Journal of Japanese Society for Magnesium Research 1993,
12, 2:113-135
Present and future of magnesium research
Durlach, J.*
Président de la SDRM
Hôpital St. Vincent de Paul, Paris
*Correspondence: 64 Rue de Longchamp, F-92200 NEUILLY Seine,
FRANCE
A critical appraisal of the knowledge of Mg allows
to review the present trends and to suggest further research. In
basic sciences, progress concerns geochemistry, agriculture,
phytophysiology, analytical techniques, biochemistry and cellular
biology. Further advances should namely apply to the
identification of new lines of plants with better Mg with all the
components of membranous pathways and evaluate the importance of
supramolecular chemistry in Mg biology. In physiology, 2
important notions must be remembered: discrimination between the
consequences of acute and chronic Mg deficiency and distinction
between 2 types of Mg deficit:Mg deficiency and Mg depletion.
Further research might for example concern the possible links
between 2 types of targets in Mg deficiency separately studied
until now and bear upon diverse genetic or acquired models of Mg
depletion. Basic differences between pharmacological and
physiological Mg actions lead to discriminating between the 2
types of Mg load constitutes the best tool for diagnosis of Mg
deficiency. Systemic use of the pharmacological properties of Mg
may constitute simple and unexpensive treatment, in cardiology
and obstetrics particularly but it may induce Mg toxicity.
MgSO4 routinely used for Mg parenteral therapy appears
among the soluble Mg salts to possess the least advantageous
properties. 2 main directions for further research seem of
interest: in vitro and in vivo screening of the
pharmacological properties of diverse Mg salts and validation of
the best indications of parenteral Mg by comparing with the
reference treatment in wide ranging clinical trials. The clinical
and paraclinical pattern of Mg deficit is now well established.
Future clinical approach of Mg deficit might require a thorough
medical examination. It may affect a high or a limited number of
targets which should be all systematically investigated. For
example: stigma of neuromuscular hyperexcitability should be
integrated into the protocol of Mg supplementation concerning
cardiovascular, allergic, pregnant, aging or sport populations.
In therapeutics, the dangers of using the pharmacological
properties of induced iatrogenic overload contrast with the
atoxicity of a physiological oral Mg supplement which by simple
normalizing the Mg intake palliates Mg deficiencies. The main
direction for future research concerns large epidemiological Mg
intervention trial carried out on various populations whatever
the age but mainly on population with higher risk of Mg
deficiency: infants, children, aged persons, pregnant women in
developing countries and low socioeconomic classes particularly.
A lot of sofar unsolved problems remains and large avenues are
open for further research.
INTRODUCTION
The history of Magnesium can be broken down into several
successive chapters. The early historical period from the 18th
century to the first quarter of our century mainly concerned the
development of chemical and pharmacological knowledge. The modern
period began in 1926 when the essential character of magnesium
was acknowledged. The early part of the modern period, up to the
60's, established the basis of our present knowledge at the
physiological, epidemiological, clinical and therapeutical
levels1.
Since then the scope of magnesium research has been widening
while getting at the same time more specialized. National and
international meetings on magnesium2-5, regular
publications of original papers in the national and international
reviews6 on magnesium research have brought up to date
our present magnesium background.
But all the scientific fields always remain open and there
still are many problems to be solved.
The aim of this lecture is to give an overview of the current
trends of magnesium research and to suggest further studies.
1. Some data concerning basic sciences.
2. Physiological data with particular stress on the
differences between the consequences of acute and chronic
magnesium deficiency. It is also important to discriminate
between the two types of magnesium deficit: magnesium deficiency
and magnesium depletion.
3. Pharmacological data showing how they basically differ from
the physiological data. This accounts for the different
significance of oral and parenteral magnesium load tests when
investigating magnesium status.
4. Clinical data concerning clinical studies as such and also
epidemiological trials. The clinical pattern may bear upon either
a high of a limited number of targets. But all should be
systematically investigated.
5. Therapeutical data laying stress on the different
indications concerning both uses of physiological oral magnesium
supplements and of pharmacological magnesium load. The former is
only meant to palliate the insufficient intake observed in
magnesium deficiency and is therefore atoxic since physiological.
The latter is used to obtain a pharmacological effect
irrespective of the magnesium status and may induce magnesium
toxicity. It must be monitored in acute forms and carefully
researched in chronic administration.
