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Magnesium Research (1994) 7, 3/4, 313-328
State-of-the-art Review


Magnesium and therapeutics

J. Durlach*,V. Durlach†, P. Bac‡, M. Bara§ & A. Guiet-Bara§


*SDRM, Hôpital St. Vincent-de-Paul, Paris, France; †U62, Clinique Médical, CHRU, Reims, France; ‡Laboratoire de Biologie Animale, Faculté de Pharmacie, Chatenay-Malabray, France; §Laboratoire de Physiopathologie du Développement Université Pierre et Marie Curie, Groupe Interactions cellulaires, Paris, France


Summary: Two different types of therapy with magnesium are used: physiological oral magnesium supplementation which is totally atoxic since it palliates magnesium deficiencies by simply normalizing the magnesium intake and pharmacological magnesium therapy which may induce toxicity since it creates iatrogenic magnesium overload. Primary and secondary magnesium deficiencies constitute the sole indication of physiological oral magnesium therapy. It is therefore necessary to be well acquainted with the clinical and paraclinical pattern of magnesium deficit and to discriminate between magnesium deficiency due to an insufficient magnesium intake which only requires oral physiological supplementation and magnesium depletion related to a dysregulation of the control mechanisms of magnesium status which requires more or less specific regulation of its causal dysregulation. Physiological oral magnesium load constitutes the best tool for diagnosis of magnesium deficiency and the first step of its treatment. Physiological oral magnesium supplementation (5 mg/kg/day) is easy and can be carried out in the diet or with magnesium salts, with practically only one contra-indication: overt renal failure. Specific and aspecific treatments of magnesium depletion are tricky using for example magnesium sparing diuretics, pharmacological doses of vitamin B6, physiological doses of vitamin D and of selenium. In order to use the pharmacological properties of induced therapeutic hypermagnesaemia, high oral doses of magnesium (> 10 mg/kg/day) are advisable for chronic indications and the parenteral route is suitable for acute indications. There are 3 types of indications: specific (for the treatment of some forms of magnesium deficit i.e. acute), pharmacological (i.e. without alterations of magnesium status) and mixed--pharmacological and aetiopathogenic--(for example complications of chronic alcoholism). Today pharmacological magnesium therapy mainly concerns the obstetrical, cardiological and anaesthesiological fields. The main indications are eclampsia, some dysrhythmias (torsades de pointe particularly) and myocardial ischaemias. But it is now difficult to situate the exact place of the pharmacological indications of magnesium. Magnesium infusions can only be envisaged in intensive care units with careful monitoring of pulse, arterial pressure, deep tendon reflexes, hourly diuresis, electrocardiogram and respiratory recordings. High oral magnesium doses besides their laxative action may bring latent complications which may reduce lifespan. There may remain some indications of the laxative and antacid properties of non soluble magnesium, particularly during intermittent haemodialysis. Lastly local use of the mucocutaneous and cytoprotective properties of magnesium is still valid, in cardioplegic solutions and for preservation of transplants particularly.


Key words: Magnesium, physiology, pharmacology, therapeutics, toxicity, anaesthesiology, arrhythmias, ischaemia, eclampsia, hyperventilation, nervous hyperexcitability, tetany.


Introduction

For a long time, magnesium only had a modest place in therapeutics, being used solely for its cathartic or neutralizing properties in oral preparations or for its sedative and antispasmodic properties parenterally. Now two different types of therapy with magnesium are used: atoxic physiological oral magnesium therapy and pharmacological magnesium therapy which may induce toxicity. Today continually increased knowledge of the clinical forms of magnesium deficit in human beings1 is showing us in what circumstances and in what manner we can remedy magnesium deficiency using physiological doses of magnesium. Chronic primary magnesium deficiency constitutes the major indication of this main form of magnesium therapy. These palliative oral doses of magnesium meant to balance magnesium deficiency are obviously devoid of any toxicity since their purpose is to restore to normal the insufficiency of the magnesium intake. Their indications rest on well founded epidemiological trials2. Conversely parenteral magnesium or high oral doses of magnesium possess all the pharmacodynamic properties of magnesium overload and are capable of inducing toxicity. They must therefore always be administered with caution in more or less specific indications 3.

In this study on therapy with magnesium we will successively consider: (1) The uses of physiological oral magnesium doses, the main form of magnesium therapy, involving first and foremost adequate knowledge of this sole indication: magnesium deficiency. The technique of oral physiological magnesium supplementation will be analyzed; (2) The indications for and techniques of several pharmacological applications of magnesium: mainly the properties of a magnesium overload induced through either high doses of oral magnesium, or parenteral magnesium therapy using soluble magnesium preparations; accessorily, laxative and antacid magnesium therapy which uses most often non or little soluble magnesium salts; lastly, some types of local magnesium therapy: mucocutaneous or cytoprotective.

It is necessary to highlight the contrast between the dangers of using the pharmacological properties of induced iatrogenic magnesium overload and the atoxicity of a supplementation with physiological oral doses of magnesium which by simply normalizing the magnesium intake palliates magnesium deficiencies.


Physiological oral magnesium therapy

Today the main form of magnesium therapy is oral magnesium physiological supplementation of magnesium deficiencies. It is therefore necessary to be well acquainted with the clinical pattern of its sole indication. Since chronic primary magnesium deficiency is the most commonly observed form of magnesium deficiency, it will serve therefore as our descriptive model.

Clinical forms of chronic magnesium deficiency1-4

Open and controlled trials have established the clinical and paraclinical pattern of chronic magnesium deficiency (CMD). Whatever the age nervous consequences must 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, effort 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 consult a wide range of specialists as well as the general practitioner. It includes non-specific central, peripheral and autonomic manifestations.

The neurotic, or rather, 'central' symptoms consist of anxiety, hyperemotionality, fatigue, headaches (and sometimes migraine), insomnia, light-headedness, dizziness, nervous fits, lipothymiae, sensation of a 'lump in the throat', of 'nuchalgia' 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 hypotension or conversely to borderline hypertension. In fact, the dysautonomic disturbances involve both the sympathetic and the parasympathetic systems.

