The space environment provides several challenges: variable gravity; constant radiation; extreme temperature and pressure; and on other planets, a new physical and chemical environment - perhaps even an entire ecosystem. These challenges in human induce physiological changes that may lead to pharmacokinetic and pharmacodynamic changes of drug administered to crew in space shuttle. In addition, space environment exerted on micro organisms, which are inevitably present by way of contaminants and crewmember microflora, thus making the occurrence of adaptive response probable. Various factors associated with the space flight environment have been to potentially compromise the immune system of crewmember, increase microbial proliferation and microflora exchange, alter virulence and decrease antibiotic effectiveness.
Human space flight is a complex undertaking that entails numerous technological and biomedical challenges. Since the beginning of the 1960s, humans have embarked on the conquest of space: a new world, but hostile for a number of different reasons. The primary hostile factor is the lack of gravity, which can induce space motion sickness and induces several physiological changes in the human body. The first signs of exposure to a zero-gravity atmosphere include symptoms such as headache, nausea, vomiting, congestion, back pain, and sleeplessness.
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Space motion sickness, as is commonly known, is experienced by 50% or more of astronauts during the first few days of exposure to the microgravity environment of space. The symptoms of space motion sickness are similar to those of sea sickness, air sickness or car sickness. They vary considerably among individuals but may include (Lathers et al., 1989; Berry, 1973) decreased mental alertness and a general feeling of apathy, lethargy, voluntary restriction of head and body movements. The symptoms are generally manifest within the first 24 h of spaceflight and certainly within the first 36 h. They usually peak at 48 h and recovery is almost always complete by 3-4 days.
PHYSIOLOGICAL CHANGES IN MICROGRAVITY
Space flight results in loss of bone mass, especially in weight-bearing bones, a condition that is suggested to be similar to disuse osteoporosis. The skeletal unloading experienced by astronauts in microgravity causes a site-specific loss of as much as 1% to 2% per month of bone mineral density. Os calcis density decreased after short space flights and after long space flights (Nicogossian et al., 1994). During short space flights (1-14 days), an increasing negative calcium balance was found. During long space flights (> 2 weeks), excretion of calcium into urine increased in the first month. After 10 days of flight, the fecal calcium excretion increased continually throughout the flight. On the Mir year long mission, bone measurements showed a 10% reduction of lumbar vertebrae as compared to preflight (Grigoriev et al., 1991).
Muscle strength, tone, and endurance decreased significantly during space flight, both in humans and animals. In rats, a 37% decline in muscle mass was reported after one week of microgravity (Fitts et al., 2001). Muscle atrophy and loss in lean body mass, associated with a decline in peak force and power are reported (Leonard et al., 1983). The maximal voluntary contractions of the plantar flexor decreased 20% to 48% in humans after 6 months in space (Nicogossian et al., 1994). An increase in sodium current density may reduce the resistance to fatigue of antigravity muscle fibers, an effect that may contribute to muscle impairment during long-term space flight (Desaphy et al., 2001). The main losses were found in antigravity muscle groups (Thornton et al., 1977; Grigoriev and Egorov, 1992; Stein and Gaprindashvili, 1994).
The immune system is a complex network of highly specialized cells and organs that work together to defend the body against foreign invaders. Space flight has been shown to induce varied immune responses, many of them potentially detrimental. Some of these changes occur immediately after arriving in space while others develop throughout the span of the mission (Sonnenfeld, 1998). The causal factors include microgravity, the stress due to high-demand astronaut activities and the social interactions of confinement (Meehan et al., 1993), diet (Heer et al., 1995; Beisel and Talbot, 1985), lack of load bearing (Schmitt et al., 2000; Armstrong et al., 1993) and radiation (Mortazavi et al., 2003), Photoimmunomodulation, although not frequently mentioned, has been addressed by other researchers (Hug et al., 2001). To date, the only consistent effects on the immune system observed have been a reduction in T-cell counts and a decrease in natural killer (NK) cell concentration and functionality (Sonnenfeld and Shearer, 2002; Levine and Greenleaf, 1998), a reduction in cell-mediated immunity, altered cytokine production (Crucian et al., 2000; Levine and Greenleaf, 1998; Konstantinova and Fuchs, 1991), and constant levels of immunoglobulins (Levine and Greenleaf, 1998). More recent research shows that there is an increased susceptibility to infection under space flight conditions (Mehta et al., 2000, 2004; Aviles et al., 2003). The main concern of a weakening immune system in the closed environment of a spacecraft is the possibility of having altered ability to heal from bacterial and certain fungal, viral, and parasitic invasions.