I. BASIC SCIENCES
I.1. PRESENT TRENDS
Several recent books concerning the role of magnesium in
various fields of basic sciences such as geochemistry,
agricultural practice and phytophysiology7,8 testify
to the constantly renewed interest taken in this ion. Low
magnesium contents in soils affect plant growth and health.
Magnesium fertilization may favourably influence the yield and
mineral contents of plants and contributes to healthy animal and
human nutrition, but balanced K, Ca, and Mg dosages should be
aimed at. Magnesium bioavailability varies according species and
strains. During winter sleep in trees and hibernant animals
increases in magnesium concentration are observed in plant juice
and in animal blood serum4. Al-induced magnesium
depletion is one of the causes for forest decline. It is linked
with soil acidification which may be enhanced by human activities
and by acidic rain caused by industrial
pollutions3,7,8. Among the various analytical
techniques for measuring magnesium in tissues10, two
should be remembered: the ionized selective electrode (ISE)
technique and that of particle induced X-ray emission (PIXE). The
main biologically active magnesium form is free Mg2+.
Mg2+ ISE using new chemical sensors seems to allow
reliable assessments of ionized magnesium11, but
silicone may constitute a cause for preanalytical error in these
ionized magnesium measurements12. PIXE is a well known
fluorescence technique for element analysis of biological
material, particularly used for detection of heavy metals. But
now this non-destructive method with multielement capacity may be
also used for detection of light elements and for magnesium
particularly. More than ten elements are mapped in a single run.
PIXE appears as a powerful complementary technique to electron
probe analysis studying simultaneously magnesium and various
element distribution13.
The relevance of magnesium in cellular biology has been
recently brought forth14. Present knowledge of
magnesium chemistry mainly concerns complex physical and
biological magnesium binding, competition between magnesium and
cations (i.e. Ca2+, H+) or amines,
structural factors such as differences between ionic radius
according hydratation and its cellular and subcellular
stabilizing effects, spatial distribution and mechanisms of its
role in photosynthesis and in enzyme functions15-17.
The effect of magnesium on membrane constitutes a basic mechanism
of its biological effects. In vivo, magnesium deficiency
increases membrane fluidity and permeability18.
Numerous in vitro studies on tight as well as on leaky
membranes have analyzed the mechanisms of the rigidiftying
effects of magnesium and its actions on transmembrane
transports15,19-22. It seems that ionic permeability
might depend on the screening-binding effects of magnesium on
membrane. They appear to be related to magnesium hydratation and
to the nature of the present anions17,23. Magnesium
may act in various biological systems through its effects on
water structure. [Mg (H2O)6] 2+ may break important
hydrogen bonds in the clusters of water (H2O)n,
forming new hydrogen bonds in the presence of hexa-hydrated
magnesium cations24.
I.2. FURTHER RESEARCH
This short overview stresses the relevance of magnesium in
basic sciences. Further advances in agronomy should apply to the
identification of new lines of plants with better magnesium
uptake from soils while insuring good yield and health for the
plant.
At the interfaces between biochemistry and membranology,
future research should deal with the interactions of magnesium
with all the components of enzymatic, non enzymatic, cellular and
paracellular membranous pathways not only of ions but also of
oses, aminoacids, polyamines...
Moreover it seems, after the seminar papers by T.
THEOPHANIDES24 and the discovery of the major
importance of supramolecular chemistry in
biology25,26, that magnesium should also be studied in
the light of this new branch of knowledge.
II. PHYSIOLOGICAL DATA
II. 1. PRESENT TRENDS
Two important notions should be remembered.
1. Discrimination between the consequences of acute and
chronic magnesium deficiency
2. Distinction between two types of magnesium deficit:
magnesium deficiency and magnesium depletion.
II. 1.1. - Acute and chronic consequences of magnesium
deficiency
The physiological properties of magnesium are now well known,
They cover development, neuromuscular, cardiovascular, renal,
bone and endocrine apparatus, reproduction, coagulation, humoral
balance, immune and other defence processes. They namely exhibit
a variety of antistress functions: thermoregulation and
anti-allergic, anti-toxic, anti-hypoxic, anti-inflammatory
systems, through anti-oxydant properties particularly. These
physiological properties are relevant with the multiple effects
observed in vivo during acute magnesium
deficiency and with their specific reversibility through oral
magnesium supplementation with physiological doses15.
