew on what they took and when they took it (confidential PMCs) Subjective questions interpretation of responses Rigorous evaluation of data Understanding pharmacokinetic changes and physiological factors

32 Pharmacotherapeutics and Drug Development for Space Missions Pharmacokinetics rate and extent of absorption, distribution, metabolism, and elimination Pharmacodynamics processes associated with the rate, duration, and extent of pharmacologic and toxicologic effects Microgravity induces a wide range of physiological and biomedical changes Primary goal is to understand the relationship of these changes and the bioavailability and efficacy of the medications used in-flight

33 Test Beds for the Study of Space Pharmacokinetics GI Absorption Blood flow, ph, and motility influence bioavailability Gastric emptying and intestinal motility influence by the absence of gravity Changes in microbiota and intestinal homeostasis After 14 days in-flight significant reduction in bacterial species Emergence of Klebsiella and Pseudomonas 1,2 Malabsorption of nutrients, fluids and electrolytes 1 Ilyin VK. Microbiological status of cosmonauts during orbital spaceflights on Salyut and Mir orbital stations. Acta Astronautica 2005; 56: Taylor GR. Recovery of medically important microorganisms from Apollo astronauts. Aerospace Med 1974; 45:

34 Test Beds for the Study of Space Pharmacokinetics GI Absorption Lactulose-breath hydrogen test Transit time from mouth to cecum (indirect measure of GI transit time) Ground-based study (10 day head-down bed rest) Decreased 63% in normal subjects Mouth-to-cecum transit time of lactulose in normal subjects before and after 10 days of 6 head-down bed rest.

35 Test Beds for the Study of Space Pharmacokinetics GI Absorption Mean Gastrointestinal (GI) transit time in normal subjects before and after head-down bed rest and space flight. Lactulose-breath hydrogen test Shuttle and Mir-18 crew members during flight Sustained increase in GI transit time throughout the mission Time (min) GITT, Lactulose Breath H2 Test Astronauts (Mir&STS) Bed Rest Pre FD 3 FD 30 FD 56 FD 88 Postflight

36 Test Beds for the Study of Space Pharmacokinetics GI Absorption Rate and extent of absorption from tablet is a function of dissolution rate (solubility) maybe influenced by dehydration and GI motility Impacts bioavailability of orally-administered medications Methanogenic bacteria in the distal colon (converts H 2 to CH 4 ) High breath concentrations of H2 indicate a possible proliferation of H. pylori 1 Fecal samples from Mir-18 did not show any anomalies 1 Sousa T, Paterson R, Moore V, et al. The gastrointestinal microbiota as a site for the biotransformation of drugs. Int J Pharmaceut 2008; 363:1-25.

37 Test Beds for the Study of Space Pharmacokinetics Hepatic and Renal Clearance Ground-based study using rats (30 angle reported total body clearance of antipyrine and indocyanine) - pharmacokinetic parameters may be altered in simulated microgravity Limited studies in-flight on hepatic metabolism and function Underlying mechanism are difficult to identify

38 Test Beds for the Study of Space Pharmacokinetics Therapeutic Response Monitoring ADME rates measured on the ground in plasma Evaluating saliva to monitor kinetics and dynamics of acetaminophen and scopolamine Non-invasive testing No or limited cold storage of samples Courtesy of NASA

39 Test Beds for the Study of Space Pharmacokinetics Microgravity Analogs Bed rest studies Oral and IV administered scopolamine evaluated after 24 hr anti-orthostatic bed rest Bioavailability of Oral Scopolamine During Bed Rest Subject Bioavailability Control period Bed rest period Mean (SE) 26.0 (9.0) 17.3 (6.0) Courtesy of NASA

40 In-Flight Pharmacokinetics Acetominophen concentration in saliva measured in 12 STS crew members pre- and in-flight Adsorption declined during flight Variability between crew members individual adjustments to microgravity APAP Pharmacokinetics - Saliva concentration-time profiles fasted state Tablets, (n=7 STS crew member s). Courtesy of NASA

41 In-Flight Pharmacokinetics Other delivery methods Change in salivary flow rate after administration of 0.4mg scopolamine Courtesy of NASA

42 In-Flight Pharmacokinetics Other delivery methods Plasma scopolamine concentration profiles after intravenous, intranasal, and oral 0.4mg dose Courtesy of NASA

43 In-Flight Pharmacokinetics Other delivery methods Bioavailability of intranasal scopolamine compared to that of oral scopolamine Courtesy of NASA