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The urinary sodium, potassium, and chloride generally increased in microgravity, while serum osmolality and sodium are decreased throughout flight (Leach et al., 1988). Data from Spacelab-2 showed that after an increase early in flight, the atrial natriuretic factor (ANF), one of the hormones that regulates sodium and water excretion, was decreased by 59% and blood sodium decreased by 1% late in flight, whereas potassium had been increased by 9%(Leach et al., 1988). On the other hand, the excretion of sodium, potassium, and water was decreased the day after landing compared to the preflight period (Natochin et al., 1975). A slight increase in serum sodium immediately after landing compared to preflight was also observed, while potassium and calcium were unchanged (Natochin et al., 1975).
Alterations in hormone levels during space flight are strongly related to stress and the cardiovascular adaptive response to the microgravity environment. During long space flights (> 2 weeks), cortisol levels are increased, and adrenocortotropic hormone (ACTH) and insulin are decreased. Postflight, angiotensin, aldosterone, thyroid-stimulating hormone (TSH), and growth hormone (GH) levels are also increased (Nicogossian et al., 1994). Microgravity also stimulates functional activity of the parathyroid and suppresses the thyroid C cells, which affects the production of parathyroid hormone and calcitonin, respectively (Kaplanskii et al., 2001). This may play a significant role in the pathogenesis of disorders in calcium turnover in microgravity.
Several studies have demonstrated that the activities of a variety of enzymes, including certain drug metabolizing enzymes, are altered in animals that are subjected to space flights. The activities of some intestinal digestive enzymes, including leucine aminopeptidase, acid phosphatase, adenosine triphosphatase, and glucose-6-phosphatase, showed a transient increase during space flights ( Groza et al .,1983a,1987 and Groza et al., 1983b). The activity of Hydroxymethylglutaryl-CoA (HMG-CoA) reductase, the rate-limiting step in the biosynthesis of cholesterol, was also shown to increase in microgravity (Merrill et al., 1990). In rats flown on Cosmos, the amount of microsomal P-450 and the activity of aniline hydroxylase and ethylmorphine- N-demethylase, cytochrome P-450-dependent enzymes, were decreased (Merrill et al., 1990).
Red Blood Cell Mass
Astronauts have consistently returned from space flight with decreased red blood cell (RBC) mass (Grigoriev et al., 1991; Huntoon et al., 1994; Dong and Shen, 2001). On Spacelab Life Sciences missions (SLS-1 and SLS-2), RBC count and hemoglobin increased in crewmembers in early flight due to a rapid decrease of plasma volume (PV). However, the hematocrit did not change (Alfrey et al., 1996(a)). The smaller mean cell volume and RBC size (decrease in the number of young cells that are larger in size) may have allowed the hematocrit to stay unchanged (Alfrey et al., 1996(b)). Erythropoietin levels were decreased throughout the flight (Alfrey et al., 1996(a)), which could be the cause of the increased neocytolysis (destruction of young red blood cells (Trial et al., 2001).
Cardiovascular adaptation to microgravity is probably, together with bone physiology, the well-studied response of the body to weightlessness. Orthostatic intolerance is observed in most astronauts after returning to Earth and is a consequence of cardiovascular adaptation to weightlessness (Graebe et al., 2004). Postflight stroke volume, left ventricular end diastolic volume, and estimated left ventricular mass decreased compared to preflight, while heart rate and mean blood pressure (both systolic and diastolic) were elevated and remained higher than preflight levels during the mission ( Charles et al., 1994).