The experimental and clinical forms of chronic marginal
magnesium deficiency are getting better identified. But they
differ from overt signs of acute deficiency127. For
example, acute experimental magnesium deficiency in the rat may
induce decreases in skeletal muscle and myocardium magnesium and
in serum alkaline phosphatase. It causes non-significant
modifications of total cholesterol, increase of insulin
secretion, arterial hypotension with hyperreceptivity of
adrenergic agonists and infertility.
Reversely, this is not observed in chronic marginal
experimental magnesium deficiency: magnesium concentration is not
significantly modified in skeletal muscle and myocardium
28 nor is serum alkaline phosphatase29. But
total cholesterol increases significantly30 and
insulin secretion decreases31. As a rule blood
pressure is not modified 32,33 unless late nervous,
renal or arterial secondary alterations, uncontrolled by
magnesium supplementation bring an increase34.
Adrenergic receptivity is decreased, like in aging35.
Pregnancy is possible, but the offspring is less with a higher
mortality rate27,36,37.
It should not be permitted today to extrapolate from
physiological data observed in overt acute magnesium deficiency
to physiological consequences of chronic magnesium deficiency
which constitute the main indication of epidemiological trials as
a risk factor38. For example, this background
invalidates the use of magnesium skeletal concentration as a
relevant marker of chronic marginal deficiency28. It
explains why measure of total cholesterol should be included in
the follow up of the effects of magnesium supplementation in
dyslipidemias30,39 and allows to consider the part
played by chronic magnesium deficiency in the physiopathology of
aging40-41.
II . 1 . 2. Discrimination between the two types of magnesium
deficit: magnesium deficiency and magnesium depletion
In the case of magnesium deficiency, the disorder
corresponds to an insufficient magnesium intake: it merely
requires oral physiological magnesium supplementation. In the
case of magnesium depletion the disorder which induces
magnesium deficit is related to a dysregulation of the control
mechanisms of magnesium metabolism, either failure of the
mechanisms which insure magnesium homeostasis or intervention of
endogenous or iatrogenic perturbing factors of the magnesium
status. Magnesium depletion requires more or less
specific correction of its causal dysregulation. Epidemiological
trial through oral physiological magnesium supplementation only
concerns chronic marginal magnesium
deficiency1,38,42,43.
The usual experimental method where magnesium deficit is
induced by a low level of magnesium in the diet typically
constitutes a model of primary magnesium deficiency, with
specific reversibility of the symptoms by simple physiological
oral magnesium supplementation1,42. Reversely the line
of MGL mice appears to constitute an animal model of genetically
primary magnesium depletion, which is not controlled by
physiological oral magnesium intake44.
In front of each type of magnesium deficit, whether primary or
secondary, it is imperative to determine the respective parts of
magnesium deficiency and of magnesium depletion. For example,
primary deficit in sports medicine seems to be more often related
to depletion than to deficiency 45 while in aging the
two mechanisms are usually associated 41. In secondary
magnesium deficits, the part of magnesium deficiency may prevail
over that of magnesium depletion namely in the magnesium deficit
due to chronic alcoholism46,47 whereas it is usually
the reverse in the magnesium deficit due to diabetes
mellitus48. This last notion perfectly agrees with the
absence of a relationship between diabetes mellitus mortality
rates and drinking water magnesium concentrations
49.
II. 2. FURTHER RESEARCH
Some recent studies have drawn avenues for further
physiological research. For example two apparently independent
targets of magnesium deficiency could be envisaged. The seminar
paper by W.B. WEGLICKI50 showed that nervous and
inflammatory consequences of magnesium deficiency are joined up.
The release of neuropeptide substance P may be the earliest
pathophysiological event leading to stimulation of the
inflammatory cytokines: interleukin 1, interleukin 6 and Tumor
Necrosis Factor which may then stimulate the free radical
mechanism of the pro-inflammatory state caused by magnesium
deficiency. Further research on acute or chronic magnesium
deficiency might concern the possible links between two types of
well documented consequences of magnesium deficiency, but which
until now have been separately studied: for example alterations
of mineral status, and of iron metabolism
particularly51,52, and stigma of oxydative
damage40,50. These latter defects should be studied
using all the parameters of anti-oxydant systems: sulfur
compounds, Se, vitamins, enzymes ...40,41,
Other research might bear upon diverse genetic or acquired
models of various types of magnesium depletion in order to study
their physiopathological mechanisms and aim at their control.
This would permit to complete the too scarce present studies both
on genetic44,53 and acquired models such as magnesium
depletion due to interaction between aluminium load and low
magnesium intake54-57 or interaction between diverse
types of stress and magnesium
deficiency41,104,105.