The evolution may be studded with various acute paroxysmal 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 hypoglycaemia, 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 as 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 ear lobe to the labial commissure, avoiding the lightning contraction of a 'false Chvostek's sign' by taping 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 (ECC)). 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) trains(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 distinguished: one with simultaneous clinical and neurophysiological criteria: EI=2, the others with only one criterion of their tetanic state: EI=1 with two subgroups, either clinical (through positivity of the Chvostek's sign alone), or electromyographic (through positivity of EMG alone). The ECC is the best tool for detecting mitral valve prolapse (MVP). With time-motion (TM) mode, three tracings are classical: a 'cuplike' tracing of mesotelesystolic mitral valve prolapse (of more than 2 mm), a 'hammocking' tracing of holosystolic mitral valve prolapse (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 time-motion 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 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: ΔD = end diastolic diameter - end systolic diameter / end diastolic diameter.

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 daily magnesuria, 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 due to chronic magnesium deficiency, with or without mitral valve prolapse. Normal levels do not rule out the diagnosis of chronic magnesium deficiency. The histograms of latent tetany patients (with or without mitral valve prolapse) and of controls overlap. If the tetanic group reveals gaussian-type magnesaemia curves with significant lower means (P less than 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 magnesaemia5,6,7. Lymphocyte Mg/cell appears as the most interesting static intra-cellular magnesium item8. In particular clinical forms, record should be completed with corresponding clinical and paraclinical explorations. Rhinoscopy in rhinitis to discriminate between pseudo-allergic vasomotor and allergic 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, electropolygraphic study of afternoon sleep in dyssomnia, lipid profile in atheromatous dyslipidaemias9,10,11.

Several risk populations require special attention. Pregnant women because of the consequences of deficiency on mother, foetus, neonate and infant12 and perhaps on the adult13. Geriatric14,15 and sport16 populations where magnesium deficiency is most often associated with magnesium depletion. These last two examples illustrate the necessity of distinguishing between two types of inducing mechanisms of magnesium deficit1,4. 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 perturbating factors of magnesium status. Magnesium depletion requires more or less specific correction of its causal dysregulation.

This differential diagnosis between these two types of magnesium deficit is of major importance in case of primary magnesium deficit. It is also interesting in case of secondary magnesium deficit. Although they initially always require their own specific aetiologic treatment, this major therapeutic measure cannot always be performed. It may not be possible to get an alcoholic to quit drinking or to manage diabetes mellitus perfectly. In such cases, a careful analysis of the mechanisms inducing the magnesium deficit can lead to an effective therapy. In chronic alcoholism, magnesium deficiency secondary to an insufficient magnesium entry is frequent1 whilst in diabetes mellitus the part of the deficiency appears usually much more accessory than the dysregulations inducing magnesium depletion1. In chronic alcoholism oral magnesium supplementation frequently constitutes an interesting adjuvant treatment1,17a, while it is much more rarely efficient in diabetes mellitus. However in magnesium depletion it is always wise to maintain a sufficient magnesium intake to allow the means of correcting the dysregulation to have a substrate. It may thus constitute a necessary adjunct to the treatment 1,17b,17c.

Technique of physiological oral magnesium therapy

Effect of oral physiological magnesium supplementation is the best tool for establishing the diagnosis of magnesium deficiency. Physiological oral doses of magnesium are totally devoid of the pharmacodynamic effects of parenteral magnesium which are observed irrespective of magnesium status: they are without clinical effects when magnesium status is normal. But correction of symptoms by this oral magnesium load will not only be studied on extra- and intra-cellular magnesium parameters, but also on all the well known--but non specific--clinical and paraclinical items. For example stigma of neuromuscular hyperexcitability should be integrated in the protocol of physiological oral magnesium supplementation concerning allergic, vascular, pregnant or sport patients1,2,14-16,18.

Chronic primary magnesium deficit affects a large proportion of the population (15-20 per cent). This prevalence seems consistent with the estimation of nutrient deficiency using probability analysis in populations where the mean magnesium daily intake is slightly above 4 mg/kg/day versus a recommended dietary amounts of magnesium set a 6 mg/kg/day1,19-22. The first step of physiological oral supplementation should be achieved through dietetic means. But usually magnesium and energy content of food correlate1,2,6: magnesium rich products are also rich in energy. Except for some vegetarian diets1,15 supplementation should be achieved using a high magnesium density nutrient with the best possible availability1,19-21. This requirement is met by magnesium in water, which must have a probable link with the importance of its hexahydrated form in biological systems1,19,20,24-26. 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 water 1,19,20,27-29. If it is only a question to correct in vivo an experimental magnesium deficiency, all magnesium salts have a comparable bioavailability, either mineral salts i.e. chloride, or organic salts i.e. acetate, citrate, methionate, aspartate, lactate, glutamate, 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 alkalosis1,21 or the anions may act differently on various targets: for example at the membranous level30,31. Tolerance of these physiological doses is excellent. Acceleration of intestinal transport is observed only in susceptible subjects: for example patients with colitis1. The contraindications are obvious1. Two are exceptional: myasthenia and hypermagnesaemic periodic paralysis. There is only one contraindication: overt renal insufficiency (creatinine clearance less than 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 therapy1. Magnesium may impair the properties of several drugs: for example 4-quinolones, tetracyclines, several aminoglycosides, vancomycin. The use of these antibiotics constitutes another transient contraindication1,32.

