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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:

Formula for delta D

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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