III. PHARMACOLOGICAL DATA
III.1. PRESENT TRENDS
Pharmacological effects are observed irrespective of the
magnesium status. They are established either in vitro, in
situ, or in vivo when parenteral or large oral
intake is high enough to exceed any homeostatic capacity which
may prevent magnesium overload58,59. These basic
differences between pharmacological and physiological magnesium
actions lead to discriminate between the two types of magnesium
load tests. Clinical efficiency of parenteral magnesium
administration should not be used as a diagnostic tool attesting
to magnesium deficiency. Reversely physiological oral doses of
magnesium are totally devoid of the pharmacodynamic effects of
parenteral magnesium and without clinical effects when magnesium
status is normal. Correction of symptoms by this oral magnesium
load constitutes the best proof that they were due to magnesium
deficiency1,38,42,60.
Among the local indications of the pharmacological properties
of magnesium the use of its cytoprotective properties in
solutions used in cardiac surgery is still subject to discussion
58,59,61.
Systemic use of the pharmacological properties of magnesium
mainly concern parenteral magnesium therapy (either bolus or
infusion) most often in acute indications. High oral magnesium
supplementation is preferred in chronic indications. The main
pharmacological properties of parenteral magnesium are
antispasmodic, curariform and ganglioplegic, antiarrhythmic and
hypotensive, antithrombotic and also cytoprotective. These last
ones are linked to its antihypoxic and cellular and subcellular
stabilizing effects58,59. It mainly applies to the
nervous, cardiovascular and obstetrical
fields58,59,62. Parenteral magnesium therapy is
generally used in purely pharmacodynamic indications, rarely for
specific treatment of severe magnesium deficit, sometimes in
mixed indications combining useful pharmacodynamic effects and a
treatment for magnesium deficit that is linked to the
physiopathology of the syndrome58,59: for example
acute complications of chronic alcoholism or antithrombotic
treatments. Moreover magnesium may reduce an increased secretion
of endothelin through pharmacological and/or physiological
mechanisms63,64. Several experimental and clinical
studies justify the use of intravenous magnesium as simple
unexpensive and safe treatment particularly in acute ischaemic
heart diseases, in cardiac dysrhythmias
39,58,59,62,65-58, in pre-eclampsia, eclampsia and
premature delivery58,59,62,63,69. Curiously the most
widely magnesium salt used in parenteral magnesium therapy is
magnesium sulfate. This salt has however among the soluble salts
of magnesium the least advantageous pharmacological
properties23,58,59,71, For example comparing the
effects on the ionic transfer components through the isolated
human amniotic membrane, we have observed that MgCl2
interacts with all the exchangers, while the effect of
MgSO4 is limited to paracellular components without
interaction with cellular components. Whatever the concentration,
MgCl2 increases the ionic flux ratio between mother
and foetus while MgSO4 decreases it until it reaches a
value close to 1. Regarding the mechanisms of deleterious effects
on calcium homeostasis observed in pregnant women receiving
long-term magnesium therapy for preterm labor, it seems necessary
to discuss the respective part not only of the magnesium cation
but also of the SO4 2-anion72.
It is obvious that correct use of parenteral magnesium therapy
must prevent magnesium overload accidents with careful monitoring
of pulse, arterial pressure, deep tendon reflexes, hourly
diuresis, electrocardiogram and respirator rhythm
recordings58,59,62. Great caution is necessary when
prescribing chronic administration of magnesium in
pharmacological doses for treatment of hypertension73
or chronic stable ventricular ectopy62,74. Long term
magnesium toxicity might be observed75.
III. 2. FURTHER RESEARCH
Two main directions appear to be of interest
1. In vitro and in vivo screening of the
pharmacological properties of diverse magnesium salts
2. validation of the best indications of parenteral magnesium
by comparing this simple and unexpensive treatment with the
reference treatment in wide ranging clinical trials.
Lastly, since the mechanisms of botulinism toxicity and those
of magnesium overload are very similar, it is tempting to suggest
to test the efficiency of local magnesium injections in the
indications of botulin toxin therapy since they appear less
expensive and less toxic76,77.