Lastly, within the limits of our present knowledge, we can eventually consider as a relative contraindication of magnesium therapy, magnesium solid tumours in a state of development since their growth may be stimulated by magnesium1,33. 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 cystotatic treatment--such as Cis-Pt--which prevents the risk of inducing magnesium excess in the sites where magnesium excess is noxious 1,33. 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 depletion1: 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 antistress 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 pregnancies1. Further research on the tricky problem of treatment of magnesium depletion might bear upon diverse genetic or acquired models of magnesium depletion in order to study their physiopathological mechanisms and aim at their control18. Various types of more or less severe magnesium depletion are used: genetic models34-38 and acquired models which associate low magnesium intake with diverse types of stress: aluminium load, cardiac or nervous insults39-42,43,44-48. Models which may be cured appear particularly appropriate to screen treatments of magnesium depletion34,47,48. Recent experimental data have stressed the links between magnesium and selenium status14,49. Glutathione peroxidase may be lowered either by selenium deficiency--whose classical marker it is--or by magnesium deficiency. In some cases in which magnesium deficit was not controlled by simple physiological oral magnesium supplementation, magnesium depletion was cured by the addition of 200 Ý/day of oral selenium as seleno-methionine to the same magnesium supplementation. This treatment simultaneously normalized reduced erythrocyte magnesium and glutathione peroxidase concentrations50.

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 ..., antioxidants i.e. sulphur compounds, selenium, vitamins C and E1,9,10,14,15,18,32,49,51,52a,b or parenteral magnesium therapy.

Pharmacological magnesium therapy

Induced magnesium overload

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 applications.

The pharmacodynamic properties of magnesium are antispasmodic curariform and ganglioplegic, bradycardic, antiarrhythmic, vasodilating and hypotensive, antithrombotic, antianoxic, stabilizing, antitoxic versus several pollutants, cytoprotective and thus antistress1,27,33,53-56.

To prevent magnesium overload accidents, one must understand the symptoms of magnesium overload1.

Indications

They are of three types: specific, pharmacological or mixed.

Specific indications

Parenteral magnesium treatment is specifically used for the treatment of magnesium deficit in its acute form often with magnesium-dependent hypocalcaemia and/or hypokalaemia, when the oral route is prohibited (parenteral nutrition, anaesthesias, coma) or after the failure of oral magnesium therapy1.

Pharmacological indications

The pharmacological properties of magnesium have enabled it to be used in many illnesses where no magnesium deficit has been described: intoxication with anticholinesterases (especially TEPP or DFP), aconitine or strychnine; treatment for convulsions in hyperoxia, decompression disorders (caisson disease), or gas embolism and treatment in porphyria that does not increase ALA synthetase activity; treatment for certain forms of migraine and hiccups; as a relaxant that facilitates certain kinds of psychological or neurologic examination and is used in anesthesiology or during kinesitherapy; antihypoxic treatment, especially with high altitude sickness or for carbon monoxide poisoning; antiarrhythmic treatment in any kind of tachyarrhythmia, for example, in digitalis excess, in lithium poisoning, in alcoholism, in cardiac failure, in post-myocardial infarction period and particularly in ventricular dysrhythmia such as in 'torsade de pointes'; and treatment of cases of tissue calcinosis such as ossifying myositis (neurotic, traumatic or progressive) or para-articulatory ossification after the implantation of articular endoprostheses 1,9,10,18,27,32,44-46,67,70a,70b.

Mixed indications: pharmacological and aetiopathogenic

These types constitute very interesting indications for magnesium therapy. The list of the types of treatment possible is quite long: treatment for delirium tremens and the different acute complications of alcoholism, most often in hypertonic form and associated with treatment of the various withdrawal syndromes; treatment for cranial trauma and many nervous crises, not only the tetanic forms but also 'grand mal', loss of consciousness, hypoglycaemic episodes, vagovagol syncope, swooning, 'panic attacks'; treatment for hypertensive diabetic and atherosclerotic vasculopathy or for various types of central and peripheral arteriopathies (cerebral, ocular, of the lower limbs, coronary and especially for myocardial infarction); treatment of phlebitis in association with major anticoagulation treatments; treatment for acute intoxication by citrates, by aluminum phosphide, by ricin and fluoride compounds as well as for intoxication by the major pollutants, Pb and Cd, and perhaps Hg, ultimately alternating with chelation treatment; treatment for dilutional hyponatraemia and ketosis. Finally the rarity of gynaecological indications which are in practice limited to a few cases of severe dysmenorrhea contrasts with the importance of obstetric indications: treatment for pre-eclampsia and eclampsia, tocolysis in premature labor, tetanization of the uterus, fetal distress syndrome and meconial contamination, and even, by virtue of magnesium's role in the synthesis of surfactant, prevention of hyaline membrane disease. Lastly parenteral magnesium is interesting in the treatments of anaphylactic shock and of asthmatic crisis--with possible consecutive management of a secondary acute respiratory failure--whereas the effects of magnesium aerosols are dubious for the latter indication1,9,10,18,27,32,58,67,71-81b.

Today parenteral magnesium therapy mainly concerns the obstetric, cardiovascular and anaesthesiological fields.

In obstetrics, the main indication is pre-eclampsia74-77. But prevention or treatment of eclamptic convulsions does not rely on a specific central action of magnesium, since the central nervous system is protected from hypermagnesaemia by the blood-brain barrier1,74,75,77,82,83. The mechanisms of parenteral magnesium action on the brain seem indirect through the antithrombotic beneficial effects on platelet1 and endothelial functions (↑ PGI2, ↑ EDRF (↑ NO), ↓ thromboxand, ↓ endothelin, ↓ angiotension II)58-62b on microvascular obliteration--the hallmark of eclampsia58--and on vasospasm by acting as a calcium antagonist82,84,85. Analysis of the mechanisms of the protective action of parenteral magnesium on the central nervous system O2 toxicity brings to similar conclusions as to the preponderance of the systemic indirect factors over the pharmacological central anticonvulsant actions of parenteral magnesium1,68,86. Nevertheless among the major treatments of preeclampsia, phenytoin75 induces more rapid cervical dilatation, smaller fall in haematocrit after delivery, lower incidence of hot flushes and less dyspnoea and weakness in mother as well as less side effects on fetal heart tracings, than magnesium infusions do87,88.

A critical and comprehensive review of tocolytic agents to stop preterm labour concludes that the only effective drugs are the prostaglandin inhibitors. An analysis of randomized, placebo-controlled, clinical trials showed that parenteral magnesium is not better than placebo89 Moreover in a high risk group of patients, without clinical disturbances of magnesium status, physiological oral magnesium supplement was not effective which demonstrates that there is no magnesium deficiency in this population90.

