(Presented at The 10th International Magnesium Symposium, Cairns Australia, September 7-11,2003. Magnesium Research (in press)

THE CASE FOR A SUBCUTANEOUS MAGNESIUM PRODUCT
        AND DELIVERY DEVICE FOR SPACE MISSION

Interplanetary travel1 and even a brief lunar mission (Apollo 15) 2 have the potential of injuring the normal cardiovascular system even without the adverse effects of radiation-induced oxidative stress.  Even in the absence of atherosclerosis, space flight (SF) may be complicated by arrhythmias, myocardial. infarction and despite  invariable  dehydration,  congestive  heart failure.3  In vitro, 4 animal 1 and human 5 studies indicate that the endothelium is vulnerable to SF-related dysfunction/injuries with magnesium (Mg) ion deficits playing a central role.1,6

There  is  loss  of  Mg  storage  sites  in  skeletal  muscle  and  bone complicating hypokinesia, invariable malabsorption secondary to microgravity, and several vicious cycles involving or triggered by a Mg ion deficit. As a result of these mechanisms, there is oxidative stress1,  elevations of inflammatory cytokines 7 and insulin resistance conducive to self-sustaining vascular inflammation.3 (Figure 1)

SF-related thrombocytopenia 8 is probably responsible for the reductions of vascular endothelial  growth factor  (VEGF)  since platelets are the primary source of VEGF.9  The etiology of the thrombocytopenia has not been established but could be at least partially precipitated by reductions in nitric oxide (NO)10 demonstrated by SF-related reductions of cyclic GMP.5  In addition it is tempting to speculate that prevention or correction of a SF-related Mg deficit, 8 may  offset   removal   of  platelets   into a sequestered  site in the reticuloendothelial system complicating platelet-leukocyte adhesions. 11

Both  Mg  and VEGF  regulate  endothelial  function  and  repair  and  are required  for  angiogenesis.1,6,12,13    In  the  presence  of  SF-related  insulin resistance14 there would be in addition diminished VEGF expression.13  (Figure 2)

In  addition  to  the  previously mentioned  SF-related  vicious  cycles, another is triggered by elevations of inflammatory cytokines (interleukin 6)7 and elevations  of tumor necrosis  factor-a  (TNF-a)15 complicating a Mg  ion deficit with in turn further loss of the skeletal muscle reservoir.16  TNF-a elevations have also been shown complicating sleep deprivation,17 with the average duration of sleep on SF reduced to 6 hours.14 
(Figure 3)

The calcium (CA) blocker effect of Mg may serve an important function since it has been postulated that with elevations of carbon dioxide, demonstrated on MIR there may be an intracellular shift of CA.14

The endothelium is vulnerable to injuries not only because of SF-related vicious cycles as previously emphasized, but also prior and during a space walk because  of  the  requirement  of  100%  oxygen  to  reduce  the  potential  for decompression sickness;18 the latter may also cause endothelial injuries and may trigger further reductions in platelets19 with in turn further reductions in VEGF.9   The antioxidant effect of Mg14 would be helpful in reducing these potential complications of hyperoxia.

Because of microgravity-related malabsorption14 and potential hepatic20 and renal21 dysfunction, which may be at least partially triggered by diffuse 2 endothelial dysfunction, pharmaceuticals other than for emergencies and symptomatic relief appear contraindicated.

But  a  strong  case  can  be  made  for  a  subcutaneous  Mg  product; intramuscular injections are too painful.   In addition, a chloride (CL) would be required to correct a potential aldosterone-induced CL loss complicating microgravity8 and to prevent a hypokalemic alkalosis.14

Classen's  experience with subcutaneous Mg-1-aspartate-hydrochloride  in rats,  indicates that  to maintain a  therapeutic  level  injections might  be required as frequently as every 4 to 6 hours.   (Personal communication H. G. Classen)

There has been very limited experience with subcutaneous Mg in humans as well.  Recently, a case was reported for which a subcutaneous portable pump was utilized in a 28-year-old male with both Mg malabsorption as well as decreased Mg renal retention.   The patient's symptoms were relieved in this case with “continuous Mg sulfate infusion.” 22

In order to provide some protection to the endothelium from oxidative stress and decompression sickness resulting from a space walk with a duration up to 8 hours,18 subcutaneous injections resulting in only perhaps a 4 to 6 hour therapeutic level (personal communication, H. G. Classen) can not be utilized. Furthermore, because the port can become displaced posteriorly as a result of vigorous movements during a space walk for example, a subcutaneous pump22 would not be reliable.

A device developed by Santini et al.23 opens the door for other devices; this is a subcutaneous computer chip, the size of a pocket watch, containing thousands of microreservoirs and which can be inserted subcutaneously and operated remotely with electrochemical dissolution of thin anode membranes.  It appears to be an attractive alternative, but this device can not be replenished once it leaves the manufacturer.   Such a device must be suitable for SF requirements extending for durations of 2 years or longer, eventually for perhaps interplanetary travel.1

Finally  since  there  is  potential  impairment  in  renal  function21 complicating potential diffuse endothelial dysfunction, frequent monitoring of Mg levels are required with high reliability.   Measuring intracellular Mg levels as developed by Silver14 would serve this purpose well.  Furthermore, the equipment could be reduced in size, and is suitable for SF, and tests can be repeated as often as necessary; it requires relatively little technical training. (personal communication B. B. Silver)

Conclusions: In order to prevent cardiovascular complications with potential diffuse endothelial injuries and because of pharmaceutical constraints, as well as malabsorption, it is vitally important to develop a subcutaneous Mg product, preferably a chloride, and a reliable replenishable delivery device.  Because of potential renal dysfunction, close monitoring of Mg administration is imperative.

William J. Rowe, M.D.

Former Assistant Clinical Professor of Medicine
Medical College of Ohio at Toledo

REFERENCES

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