IV. CLINICAL DATA
IV. 1. PRESENT TRENDS
Open and controlled trials have established the clinical and
paraclinical pattern of primary chronic magnesium deficiency
(CMD)38,42,60,78-82. Whatever the age nervous
consequences should be first studied: clinical and paraclinical
symptoms of latent tetany (hyperventilation syndrome, chronic
fatigue syndrome, spasmophilia, cryptotetany) with or more often
without "idiopathic" mitral valve prolapse (idiopathic Barlow's
disease, Da Costa syndrome, soldier's heart, effeort syndrome,
neurocirculatory asthenia) with or without pseudoallergy (through
peripheral hyperreceptivity) more often than allergy (Type I
mainly). The non-specific pattern of this symptomatology brings
the patient to consulting a wide range of specialists as well as
general practitioners. It includes non-specific central,
peripheral and autonomic manifestations.
The neurotic, or rather, "central" symptoms consist of
anxiety, hyperemotionality, fatigue, headache (and sometimes
migraine), insomnia light-headedness, dizziness, nervous fits,
lipothymiae, sensation of a "lump in the throat", of "nulchalgia"
and "blocked breathing".
The peripheral signs are acroparaesthesiae, cramps, muscle
fasciculations and myalgiae,
The functional disorders include chest pain, sine materia
dyspnoea, blocked respiration, precordialgia, palpitations,
extrasystolae, dysrhythmias, Raynaud's syndrome, trends to
orthostatic hypotention or conversely to borderline hypertension.
In fact, the dysautonomic disturbances involve both the
sympathetic and the parasympathetic systems.
When the chest pain mimics coronary heart disease, its relief
with propranolol and worsening by nitrates may help to
distinguish between a benign disorder and a trouble from coronary
origin.
The evolution may be studied with various acute paroxymal
manifestations which can also sometimes be seen as initial signs
of the illness. The major crises of acute tetany or of grand mal,
even reduced to a simple loss of consciousness, remain relatively
rare. It is more often a question of nervous crises: neurotic,
from the "attack of nerves" to the "hysterical crises", or
autonomic: lipothymia, reactive hypoglycemia, pseudo-asthmatic
crisis, vagovagal syncope or, on the contrary, paroxysmal
tachycardia. Sometimes, centripetal tingling sensations and
stiffness of the extremities confer on these nervous crisis a
tetanoid character. But, essentially, they all have in common the
fact that they occur in a context of fits of anxiety, even
sometimes with the impression of imminent death (panic attack),
which cause hyperventilation gaseous alkalosis and self
perpetuation of the crises. Physical examination must
systematically research the signs of neuromuscular
hyperexcitability as well the Chvostek's sign as precordial signs
of mitral dyskinesia inducing mitral valve prolapse.
A genuine Chvostek's sign must be systematically sought. With
a small (children's) reflex hammer the examiner percusses the
soft parts of the cheek at the centre of a line running from the
ear lobe to the labial commissure, avoiding the lightening
contraction of a "false Chvostek's sign" by tapping the bone of
the zygomatic apophysis. It is important to consider the quality,
and not the intensity, of this clinical criterion of
neuromuscular hyperexcitability. It is only its presence or its
absence which is significant, respectively quoted 1 or 0.
The examination of the precordial area will be carefully
conducted in order to search either for a non-ejection systolic
click, or for a mid-to-end systolic or pansystolic murmur, or
both, particularly in orthostatism in complete expiration and in
the left lateral decubitus position.
Two routine tracings should always be made: a
neurophysiological examination (electromyogram (EMG)) and a
cardiological examination (echocardiogram (ECG)).
In EMG testing for latent tetany, a Bronck's needle is
inserted into the first dorsal interosseous muscle of the left
hand. The three classical facilitation tests are used: tourniquet
induced ischaemia lasting 10 min, post-ischaemia lasting 10 min
after removal of tourniquet and lastly hyperventilation lasting 5
min. If the EMG shows one (or several) train (s) of autorhythmic
activities, "beating" for more than 2 min of one of the three
tetanic activities (uniplets, multiplets or complex tonicoclonic
tracings) a positive response is defined. As determined for the
clinical criterion of tetanic hyperexcitability, this
neurophysiological criterion is only considered as a two class
variable. Either its presence or its absence is significant,
respectively quoted 1 or 0.
The "excitability index" (EI) is defined as the sum of the two
criteria of tetany. It allows different classes among tetanies to
be distinguish: one with simultaneous clinical and
neurophysiological criteria: EI=2, the others with only one
criterion of their tetanic state: EI=l with two sub-groups,
either clinical (though positivity of the Chvostek's sign alone),
or electomyographic (through positivity of EMG alone).