In the cardiovascular field, arrhythmias and ischaemias constitute the main indications of parenteral magnesium.

All topographical forms of primary or secondary cardiac arrhythmias may benefit form parenteral magnesium administration: atrial arrhythmias (multifocal tachycardia or fibrillation), supraventricular tachycardia (reentrant sinoatrial, reentral atrio-ventricular), ventricular arrhythmias (torsades de pointes particularly). Parenteral magnesium effects on heart functions bring together: reduced excitability due to a shift of excitable threshold to more depolarised potentials, reduced automotricity due to decrease rate of slow diastolic depolarization and delayed stimulus conduction due to increase of atrio-ventricular node conduction time. The ionic mechanisms underlying the anti-arrhythmic effects of parenteral magnesium are numerous. Among others, negative inotropism seems due to reduction of both Ca2+ influx from extracellular space and calcium release from intracellular calcium stores acting on both ryanodine sensitive and IP3-sensitive calcium release channels70,91. Cardiac arrhythmias are usually pharmacological indications of parenteral magnesium. It is erroneous to claim, as, among others, Iseri et al., do 2, that the efficiency of pharmacological magnesium infusions justifies oral magnesium physiological magnesium supplementation. Such supplements are only appropriate in mixed (pharmacological and aetiopathogenic) indications where primary or secondary magnesium deficiency exists for example in alcoholism and some cases of cardiac failure1,92-94.

To determine the just place of parenteral magnesium therapy in cardiac arrhythmias randomized, double blind controlled trials vs. placebo and reference drugs are necessary. In such conditions, prophylactic magnesium infusion seems to lessen the incidence and severity of atrial fibrillation after coronary artery by-pass grafting, but remains inefficient on ventricular arrhythmias95. However in another trial, a similar magnesium administration decreased the frequency of ventricular dysrhythmias96. Because of the vast array of safe and effective drugs such as ATP and verapamil available for terminating supraventricular tachycardia, there appears to be little role for clinical use of parenteral magnesium in this setting97,98. However the overall efficacy for conversion to sinus rhythm through this magnesium therapy seems at least as effective as with verapamil. It acts more rapidly and with fewer side-effects99. In the control of warning ventricular arrhythmias, combination of magnesium infusion with low doses of lidocaine is more effective than lidocaine alone and avoids the toxic effects that higher doses of lidocaine may cause66,100. In torsades de pointe magnesium infusion can be given safely as a first aid therapy, especially when conventional treatments might prove difficult or deleterious101. It does not jeopardize the therapeutic effects of artrial pacing since it does not affect the QT interval102.

The logistic use of parenteral magnesium seems now an essential therapy in the treatment of acute ischaemic heart disease and a potential role in cerebral ischaemia. In both animal and human studies, intravenous magnesium is useful in treatment of acute myocardial infarction73,103,104. In earlier studies the beneficial effects on mortality were attributed to an antiarrhythmic effect of magnesium infusion1,105, but it seems that the benefit relies mainly on anti-stress properties of parenteral magnesium1,9,71,72,106. This indication of intravenous magnesium is pharmacological. Myocardial infarction is the typical example of a painful illness where stress induces magnesium depletion. The usual parenteral doses would not suffice to restore its balance. The failure of physiological oral magnesium supplementation to influence post-infarction cardiac events demonstrates that no magnesium deficiency intervenes107. Nervous focal ischaemia--and trauma--seem relevant indications of magnesium infusion therapy. These insults induce local magnesium depletion, disruption of blood-brain barrier enabling a higher level of neuroprotector magnesium to reach the nervous tissue and to reduce focal impairment12,44-48,108,113 but these beneficial effects are observed with massively increased plasma magnesium only. Further research with lower parenteral magnesium administration is still requested. One should make the greatest reservations on the possible but unproven role of magnesium deficit in the aetiology of strokes9.

The pharmacological hypotensive action of parenteral magnesium should rarely be used. This transient effect69 may be opposed to its persistent cerebral vasodilating effect 7,82.

Lastly it will be interesting to study the pharmacological effects of magnesium in the therapy of consummation coagulopathy since it may be associated with magnesium deficits1,114 and with reduced release of PGI258.

The muscle relaxant activity of magnesium infusion and its anti-stress activities may account for its use in anaesthesia. It has been used to treat postanaesthetic shivers115, to prepare brain-dead patients for organ donation with large fluxes of magnesium116, to manage sympathetic and parasympathetic overactivity in severe tetanus117, in phaeochromocytoma resection60,118, in the prophylactic or curative treatment of reactive hypertension caused by endotracheal incubation69. Among the interactions of hypermagnesaemia with anaesthetic agents, the enhancement of the non-depolarizing and depolarizing muscle relaxants should be highlighted. A pattern of Lambert-Eaton syndrome or of magnesium excess may be observed 1,4,69.

Technique

Curiously, the most widely used preparations are those with magnesium sulphate. This salt has, among the soluble salts of magnesium, the least advantageous pharmacological properties 1,24,30,31. The use of isotonic preparations of other soluble salts of magnesium would be better for example (MgCl2, 6H2O), magnesium acetate (Mg(C2H3O2)2, 4H2O), pyrrolidone carboxylate, aspartate... Intravenous route is customary because of the painful character of the intramuscular route. Bolus inducing a sensation of increased warmth should never exceed 100 mg (0.1 mM/kg/day). Rapid administration is dangerous119, the intravenous injection must be very slow (a minimum of 3 min for injection of 100 mg(1)). One or two bolus per day are possible. For venous perfusions we use as a normal well tolerated dose 100 mg per hour for perfusions from 4 to 6 h: 400 to 600 mg (17 to 25 mM) for each perfusion. Massive doses reach four 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 monitoring of pulse, arterial pressure, deep tendon reflexes, hourly diuresis and electrocardiogram and respiratory rhythm recording1.

