Experimental models and research on the pharmacotherapy of astronauts

1. Experimental models and research on the pharmacotherapy of astronauts By Maria Traykova, PhD Chemistry, Department of pharmacology and toxicology, Medical University of Sofia, Bulgaria

2. The pharmocotherapy of astronauts has two aspects: • Spaceflight pharmacotherapy • Post-spaceflight pharmactherapy. This presentation is dedicated to the scientific models in the spaceflight pharmacotherapy.

3. ISS – 400 km

4. Factors that affect the health of the astronauts during space flight The open space environment Working conditions in the open space and in the spacecraft Living conditions, physical exercises, relaxation

5. Deleterious effects of the open space environment: Lake of Oxygen Microgravity Microwaves Irradiation Variations in the magnetic field Streams of elemental particles, solar wind

6. Ergonomics (working conditions)

7. Living environment In the spacecraft

8. From the Physiology Slide Set of the American Society of Gravitational and Space Biology (http://asgsb.org/slidesets/slidesets.html).

9. Complains that insist medications

10. Reasons leading to health complains in space flight:

11. Some of the most frequent reasons for using medications in spaceflight: • Discomfort • Irritability due to boredom • Depression • Motion sickness • Insomnia • Skin irritation and lesions • Urinary tract infections • Breathing problems

12. The use of medications is most frequent during short missiona (upto two weeks) • Now 75% of the astronauts declare that they used medications during spaceflight. • Some of the astronauts do not inform the ground medical staff about medications used.

13. Some medications used in Apollo and Mir spaceflight program (1975): • Oral: • Aspirin • Acetamidophen • Triptolidin • Cyclisine • Secobarbital • Diphenoxillate • Dipiridamole • Chinidine • Nasal: • Oxymethazoline

14. Now available: • Pills • Capsules • Injections (ready for use) • Rectal capsules • Eye drops • Topical medications The astronauts are obliged to use any medication after consulting with the ground medical staff.

15. Are the medications in space as effective as on Earth? At least in 20% of the cases NO

16. altered medication’s biological activity and stability Altered expression and virulence of the microorganisms Altered human physiology How the pharmacological effect is altered? Pharmacodynamics Pharmacokinetics Why the pharmacological effects differon Earthcompared to spaceflight?

17. Model investigations in spaceflight pharmacology : • Astronauts – before lift off, during flight mission, and after landing • Experimental animals and microorganisms on board of the spacecraft (ISS) • Human (volunteers) experimental models of microgravity on earth. • Experimental animal models of spaceflight conditions on earth • Spaceflight experiments for stability and bioactivity of medications

18. Microgravity effect on the gastric passage: (lactulose hydrogen breath test ; 2 космонавти) The microgravity increases the time ofthe gastric passage. This effect remains few days after landing. http://humanresearch.jsc.nasa.gov/elements/smo/docs/EB_2008/HRP_EviBook08_Ch21_Pharmacology_Report.pdf

19. Cmax M Tmax Medication: acetamidophen; Dose: 630 mg, in 2Х325 mg,oral; Tests: prior lift-off and after 4 days being in orbit. Total population: 17 individuals, during 10 consequent missions Bioavailability tested in: saliva 9.20.4 1.050.05 10 0.50.0 6.20.2 1 Tmax hrs Cmax mg/ml 0 0 Prior lift-off day 4-th Prior lift-off Day 4-th Putcha L, Cintrón NM. Pharmacokinetic consequences of spaceflight. Ann N Y Acad Sci. 1991:28;618:615-618. Space flight effects on Cmaxи Tmax:

20. Some spaceflight experiments done in 2012 in ISS:

23. Human Experimental model of microgravity on Earth(head-down tilt bed rest) Bed rest with head at angle of -6°compared with the head position:

24. Experimental design: Short term: Groups : 1 contr., maximum 3 exp. Group size: 8 - 12 Ambulatory period: 5 days Experimental period: 5 days Rehabilitation: depending on the condition of the participants Medium term: Groups : 1 contr., maximum 2 exp. Group size: 8 - 12 Ambulatory period: 7 - 14 days Experimental period: 21 days Rehabilitation: 7 – 14 days Long term: Groups :1 contr., 1 exp. Group size: not specified Ambulatory period: 14 days (5 days adaptation to spaceflight diet) Experimental period: 60 days Rehabilitation: 7 – 14 days Head-down tilt bed rest Angles checked: 0 to -15°; Optimal angle: -6° Durations: Short term – 5 days Medium term - 21 days Long term - 60 and more days

25. Head-down tilt bed rest -goals: • Short term: Search for countermeasures against microgravity effects and for markers of the mictrogravity effects (microgravity markers). • Medium term: Screening and verification of the countermeasures against microgravity and of the determination of the microgravity markers. • Long term: • Final verification of the countermeasures against microgravity and of the determination of the microgravity markers. The procedures and methods verified are then applied in spaceflight conditions at the spacecrafts (and ISS). • Simulation of long-term spaceflight for detailed analysis of long-during microgravity on the human physiology.