The ECG is the best tool for detecting mitral valve prolapse
(MVP). With time-motion (TM) mode, three tracings are classical:
a "cuplike" tracing of mesotelesystolic MVP (of more than 2 mm),
a "hammocking" tracing of holosystole MVP (of more than 3 mm), an
isolated systolic anterior motion (SAM) observed without
obstruction nor any septal thickening sign and in the absence of
false systolic anterior motion. Two-dimensional echocardiography
appears to be more accurate than TM echocardiography. It
eliminates a number of artefacts and, particularly, in the
section of parasternal longitudinal cut and the apical cut of the
four heart chambers. The criterion for mitral valve prolapse is
the billowing of one or both leaflets below the level of the
mitral ring. It is very important to assess the leaflet thickness
as well as its whole morphology and to appreciate the ventricular
kinetic by calculating:
Pulsed doppler echocardiography allows the detection of
associated mitral regurgitation.
Four routine ionic investigations should always be made:
plasma Mg (pMg), erythrocyte Mg (eMg), calcaemia and daily
calciuria, which can be completed by the research of proteinuria
and of urinary infection.
These must first demonstrate normocalcaemia and the absence of
hypercalciuria susceptible to induce a secondary magnesium
deficit, Next, the evaluation of pMg and eMg with reliable
methods, such as atomic absorption spectrophotometry, allows the
diagnosis of primary magnesium deficit through hypomagnesaemia in
one-third of the cases of latent tetany (LT) due to CMD, with or
without MVP. Normal levels do not rule out the diagnosis of CMD.
The histograms of LT patients (with or without MVP) and of
controls overlap. If the tetanic group reveals gaussian-type
magnesaemia curves with significant lower means (P<0,001) both
for pMg and eMg, their constitutive elements can be individually
hypomagnesaemic (one-third of the cases), normomagnesaemic
(almost two-thirds of the cases) and even, although seldom,
hypermagnesaemic. Nevertheless one must emphasize the remarkable
constancy of magnesaemia which lends importance even to small
variations of magnesaemia.
Lymphocyte Mg/cell appears as the most interesting static
intracellular magnesium item83.
In particular clinical forms, record should be completed with
corresponding clinical and paraclinical explorations. Rhinoscopy
in rhinitis, skin tests with not only allergens but also with
histamine, acetylcholine, and plasma IgE in allergic or
pseudo-allergic forms, electroencephalogram and head scan in
convulsive forms, psychometric investigations in psychic forms,
electronystagmogram and optokinetic test in dizziness,
electropolugraphic study of afternoon sleep indyssomnia, lipid
profile in atheromatous dyslipidemias39.
Several risk populations require special attention: pregnant
women because of the consequences of deficiency on mother,
foetus, neonate and infant37 and probably during the
whole life84, geriatric37 and
sport45 populations where magnesium deficiency is most
often associated with magnesium depletion.
In secondary magnesium deficit, the very symptomatology of
this ionic disturbance is more or less hidden behind the
symptomatology of the causal disease. Effect of oral
physiological magnesium supplementation is the best tool for
establishing the diagnosis of magnesium deficiency. In magnesium
depletion the response to this oral loading remains negative, but
the control of the magnesium metabolism dysregulating factor (s)
is efficient when effective.
Secondary magnesium deficits require their own specific
etiologic treatments.
IV. 2. FURTHER RESEARCH
The clinical approach to each clinical forms of magnesium
deficit might require a thorough medical examination with
particular attention to its established clinical and paraclinical
pattern. Any nutritional deficiency may affect either a high or a
limited number of targets which should be all
systematically investigated. For example stigma of neuromuscular
hyperexcitability should be integrated into the protocol of
magnesium supplementation concerning cardiovascular, allergic,
pregnant, aging or sport populations.
Today awareness of this basic clinical rule is too often
overlooked. But it constitutes one of the prerequisites for
establishing precise indication of magnesium
therapy85.
V. THERAPEUTICAL DATA
V. I. PRESENT TRENDS
Magnesium has for a long time had only a modest place in
therapeutics being used only for its cathartic or neutralizing
properties in oral preparations of for its sedative and
antispasmodic properties parenterally. Today continually
increased knowledge of the clinical forms of magnesium deficit in
human beings is allowing us in what circumstances and in what
manner we can remedy chronic primary magnesium deficiency using
physiological doses of magnesium. That is the main form of
magnesium therapy.