Contraindications for this form of pharmacological therapy are the same as for oral magnesium therapy but one must be even more cautious because of the toxicity reaching lethality of iatrogenic magnesium overload. Well monitored, iatrogenic hypermagnesaemia should never cause respiratory arrest120 and even less cardiac arrest with assisted respiration. Hypocoagulation disturbances and hypothermia seem related to the importance of hypermagnesaemia1,121.

These acute complications require:

The use of high oral doses of magnesium for inducing chronic magnesium overload--for example to treat vascular hypertension or extra-systoles67,126,127--appears very questionable, not so much because of possible laxative effects as because of its potential toxicity. It is erroneous to identify the atoxicity of physiological oral magnesium supplementation (5mg/kg/day) which only ensures normal equilibrium of magnesium balance with a similar tolerance of pharmacological high oral doses or magnesium (equal to or greater than 10 mg/kg/day) which are meant to induce chronic magnesium excess16-21. It should be possible to observe, for example, diverse metabolic consequences akin to those observed with prolonged pharmacological parenteral magnesium treatment such as calcium homeostasis disturbances124,125. They may constitute one of the factors reducing lifespan128.

Laxative and antacid magnesium therapy

Laxative magnesium therapy

Laxative magnesium therapy traditionally uses the irritative osmotic strength of large doses of magnesium salts for example hydrated MgSO4 or magnesium hydroxide. Any renal or digestive tract lesion must formally rule out its uses because of the risk of fatal accident of magnesium overload. But when cautiously used, laxative magnesium may also constitute an efficient therapy for magnesium-dependent disturbances of lipid, carbohydrate and electrolytes metabolism, in geriatric patients particularly15,129,130.

Antacid therapy

Antacid therapy uses the neutralizing capacity of Mgo or Mg carbonate. The more widespread use of magnesium-containing phosphate binders creates the risk of hypermagnesaemia. Their interest in haemodialysis patients is discussed. Theoretically their use coupled with a low magnesium dialysate may reduce phosphorus absorption. It appears better than aluminium salts with their risk of aluminium encephalopathy1, but it is difficult to determine the use of magnesium containing antacids with an optimal magnesium dialysate which efficiently avoids either hyper- or hypomagnesaemia131.

Local magnesium therapy

Topical applications of magnesium

During the first world war, P. Delbet stressed the interest of irrigating wounds with a 'cytophlactic' solution of 1.2 per cent MgCl21. Today topical use of magnesium is proposed as the best possible antagonist for hydrofluoric acid burns: bathing with a saturated ice cold solution of magnesium sulphate associated with local injections of a 10 per cent solution of magnesium acetate132. An ointment containing 25 per cent MgSO4 has local decongestive osmotic effects which make it useful as a non specific anti-inflammatory agent1. Such an ointment could be used associated with local treatment of soft tissue calcification133. Lastly in ophthalmology an eye wash with 10 per cent MgSO4 appears to have a significant effect on herpetic superficial dentritic keratitis1.

Magnesium and cytoprotection

The cytoprotective properties of magnesium make it a theoretically important element in solutions for the irrigation and perfusion of organs destined for transplant: cornea, lungs, liver, pancreas, kidney and especially the heart1,116. The role of magnesium in cardioplegy is still subject to discussion 1,27,134. The protective role of magnesium in insulin secretion135,136 makes it logical to consider its use in culture of the islets of Langerhans to make this promising treatment for insulin dependent diabetes more effective1.

Conclusion

The applications of magnesium therapy are presently in constant progress. The range of the indications of pharmacological magnesium therapy is widening: for example in intensive care where it is advisable as well in cardiologic emergencies such as myocardial infarctions and torsades de pointe as in toxicological emergencies such as acute intoxication by aluminum phosphide. But its main indication concerns the control of chronic primary magnesium deficiency with physiological oral magnesium therapy. Its pattern has now been clearly elicited, but epidemiological intervention trials are still needed to assess its importance. There should be a follow-up of the effects 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 should contribute to highlight the importance of the clinical forms of chronic marginal magnesium deficiency which constitutes the major indication of oral physiological magnesium application.

References

1. Durlach, J. (1988): Magnesium in clinical practice, pp. 360. London, Paris: John Libbey Eurotext.

2. Durlach, J., Durlach, V., Rayssiguier, Y., Bara, M. & Guiet-Bara, A. (1992): Methodological prerequisites and systemical approach to the study of magnesium supplementation in marginal magnesium deficiency. In: Metal ions in Biology and Medicine, Vol. 2, eds. J. Anastassopoulou, P. Collery, J.-C. Etienne & T. Theophanides, pp. 383-388. London: John Libbey.

3. Durlach, J. (1991): Magnesium: clinical forms of primary magnesium deficiency. In: Modern life-styles, lower energy intake and micronutrient status, ed. K. Pietrzik, pp. l56-167. London, Berlin: Springer.

4. Durlach, J. (1992): Chronic fatigue syndrome and chronic primary magnesium deficiency. Magnes. Res. 5, 68.

5. Whang, R., Whang, D.D., Ryder, K.W.. & Oei, T. O. (1990): Routine serum magnesium determination: a contemporary clinical imperative. Magnes. Res. 4, 267-270.

6. Classen, H.-G., Nowitzki, S. & Schimatschek, H.F. (1991): Methodological aspects of research on the therapeutic effect of magnesium. Magnes.-Bull. 13, 39-45.

7. Borella, P., Ambrosini, G., Concari, M. & Bargellini, A. (1993): Is magnesium content in erythrocytes suitable for evaluating cation retention after oral physiological supplementation in marginally magnesium deficient subjects. Magnes. Res. 6, 149-153.

8. Durlach, V., Millart, H., Meyer, L., Grulet, H., Gross, A. & Leutenneger, M. (1991): Magnesium status in a group of so-called 'spasmophilic' patients. Magnes. Res. 4, 233-234.

9. Durlach, J., Durlach, V., Rayssiguier, Y., Bara, M. & Guiet-Bara, A. (1992): Magnesium and the cardiovascular system. II. Clinical data. A critical review. In: Molecular biology of atherosclerosis, ed. M.J. Halpern, pp. 513-521. London: John Libbey.