44 Future Directions Extend stability Optimize bioavailability Efficacy Minimize toxicity and side effects New technologies Radio-protective formulation matrices Dispensing technologies Tracking technologies

45 Future Directions Radioprotection, Infection and Immunity Future mission profiles and destinations will increase risk to crew health and safety Few drug options available for radio protection Amifostine inhibits apoptosis a broad spectrum radioprotective Developmental drugs as radioprotectants Ex-Rad, 4-carboxystyryl-4-chlorobenzylsulfone sodiim CBLB502 a flagellin-derived from Salmonella enterica

46 Future Directions Radioprotection, Infection and Immunity Alternative paradigms for Tx of infection Modify the pathogen don t kill it off Reduce virulence Host-directed therapies

47 Future Directions Shelf Life and Packaging of Drugs for Space Missions FDA guidelines followed on ISS (< 6 mos of expiration date medication is replaced) Exploration missions this is not possible Packaging and repackaging invalidation of expiration dates Radiation shielding and daughter ions Innovative drug delivery technologies Nanotechnology-based Nanostructures

48 Future Directions Factors Unique to the Space Environment that May Influence Stability of On-board Medications Therapeutic efficacy may be impacted by the space flight environment Loss of API content Alterations in disintegration and dissolution rate of solid dosages Loss of content uniformity Decreased anti-microbiological activity Environment (heat, light, moisture and chemical factors)

49 Future Directions Factors Unique to the Space Environment that May Influence Stability of On-board Medications Chemical properties sedimentation, discoloration, precipitation, crystal growth, and creaming of liquid/semi solids Promethazine is dispensed in tablet, injectable and suppository forms Changes to medications on STS/ISS missions occurred within the first 20 days Packaging and vibration during transport? Impact of radiation

50 Future Directions Subjective Evaluation of the Strength of Evidence in Space Pharmacotherapeutics Subject Knowledge Reference (s) Strength Remarks Release Not Available None Insufficient Additional in-flight studies required Absorption Limited Putcha,1991 Putcha, 2013 Gandia, 2005 Fair Limited to two medications Distribution Not available None Insufficient Additional in-flight studies required Metabolism Limited Cintron, 1987 Fair Additional in-flight studies Putcha, 2013 (Shuttle results book) required Elimination Not Available Putcha, 2013 (Shuttle results book) Insufficient Additional in-flight studies required Adverse reactions Not Available None Insufficient Additional in-flight studies required Drug interactions Not Available None Insufficient Additional in-flight studies required Shelf life Documented Du, 2011 Good Extending shelf life of medications is required for missions beyond LEO Empirical Information Clinical Observations based on crew reporting Putcha, 1999 Fair Post mission crew debriefing, mission medical communications

51 Key Points to Remember 1. Evidence relating to drug pharmacokinetics and pharmacodynamics in space is limited to a few formulations. 2. Efficacy of in-flight medications is based on crew medical debriefs, anecdotal clinical assessments and crew member reports. 3. Exposure of medications to space flight conditions results in faster degradation of API compared to ground-based formulations. 4. It is advisable to allocate storage space for medical kits, under appropriately monitored environmental and radiation shielding, during the design of space craft for long duration missions to ensure adequate shelf life and bioavailability.

52 Key Points to Remember 6. In low Earth orbit (U.S. missions only), all medical conditions responded to therapy and did not require unscheduled mission termination or emergency crew evacuation. 7. It appears that oral medications are not as well absorbed in space when compared to their bioavailability on Earth. 8. Intramuscularly administered medications produce the desired response in astronauts. 9. Long duration and space exploration space missions may bring about new and different medical challenges requiring therapeutic intervention strategies like telemedicine. 10. Extended duration missions should include appropriate resuscitation medications, in addition to emergency equipment.

53 Self-study Questions 1. How has microgravity expanded the scope of pharmacotherapeutics over the past five decades? 2. How has the space mission s complexity and biomedical research changed the medical formulary kits available to crew members? 3. How could comprehensive knowledge of pharmacokinetics and pharmacodynamics improve medical practice in space? 4. What are major concerns of formulary for exploration missions and what would be some of the risk mitigation strategies for optimal space therapeutics? 5. What factors should be considered for optimal kit design and contents for exploration missions? 6. Discuss the adequacy of crew training and medical debriefings on therapeutic efficacy and adverse effects for evidence-based clinical practice in space.