These palliative oral doses of magnesium meant to balance
chronic magnesium deficiency are obviously devoid of any toxicity
since their purpose is to restore to normal the insufficiency of
the magnesium intake.
Conversely parenteral magnesium or high oral doses of
magnesium possess all the pharmacodynamic properties of magnesium
overload and are capable to induce toxicity. They must therefore
always be administered with caution in more or less specific
indications.
The dangers of using the pharmacological properties of induced
iatrogenic magnesium overload contrast with the atoxicity of a
supplementation with physiological oral doses of magnesium which
by simple normalizing the magnesium intake palliates magnesium
deficiencies58,59.
V. 1.1. Physiological oral magnesium therapy
The first step of physiological oral supplementation should be
achieved through dietetic means. But usually magnesium and energy
content of food correlate58,59,68: magnesium rich
products are also rich in energy. Except for some vegetarian
diets41,58,59 supplementation should be achieved using
a high magnesium density nutrient with the best possible
availability 58,59,85-90. This requirement is met by
magnesium in water, which must have a probable link with the
importance of its hexahydrated form in biological
systems23,24,58,59,86,91,92. It is possible in natural
form, rarely in tap water, sometimes in bottled mineral
water.
Most often, the treatment is medicinal using addition of
soluble magnesium salts to ordinary
water36,43,58,60,86,93. If it is only a question to,
correct in vivo an experimental magnesium deficiency all
highly soluble magnesium salts have a comparable bioavailability
either mineral salts i.e. chloride or organic salts
i.e. acetate, citrate, methionate, aspartate, lactate,
glutamate, and pyrrolidone-carboxylate. Evidently the specific
properties of their anions may have their own importance: for
example a supply of chloride is interesting in case of coexistent
hypochloremic alkalosis58-60 or the anions may act
differently at the membranous level71,72.
Tolerance of these physiological doses is excellent.
Acceleration of intestinal transport is observed only in
susceptible subjects: for example patients with colitis
42,58,59.
The contraindications are obvious58,59. Two are
exceptional: myasthenia and hypermagnesemic periodic paralysis.
There is in practice only one contraindication: overt renal
insufficiency (creatinine clearance <15 ml).
Urinary infection with elevated urinary phosphates is a
transient contraindication with the risk of precipitating
ammonium-magnesium phosphates. Urinary residues must be cleared
up prior to any magnesium therapy58,59. Magnesium may
impair the properties of several drugs: for example 4-quinolones,
tetracyclines, several aminoglycosides, vancomycine. The use of
these antibiotics constitutes another transient contraindication
58,59,94.
Lastly, within the limits of our present knowledge, we can
eventually consider as a relative contraindication of magnesium
therapy, magnesium solid tumors in a state of development since
their growth may be stimulated by magnesium 1,26. But
palliative control of poorly tolerated magnesium deficiency is
permissible if it coincides with a well known antagonism between
magnesium and the carcinogen or with an effective cytostatic
treatment, such as Cis-Pt, which prevents the risk of inducing
magnesium excess in the sites where magnesium excess is
noxious58,59,95.
If one finds at the first monthly monitoring of a treatment of
a chronic magnesium deficit that a simple increase in oral
magnesium intake is ineffective or insufficient it is necessary
to proceed to the treatment of this magnesium
depletion58,59: in the case of renal loss of
magnesium, use of agents that reduce urinary magnesium either
magnesium-sparing diuretics i.e. amiloride (5 to 10
mg/day), spironolactone (100 to 200 mg/day), or anti-stress
hygienic or medicinal prescriptions; if these fail or immediately
in the case without urinary magnesium leakage, use of magnesium
fixing agents: i.e. pharmacological doses of vitamin B6
and physiological doses of vitamin D, progesterone in particular
cases of luteal insufficiency or high risk
pregnancies58,59. In case of failure of these two
initial stages of therapy for magnesium depletion, we use either
partial magnesium "analogues" i.e. propranolol,
verapamil, several anticonvulsants as phenytoin, baclofen ....
anti-oxydants i.e. sulfur compounds, Se, vitamin C, A
and E39-41,50,58,59,64,94,96,97,97b, or
pharmacological use of magnesium therapy through high oral doses
98,99 or parenteral route.
V. 1.2. Pharmacological magnesium therapy
In order to induce a therapeutic magnesium overload and to use
the pharmacological properties of the ion, it is necessary to go
beyond the mechanisms of magnesium homeostasis. Large doses of
magnesium given orally are advisable for chronic indications and
the parenteral route is suitable for acute
applications58,59.