In a bed rest study, the effective renal blood flow (ERBF) decreased in the first 4 h but, after 8 h, was above the normal range again (Leach et al., 1983). At the Spacelab Life Science-1 and -2, ERBF did not change significantly from preflight at any time (Leach et al., 1996). Hepatic blood flow (HBF) was measured in humans in an antiorthostatic bed rest study. The decrease in HBF during the first 24 h was not statistically significant, although it was suggested that weightlessness might induce a more pronounced effect on HBF (Putcha et al., 1988). Several studies have shown differences between lung function under different gravity conditions, especially regarding perfusion (Elliott et al., 1994; Baranov et al., 1992; Sawin et al., 1976). Pulmonary perfusion is believed to be more homogeneous in microgravity, although a residual in homogeneity is still detected (Verbandt et al., 2000; Linnarsson et al., 1996; Prisk et al., 1994). This more even distribution of capillary blood flow leads to a more efficient interface between the gas and the blood in the lungs. This may explain the improved membrane diffusion capacity observed in microgravity compared to both upright and supine preflight controls (Prisk et al., 1993). Gravity changes in regional lung ventilation parameters are also reported (Frerichs et al., 2001).
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About 40% to 70% of astronauts/cosmonauts exhibited in-flight neurovestibular effects, including immediate reflex motor responses (postural illusions, sensations of tumbling or rotation, nystagmus, dizziness, vertigo) and space motion sickness (pallor, cold, sweating, nausea, vomiting). Space motion sickness symptoms appeared early in flight and subsided or disappeared in 2 to 7 days (Nicogossian et al., 1994).
Our body generates about 5 g of reactive oxygen species (ROS) per day, mostly by leakage from the electron transport chain during oxidative phosphorylation (Halliwell, 1997). The major product of this "leakage" are the two ROS: the superoxide radical (O2-) and H2O2 (Halliwell B, 1997). Other ROS include free radicals such as nitric oxide and compounds such as ozone and HOCl. ROS can attack and damage cellular constituents such as DNA, proteins, and membrane lipids. Oxidative damage from free radicals to DNA and lipids has been implicated in the etiology of a wide variety of chronic diseases and acute pathologic states. The chronic diseases range from cancer to cardiovascular disease and neurodegenerative disease including Alzheimer and Parkinson diseases (Ames 1989; Loft and Poulsen, 1998; Morrow and Roberts, 1997; Rokach et al., 1997; Maxwell, 1995).
Russian investigators found evidence for increased lipid peroxidation in human erythrocyte membranes and reductions in some blood antioxidants after long-duration space flight (Markin and Zhuravleva, 1993; Markin et al., 1997; Markin and Zhuravleva, 1998). The potential for radiation damage during long-duration flights (particularly for flights out of low Earth orbit, where the exposure to radiation flux is greater) is currently believed to be the most serious impediment to interplanetary travel. Isoprostane excretion was decreased and 8-OH dG was essentially unchanged during a flight on Mir (Stein and Leskiw, 2000).
A subsequent post flight Studies shows both 8-oxo-7, 8 dihydro-2 deoxyguanosine (8-OH dG) and 8-iso-prostaglandin F2Î± were increased by more than two-fold after more than 3 months on Mir. The implication is that oxidative damage after an extended period in orbit is increased after landing. There is other evidence for increased oxidative damage after space flight. Spot blood analyses by Russian investigators on cosmonauts after long-duration flights showed a non-statistically significant trend for an increase in the accumulation of lipid oxidation products in the serum and erythrocyte membranes. (Markin et al., 1997)
The simplest explanation for the increased oxidative damage postflight in humans is that the increase is due to a combination of 1) the consequences of the loss of protein secondary to the in-flight reductive remodeling of skeletal muscle from the decreased work load on the antigravity muscles, 2) the in-flight protein depletion from inadequate dietary intake, and 3) the increased anabolism associated with protein repletion. With increased generation of adenosine triphosphate, leakage of ROS from the mitochondrial electron transport chain will be increased (Halliwell, 1997).