10. Durlach, J., Durlach, V., Rayssiguier, Y., Bara, M. & Guiet-Bara, A. (1992). Magnesium and blood pressure. II. Clinical studies. Magnes. Res. 5, 147-153.

11. Kisters, K., Spieker, C., Tepel, M. & Zidek, W. (1993): New data about the effects of oral physiological magnesium supplementation on several cardiovascular risk factors (lipids and blood pressure). Magnes. Res. 6, 355-360.

12. Durlach, J., Durlach, V., Rayssiguier, Y., Ricquier, D., Goubern, M., Bertin, R., Bara, M., Guiet-Bara, A., Olive, G. & Mettey, R. (1991): Magnesium and thermoregulation. I. Newborn and infant. Is sudden infant death syndrome a magnesium-dependent disease of the transition from chemical to physical thermoregulation? Magnes. Res. 4, 137-152.

13. Durlach, J. (1993): Death from infancy to older age and maternal magnesium deficiency. How long should the follow-up of the consequences of undernutrition in pregnancy be continued? Magnes. Res. 6, 297-298.

14. Rayssiguier, Y., Durlach, J., Gueux, E., Rock, E. and Mazur, A. (1993): Magnesium and ageing. I. Experimental data: importance of oxidative damage. Magnes. Res. 6, 369-378.

15. Durlach, J., Durlach, V., Bac, P., Rayssiguier, Y., Bara, M. & Guiet-Bara, A. (1993): Magnesium and ageing. II. Clinical data: aetiological mechanisms and physiopathological consequences of magnesium deficit in the elderly. Magnes. Res. 6, 379-394.

16. Rayssiguier, Y., Guezennec, C.Y. & Durlach, J. (1990): New experimental and clinical data on the relationship between magnesium and sport. Magnes. Res. 3, 93-102.

17a. Gullestad, L., Dolva, L.O., Soyland, E., Manger, A.T., Falch, D., Veierod, M.B. & Kjekshus, J. (1991): Effects of oral magnesium treatment in chronic alcoholics. In: Magnesium a relevant ion, eds. B. Lasserre & J. Durlach, pp. 405-409. London: John Libbey.

17b. Dorup, J., Skajaa, K. & Thybo, N.K. (1993): Oral magnesium supplementation restores the concentrations of magnesium, potassium and sodium-potassium pumps in skeletal muscle of patients receiving diuretic treatment. J. Internal. Med. 233, 117-123.

17c. Corica, F., Allegra, A., Di Benedetto, A., Glacobbe, M.S., Romano, G., Cucinotta, D., Buemi, M. & Ceruso, D. (1994): Effects of oral magnesium supplementation on plasma lipid concentrations in patients with non-insulin-dependent diabetes mellitus. Magnes. Res. 7, 43-47.

18. Durlach, J. (1993): Present and future of magnesium research. J. Jap. Soc. Mg Res. 12, 113-135.

19. Durlach, J. (1989): Recommended dietary amounts of magnesium: Mg RDA. Magnes. Res. 2, 195-203.

20. Durlach, J. & Mareschi, J.P. (1991): Recommended dietary amounts for magnesium: II. Updated European Consensus and future prospects. In: Magnesium a relevant ion, eds. B. Lasserre & J. Durlach, pp. 39-49. London: John Libbey.

21. Durlach, J. (1992): Apports conseillés en minéraux: le magnésium. In: Apports nutritionnels conseillés pour la population frarwiase, eds. H. Dupin, J. Abraham & I. Giachetti, pp. 37-38, 134-135. Tec. Doc., Paris.

22. Wangemann, M., Selzer, A., Leitzman, C., Golf, S., Temme, H., Graef, V. & Katz, N. (1993): On the magnesium supply of a normal diet. Magnes. Res. 6, 402-403.

23. Fine, K.D., Santa, Ana, C.A., Porter, J.L. & Fordtran, J.S. (1991): Intestinal absorption of magnesium from foods and supplements. J. Clin. Inv. 88, 396-402.

24. Bara, M., Guiet-Bara, A. & Durlach, J. (1989): A qualitative theory of the screening-binding effects of magnesium salts on epithelial cell membrane: a new hypothesis. Magnes. Res. 2, 243-248.

25. Theophanides, T., Angiboust, J. F., Anatassopoulou, J. & Manfait, M. (1990): Possible role of water structure in biological magnesium systems. Magnes. Res. 3, 5-13.

26. Meyer, H.H.C. & Classen, H.-G. (1991): Prevention of severe dietary magnesium depletion in SD rats preferring magnesium enriched versus demineralized drinking water. Magnes. Res. 4, 256.

27. Classen, H.-G. (1990): Magnesium and placebo effects in human medicine. In: Metal ions in biological systems, Vol. 26, eds. H. Sigels & A. Sigels, pp. 597-609. New York, Basel: Marcel Dekker Inc.

28. Fehlinger, R. (1990): Therapy with magnesium salts in neurological disease. Magnesium Bull. 12, 35-42.

29. Fehlinger, R. (1991): Therapy with magnesium salts in the tetanic syndrome and associated diseases: a critical appraisal. In: Magnesium: a relevant ion, eds. B. Lasserre & J. Durlach, pp. 391-404. London: John Libbey.

30. Durlach, J., Durlach, V., Bara, M. & Guiet-Bara, A. (1992): A new method of in vitro prescreening evaluation of several magnesium salts. Meth. Find. Exp. Clin. Pharmacol. 14, 305-310.

31. Bara, M., Guiet-Bara, A. & Durlach, J. (1994): Comparative effects Of MgCl2 and MgSO4 on the ionic transfer components through the isolated human amniotic membrane. Magnes. Res. 7, 11-16.