Curiously the most widely used preparations for parenteral use
are those with magnesium sulfate. This salt has among the soluble
salts of magnesium the least advantageous pharmacological
properties58-60,71,72. It is better to use isotonic
preparations of other soluble salts of magnesium for example
(MgCl2, 6H2O), magnesium acetate (Mg
(C2H3O2)2, 4H2O),
pyrrolidone carboxylate, aspartate ... Intravenous route is
customary because the painful character of the intramuscular
route. Bolus inducing a sensation of increased warmth should
never exceed 100 mg (O, I mM/kg/day); one or two bolus per day
are possible. For venous perfusions we use as a normal well
tolerated dose 100 mg an hour for perfusions of 4 to 6 hours: 400
to 600 mg (17 to 25 mM) for each perfusion. Massive doses reach 4
perfusions per day: 2400 mg (or 100 mM).
It is obvious that such forms of therapy are conceivable only
in intensive care units with careful
monitoring58-60.
The use of high oral doses of magnesium for inducing chronic
magnesium overload for example to treat extrasystoles or vascular
hypertension73,74 appears very questionable because of
its potential toxicity58,59,71. Conversely the use of
induced acute magnesium overload appears well founded after
control with double-blind studies: for example in acute
myocardial infarction, ventricular tachycardias, tocolysis and in
asthma crises39,58-60,65-70,96.
V. 1.3. Laxative, antacid and local magnesium therapy
Any renal or digestive tract lesions must formally rule out
cathartic use of large osmotic doses of magnesium poorly absorbed
such as MgSO4 or hydroxyde58,59. But when
cautiously used, laxative magnesium may also constitute an
efficient therapy for Mg-dependent disturbances of lipid,
carbohydrate and electrolyte metabolisms, in elderly patients
particularly41. Antacid therapy uses the neutralizing
capacity of magnesium oxide or magnesium carbonate. The use of
magnesium-containing phosphate binders in chronic hemodialysis
patients is discussed. It may create the risk of hypermagnesemia
which may interfere with bone mineralisation. But with an optimal
magnesium dialysate which efficiently avoids either hyper or
hypomagnesemia and their deleterious effects the use of
magnesium-containing antacids may be better than aluminium salts
with their risk of magnesium encephalopathies
58,59,100,101.
Local magnesium therapy mainly relies on the cytoprotective
properties of magnesium. Magnesium appears as a theoretically
important element for the irrigation and perfusion of organs
destined for transplant58,59,102. But the role of
magnesium in cardioplegy is still subject to
discussion58,59,61,62. The protective role of
magnesium in insulin secretion 58,59,103 makes its use
logical in culture of islets of LANGERHANS to make this promising
treatment for Insulin Dependent Diabetes Mellitus more
effective58,59.
V. 2. FURTHER RESEARCH
New directions of magnesium in therapeutics should concern
both the pharmacological and physiological fields.
At the pharmacological level it appears more important to
determine what are the most active and useful magnesium salts
rather than routinely use MgSO4. It is important to
promote wide range clinical trials in the main indication (s)
where this simple and unexpensive treatment will be compared with
the reference treatment.
At the physiological level research should mainly apply to the
treatments of magnesium depletion. Thorough analysis of their
different mechanisms in various models of genetic or acquired
magnesium depletion will be requested in order to compare the
effects of etiopathogenic treatments as well as those of diverse
Mg salts. Some recent studies have opened up this
path53,104,105. But the main direction of future
research concerns large epidemiological magnesium intervention
trials still needed to the importance of chronic primary
magnesium deficiency. They should be carried out on various
populations whatever the age, but mainly on populations with
higher risk of magnesium deficiency: infants, children, aged
persons, pregnant women, in developing countries and low
socioeconomic classes particularly. These should be a follow up
of the physiological oral magnesium supplementation not only on
magnesium items, but also on all the well-known but non-specific
clinical and paraclinical signs.
Its specific efficiency could contribute to highlight the
importance of the clinical forms of chronic magnesium deficiency
which constitutes the sole indication of oral physiological
magnesium application.
CONCLUSION
This too short critical appraisal of the present and future
trends of magnesium research testifies to its topicality and its
multidisciplinary character.
Still a lot of sofar unsolved problems remains and large
avenues are open for further research.
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Dr. Durlach.
This page was first uploaded to The Magnesium Web Site on
April 7, 1996
http://www.mgwater.com/
Healthy Water
Association--USA