PHARMACOKINETIC CHANGES IN MICROGRAVITY
It is likely that the physiological modifications induced by weightlessness also act on the pharmacokinetics (Houin, 1990; Saivin et al., 1997; Lesne, 1998) of the drugs present in the first-aid kit of the shuttle and administered during the spaceflight (Santy and Bungo, 1991), with pharmacological or toxicological consequences. During weightlessness, oral drug absorption is modified (Cintron et al., 1987 (a)) and the space motion sickness that disrupts the gastrointestinal motility (Thornton et al., 1987); may also exacerbate the pharmacokinetic modifications. The fluid shift may modify drug distribution and elimination by acting on the blood supply to tissues and on the plasma protein concentration (Houin, 1990; Saivin et al., 1997). The bone decalcification may change renal elimination by altering kidney function while muscular atrophy may disrupt drug distribution (Houin, 1990; Saivin et al., 1997) because of the changes in muscle (De Prampero and Narici, 2003; Fitts et al., 2001). On earth, to study the pharmacokinetics of a drug, samples are collected before and at regular intervals after drug administration. The matrices of the samples are usually blood, saliva or urine. In the case of spaceflight, these studies may be performed with saliva and urine samples but not with blood samples because it is operationally difficult.
Preflight and in-flight salivary levels of acetaminophen where shown to differ, probably due to changes in gastrointestinal transit time (Cintron et al., 1987(a)). In-flight salivary concentration-time curves of scopolamine/ dextroamphetamine, given as conventional oral tablets, also were shown to be erratic and exhibited higher intra and interindividual variability compared to those of preflight data (Cintron et al., 1987(b)). Gastric emptying in microgravity can also be altered due to changes in particle size discrimination by the stomach, which is strongly dependent on the force of gravity. Also, particles are not restricted by gravity to the lower pyloric region of the stomach anymore but move throughout all regions of the stomach. This array of factors can lead to variability in drug plasma levels Intestinal transit rate in a gravity environment is highly dependent on the motility state of the gastrointestinal (GI) tract either fasted or fed, partly due to the higher viscosity of chyme in the fed state. In space, the absence of gravity may tend to increase the transit rate along the small intestine by decreasing the dimensionless ratio of gravitational forces to viscous forces. In zero gravity, therefore, these alterations in GI emptying and intestinal transit rate could lead to inefficient absorption and erratic plasma levels (Graebe et al., 2004).
Physiological changes, such as the decrease in total body water (TBW) and plasma volume (PV), and the muscle loss described in the previous section may alter the volume of distribution of drugs. This will have an impact on the plasma and tissue concentrations achieved after the administration of a drug in space and, depending on the magnitude of the change, will require that a completely new dosing scheme be designed to avoid subtherapeutic or toxic concentrations (Graebe et al., 2004). Altered tissue binding is observed as result of protein loss, muscle atrophy, and decrease in lean body mass (Nicogossian et al., 1994).
Metabolism and Excretion
The amounts of cytochrome P-450 isoforms and other enzymes decreased during space flight and simulated microgravity (Merrill et al., 1990; Lu et al., 2002; Merrill et al., 1987), which suggests that xenobiotic metabolism, may also be altered by space flight. Altered nutritional or energy requirements may have effects on urine excretion of drugs, and dehydration may result in changes in urine excretion of drugs (Graebe et al., 2004).
PHARMACODYNAMIC CHANGES IN MICROGRAVITY
Many drugs act by altering the function of specific ion channels either directly or indirectly. It was recently shown that ion channels are gravity sensitive (Goldermann and Hanke, 2001). Gravity directly influences the integral open-state probability of native ion channels (porins) incorporated into planar lipid bilayers. In microgravity, the open-state probability is decreased, while in hypergravity, it was increased (Goldermann and Hanke, 2001). The immune system is altered in microgravity. The activity of white blood cells, such as lymphocytes, macrophages, and natural killers, was affected during space flights. Consequently, drugs that have these cells as their pharmacological targets, such as interferons, colony-stimulating factor (CSF), and other cytokines, can have their effects altered. In one study, Sonnenfeld et al., (1990) observed a depression in the capacity of femoral bone marrow cells to respond to CSF, which supports this theory, although more studies are necessary before any conclusions are made. The cardiovascular system is largely affected by the exposure to microgravity, and this may lead to modifications on the pharmacological effect of drugs such as antihypertensives and diuretics.