32. Gunther, T. (1991): Biochemical bases of the therapeutic actions of magnesium. Magnesium Bull. 13, 46-52.

33. Durlach, J., Bara, M. & Guiet-Bara, A. (1990): Magnesium and its relationship in oncology. In: Metal ions in biological systems, Vol. 26, eds. H. Sigel & A. Sigel, pp. 549-578. New York, Basel: Marcel Dekker Inc.

34. Mazur, A., Gueux, E., Remesy, Y., Demigne, C. & Rayssiguier, Y. (1989): Plasma and red blood cell magnesium in Zucker rats: influence of a high fibre diets. Magnes. Res. 2, 189-192.

35. Henrotte, J.G., Aymard, N., Leyris, A., Monier, C., Frances, H. & Boulu, R. (1993): Brain weight and noradrenaline content in mice selected for low (MGL) and high (MGH) blood magnesium. Magnes. Res. 6, 21-24.

36. Henrotte, J.G., Franck, G., Santarroma, M., Clavel, M., Mouton, D. & Motta, R. (1993): Mice selected from low (MGL) and high (MGH) red blood cell magnesium levels: recent results (Abs). Magnes. Res. 6, 304-305.

37. Aymard, N., Leyris, A., Monier, C., Frances, H., Boulu, R.G. & Henrotte, J.G. (1993): Brain catecholamines, serotonin and their metabolites in mice selected for low (MGL) and high (MGH) blood magnesium levels (Abs). Magnes. Res. 6, 304.

38. Frances, H., Monier, C. & Henrotte, J.G. (1993): Behavioural difference between mice selected for low (MGL) and high (MGH) red blood cell magnesium levels (Abs). Magnes. Res. 6, 304-305.

39. Durlach, J. (1990): Magnesium depletion and pathogenesis of Alzheimer's disease. Magnes. Res. 3, 217-218.

40. MacLeod, D.P. (1991): Environmental trace metal abnormalities and amyotrophic lateral sclerosis: an etiological role of calpain 1. Magnes. Trace Elem. 10, 51-52.

41. Mitani, K. (1992): Relationship between neurological disease due to Al load, especially amyotrophic lateral sclerosis and magnesium status. Magnes. Res. 5, 203-213.

42. Yasui, M. & Ota, K. (1992): Experimental and clinical studies on dysregulation of magnesium metabolism and the aetiopathogenesis of multiple sclerosis. Magnes. Res. 5, 295-302.

43. Millane, T. (1993): Studies of magnesium in heart transplantation: further insights into magnesium and cardiac physiology. Magnes. Res. 6, 361-368.

44. Vink, R. & McIntosh, T.K. (1990): Pharmacological and physiological effect of magnesium on experimental traumatic brain injury. Magnes. Res. 3, 163-169.

45. McIntosh, T.K. (1992): Pharmacologic strategies in the treatment of experimental brain injury. J. Neurotrauma 9, S201-S209.

46. McIntosh, T.K. (1993): Novel pharmacologic therapies in the treatment of experimental traumatic brain injury: a review. J. Neurotrauma 10, 215-261.

47. Bac, P., Herrenknecht, C., Binet, P. & Durlach, J.(1993): Audiogenic seizures magnesium-deficient mice: effects of magnesium pyrrolidone-2-carboxylate, magnesium acetyltaurinate, magnesium chloride and vitamin B-6. Magnes. Res. 6, 11-19.

48. Bac, P., Herrenknecht, C., Binet, P. & Durlach, J. (1993): Effects of various magnesium salts on the action of systemic kainic acid in magnesium deficient rats: a new model of accelerated hippocampal ageing-like injury? (Abs.). Magnes. Res. 6, 300-301.

49. Zhu, Z., Kimura, M. & Itokawa, Y. (1993) Selenium concentration and glutathione peroxidase activity in selenium and magnesium deficient rats. Biol. Trace Element Res. 37, 209-217.

50. McLaren, Howard, J., Davies, S. & Hunni-Sett, A. (1994): Red cell magnesium and glutathione peroxidase in infertile women. Effect of oral supplementation with magnesium and selenium. Magnes. Res. 7, 48-57.

51. Freedman, A.M., Cassidy, M.M. & Weglicki, N.B. (1991): Magnesium-dependent myocardium demonstrates an increased susceptibility to an in vivo oxydative stress. Magnes. Res. 4, 185-189.

52a. Rayssiguier, Y., Gueux, E., Bussiere, L., Durlach, J. & Mazur, A. (1993): Dietary magnesium affects susceptibility of lipoproteins and tissues to peroxidation in rats. J. Am. Coll. Nutr. 12, 133-137.

52b. Yamaguchi, Y., Kitagawa, S., Kunitomo, M. & Fujiwara, M. (1994): Preventive effects of magnesium on raised serum lipid peroxide levels and aortic cholesterol deposition in mice fed an atherogenic diet. Magnes. Res. 7, 31-37.

53. Guiet-Bara, A., Bara, M. & Durlach, J. (1991): Toxic metals and human amniotic ion permeability. II. Ultrastructural study and relationship with magnesium. Magnes. Res. 4, 77-81.

54. Zdanowicz, M.M. & Barletta, M.A. (1991): Magnesium protection against anthracycline toxicity in vitro, Magnes. Res. 4, 105-107.

55. Cordova, A., Escanero, J.F. & Gimenez, M. (1992): Magnesium distribution in rats after maximal exercise in air and after hypoxic conditions. Magnes. Res. 5, 23-27.

56. Bara, M., Guiet-Bara, A. & Durlach, J. (1992): A new method of prescreening evolution of the relationship between toxic and common metal ions. Meth. Rnd. Exp. Clin. Pharmacol. 14, 311-314.

57. Rizzo, M.A., Fisher, M. & Lock, J.P. (1993): Hypermagnesemic pseudo coma. Arch. Intern. Med. 153, 1130-1132.

58. Watson, K.V., Moldow, C.F., Ogburn, P.L. & Jacob, H.S. (1986): Magnesium sulfate: rationale for its use in preeclampsia. Proc. Natl. Acad. Sci. USA, 83, 1075-1078.