26. Long term head-down tilt bed rest to simulate long term spaceflight: • Goals: • To investigate in details the response of the human body to long during microgravity; • To verify diets and exercises able to daley the deleterious effects of the microgravoty on humans; Total duration: 120 days Ambulatory period: 15 days Experimental duration: 90 days Rehabilitation: 15 days

27. Spaceflight experiments with microorganisms

28. Spaceflight experiments with rodents:

29. Spaceflight rodents’ cages:

30. Наземен модел на микрогравитация при гризачи: (hind-limb suspension cage) (Оптимален ъгъл между муцунката и основата на опашката - 30%)

31. Spaceflight effects onPharmacokinetics and Pharmacodynamics

32. Effects on the bioavailability: Solubility in the gastric juices Gastric passage Gastro-intestinal resorbtion LiverFirst-passmetabolism Alteration of the blood availability in the intestinal walls microgravity • Other factors related with short-term exposure to microgravity: • Motion sickness • Intestinal micro-flora alterations • Altered excretion and activities of the intestinal enzymes • Altered time of the gastro-intestinal passage

33. Why microgravity alters the distribution volume: • Lost of fluids in the body • Lost of proteins (related with muscle atrophy) • Plasma redistribution outside of the central compartment • Altered lipid content in the blood stream • Reduced production of erythrocytes

34. Conclusions about the spaceflight effects on the bioavailability and volume of distribution: The microgravity effects on the bioavailability and distribution volume are strongly individual; There is a need for collection of larger experimental data base, that will allow to predict with enough probability the optimal doses of the oral medications. Oral medications are not a good choice at spaceflight conditions so far.

35. Effect of microgravity on the elimination: • Altered functions of the kidneys, skin and airways (lungs); • The liver metabolic functions can be altered via alteration of the blood flow, due to fluids redistribution in the body;

36. Spaceflight alteration in the liver metabolism: In astronauts: • Altered activities of liver enzymes due to microgravity effects on the activities of: • Adreno-corticotropic hormone • Thyrotropine • Plasmic renine • Alterations in the levels of anti-diuretic hormones

37. Spaceflight alteration in the liver metabolism: In rats(3-7-14 days spaceflight): • The liver content ofCР450 decreases in a half; • The levels of glycogen in the liver increased; • Altered enzymes activities on several steps of the lipid metabolism. • 50% reduced oxidative metabolism od medications (acetamidophen) These data are confirmed by experimental rat models of microgravity on earth.

38. Conclusions about spaceflight effects on clearance: Clearance may be altered due to: • Altered functions of kidneys, lungs and skin. • Altered liver functions, related with redistribution of the blood in the body. • Altered oxidative metabolism of medications in the liver, related to altered content and activities of the liver enzymes.

39. The low partial pressure of Oxygen affects the pharmacokinetics of some medications, such as: • Meperidine, • Acetazolamide, • Prednisolone, • Furosemide, • Caffeine. This might be related with the alteration (due to hypoxia) in the production and bonding properties of the erythrocyres.

40. The pharmacodynamics (dose-effect relationship) during spaceflight conditions: • Altered due to bioavailability alterations • Altered because of the changed gene expression and viral activity of the pathogens. • During spaceflight the astronauts need larger doses of some (but not all): • Sleeping medications, • Medications against motion sickness • Sedatives., • But lower doses of: • desmethyldiazepam • phenobarbital

41. Efficacy of the medications forms: • Oral pills:not good because of the strongly individual pharmacokinetics. • Inhalers and droppers:the strong interaction of fluids with the walls of the containers insist new design of the flacons. Conclusions based on the following medications: • benzocaine 20% inhaler • phenylephrine 0.25% nasal pump • oxymetazoline 0.05% in standard dropper’s bottle The questions about the right design of droppers and inhalers, as well as of the optimal doses of the medications in such containers, still remain unsolved.

42. ntibiotics(lidocaine, pronethazine) Motion sicknes medications In forms of:: Pills, rectal tablets, ointments, medical patches 6 months. Substantial degradation! ISS Physico-chemical stability and bioactivity of the medications in spaceflight Чувствителна деградация! Factors prompting degradation and loss of bioactivity: Microgravity, Irradiation, Environmental factors in the spacecraft (acidity, humidity, temperature)

43. The spaceflight effects on the circadian rhytms of the human body are not clear. It is being established that the microgravity disturbs the structure of the sleep. It is being proposed that spaceflight may affect other circadian rhythms too. The spaceflight chronopharmcology is not developed yet, but it has to be developed. Spaceflight chronopharmacology

44. The polypharmacy (co-medication): often more than one medication is being used. The self-medication: still there are astronauts who apply medications before consulting the medical team Other factors that can affect the pharmacotherapy during spaceflight:

45. Problems that have to be solved: • Related with the preparation and experimental design of the pharmacological experiments on spaceflight pharmacotherapy. • Related with the accuracy of modeling of the spaceflight conditions when using earth models. • Related with co-medication, self-treatment and the communication with the medical team on earth, if there is no medical person aboard. • The bioactivity of the active substances in the medications, as well as the drug stability have to be improved • Alternative methods that oppose the negative impact of the spaceflight on human health have to be developed and applied.

46. Благодаря за вниманието