MICROBIAL VIRULENCE CHANGES IN MICROGRAVITY
Studies on in vitro bacterial growth in space typically indicate outcomes beneficial for the microbes, such as reduced lag-phase duration and increased final cell population density relative to normal-gravity controls (Klaus, 2002; Leys et al., 2004; Nickerson et al., 2004). Because flight opportunities are infrequent, various ground-based devices designed to simulate certain aspects of microgravity are frequently used as analogs (Nickerson et al. 2004; Klaus, 2001; Nickerson et al., 2003). Many of the early studies indicated that antibiotics were typically less effective against suspension cultures in the space environment but these traits appeared to be transient and not retained in post-flight testing (Juergensmeyer et al., 1999 ; Kacena and Todd, P,1999 ; Lapchine et al., 1986 ; Lapchine et al., 1987 ; Lapchine et al.,1988 ; Moatti et al., 1986 ; Tixador et al., 1985 a ; Tixador et al.,1985 b ; Tixador et al., 1994; Klaus, PhD thesis, University of Colorado, 1994).
Although the experiments have spanned several decades, the underlying causes of reduced drug efficacy in space have not yet been identified and remain of current interest. To further complicate matters, recent reports of decreased in-flight drug potency and shelf-life are now being investigated (Du et al., 2002). Various physiological, pharmacological and pharmacodynamic changes, observed in space flight and analogs, can also affect in vivo drug efficacy (Graebe et al., 2004). Factors related to isolated, confined environments have been shown to contribute to increased resistance: ground-based isolation in an airtight environment for 96 to 175 days was found to increase the resistance spectrum and number of antibiotic- resistant organisms isolated from humans (Polikarpov and Bragina 1989). Changes in the intestinal flora composition are thought to be responsible for antibiotic resistance. A study of the microflora of cosmonauts from five space flights indicated that the crew exchanged intestinal flora in the closed spacecraft environment intestinal flora accumulates antibiotic resistance determinants from the indigenous microflora of individuals in the sealed environment during the exchange. The rate of antibiotic resistance determinant accumulation is proportional to the influx rate of immigrant strains containing new resistance determinants, and resistant strains can become dominant. It was concluded that the use of antibiotics without evaluating the sensitivity of the microflora could become a risk factor for infection (Ilyin, 1990). Coliform bacteria isolated from cosmonauts also became resistant to tetracycline, owing to microbial and plasmid exchange between the visiting and prime crews of the Salyut 7 spacecraft: no tetracycline resistant coliform bacteria were present in the prime crew before flight. Similar reports from Apollo and shuttle missions provide further evidence of in-flight microflora exchange leading to an increased presence of pathogens for crewmembers compared with preflight baselines (Pierson et al., 1993; Taylor 1974). The pathogen presence and antibiotic effectiveness during spaceflight is summarized in Table: 1
Table-1 : Effect of antibiotic in microgravity condition
Increased pathogen presence for crewmembers post-flight
Increased resistance spectrum in vivoafter space flight
Increased resistance spectrum after in vivo growth in ICE
Increased MIC in space (suspension cultures)
Decreased effectiveness of antibiotics resisted by an antibiotic-specific mechanism (suspension cultures)
Unchanged or decreased MICs in space (agar cultures)
Increased growth and/or final populations in subinhibitory antibiotic concentrations in space (suspension cultures)
Decreased drug shelf-life in space
(Pierson et al.,1993 ; Taylor, 1974)
(Ilyin,1989 ; Ilyin, 1990)
(Ilyin,1990; Polikarpov and Bragina, 1989)
(Lapchine et al.,1986 ; Lapchine, et al., 1987 ; Lapchine et al., 1988 ; Moatti et al.,1986; Tixador et al., 1985)
(D. M. Klaus, PhD thesis, University of Colorado, 1994).
(Juergensmeyer et al., 1999 ; Kacena and Todd, 1999)
(Tixador et al., 1994)
(Du et al., 2002)
Several pharmaceutical products are being employed in space to treat a variety of disorders. Hence, knowledge of the physiological, pharmacokinetic, and Pharmacodynamic aspects under microgravity would be useful in making appropriate dosing recommendations. Similarly advances in traditional laboratory research techniques can be applied to better understand how microbes adapt to the space environment, the reciprocity of studying responses to space flight to gain novel insight into the fundamental processes of drug resistance acquisition and virulence factor development might not be so intuitive. Innovations in treating clinically relevant infections will have far reaching implications across all walks of society, including those of future spacefarers.