59. Nadler, J.L., Goodson, S. & Rude, R. (1987): Evidence that prostacyclin mediates the vascular action in humans. Hypertension 9, 379-383.

60. Mastrogiannis, D.S., Kalter, C.S., O'Brien, W.F., Carlan, S.J. & Reece, E.A. (1992): Effect of MgSO4 on plasma endothelin I levels in normal and preeclamptic pregnancies. Am J. Obstet. Gynecol. 167, 1554-1559.

61. Kemp, P.A., Gardiner, S.M. & Rubin, P.C. (1993): MgSO4 reverses the carotid vasoconstriction caused by endothelin I, angiotensine II and neuropeptide - I, but not that caused by N(G)-nitro-L arginine methyl ester, in conscious rats. Clin. Sci. 85, 175-181.

62a. Nadler, J.L., Buchanan, T., Natarajan, R., Antonipillai, I., Bergam, R. & Rude, R. (1993): Magnesium deficiency produces insulin resistance and increased thromboxane synthesis. Hypertension 21, 1024-1029.

62b. Herzog, W.R., Atar, D., Gurbel, P.A., Vogel, R.A., Schlossberg, M.L. & Serebruany, V.L. (1993): Effect of magnesium sulphate infusion on ex vivo platelet aggregation in swine. Magnes. Res. 6, 349-353.

63. Jolyet, F. & Cahours, M. (1869): Sur l'action physiologique des sulfates de potasse, de soude et de magnésie en injection dans le sang. Arch. Physiol. Norm. Pathol. 2, 113-120.

64. Krendel, D.A. (1990): Hypermagnesemia and neuromuscular transmission. Seminars Neurol. 10, 42-45.

65. Meltzer, S.J. & Auer, J. (1905): Physiological and pharmacological studies on magnesium salts. I. general anesthesia by subcutaneous injections. Am. J. Physiol. 14, 366-368.

66. Choi, W.W., Warner, D.S., Monahan, D.J. & Todd, M.M. (1991): Effects of acute hypermagnesemia on the threshold for lidocaine-induced seizures in the rat. Am. J. Obstet. Gynecol. 164, 693-697.

67. Durlach, J. & Durlach, V. (1992): Deux symposia internationaux en Inde. Rev. Franç. Endocrinol. Clin. 33, 69-72.

68. Katz, A., Kerem, D. & Sherman, D. (1990): MgSO4 suppresses EEG manifestations of CNS oxygen toxicity. Undersea Biomed. Res. 17, 45-49.

69. James, M.F.M. (1992): Clinical use of magnesium infusions in anesthesia. Anesth. Analg. 74, 129-136.

70a. Volpe, P. & Vezu, L. (1993): Intra-cellular magnesium and inositol 1,4,5-triphosphate receptor: molecular mechanisms of interaction, physiology and pharmacology. Magnes. Res. 6, 267-274.

70b. McLean, R.M. (1994): Magnesium and its therapeutic uses: a review. Am. J. Med. 96, 63-76.

71a. Woods, K.L., Fletcher, S., Roffe, C. & Haider, Y. (1992): Intravenous magnesium sulphate in suspected acute myocardial infarction: results of the second Leicester Intravenous Magnesium Intervention (LIMIT-2). Lancet 339, 1553-1558.

71b. Casscells, W. (1994): Magnesium and myocardial infarction. Lancet 342, 807-809.

71c. Woods, K.L. & Fletcher, S. (1994): Long-term outcome after intravenous magnesium sulphate in suspected acute myocardial infarction: the second Leicester Intravenous Magnesium Intervention Trial (LIMIT-2). Lancet 343, 816-819.

72. Rasmussen, H.S. (1993): Justification for magnesium therapy in acute ischaemic heart disease: clinical and experimental studies. Dan. Med. Bull. 40, 84-99.

73. Mass, H., Santoni, F. & Pirazzi, B. (1993): On the use of parenteral magnesium salts in the treatment of acute ischaemic heart disease. Magnes. Res. 6, 275-290.

74a. Donaldson, J.O. (1986): Does MgSO4 treat eclamptic convulsions? Clin. Neuropharmacol. 9, 37-45.

74b. Boston, J.L., Beauchene, R.E. & Cruikshank, D.P. (1989): Erythrocyte and plasma magnesium during teenage pregnancy: relationship with blood pressure and pregnancy-induced hypertension. Obstet. Gynecol. 73, 169-174.

75. Kaplan, P.W., Lesser, R.P., Fisher, R.S., Repke, J.T. & Hanley, D.F. (1990): A continuing controversy: MgSO4 in the treatment of eclamptic seizures. Arch. Neurol. 47, 1031-1032.

76a. Smith, J.-L. G., Burns, P.A. & Schanler, R.J. (1992): Calcium homeostasis in pregnant women receiving long-term MgSO4 therapy for preterm labor. Am. J. Obst. Gynecol. preterm labor. 167, 45-51.

76b. Seydoux, J., Girardin, E., Paunter, L. & Beguin, F. (1992): Serum and intracellular magnesium during normal pregnancy and in patients with pre-eclampsia. Br. J. Obst. Gynaec. 99, 207-211.

77. Belfort, M.A. (1993): Doppler assessment of retinal blood flow velocity during parenteral magnesium treatment in patients with pre-eclampsia. Magnes. Res. 6, 239-246.

78. Chugh, S.H., Kumar, P., Mittal, A., Sharma, A., Chugh, K. & Arora, B. (1993): Magnesium levels and efficacy of magnesium sulphate therapy in acute aluminium phosphide poisoning. In: Health and disease, eds. R. Nath & K.D. Gill, pp. 45-49. New Delhi: Ashish publ..

79. McNamara, R.M., Spivey, W.H., Skobeloff, E. & Jacubowitz, S. (1989): Intra-venous MgSO4 in the management of acute respiratory failure complicating asthma. Ann. Emergency Med. 18, 197-199.

80. Tetikkurt, C., Kocyigit, E. & Disci, R. (1992): Bronchodilating effect of inhaled and intravenous MgSO4 (compared with aerosol terbutaline). Magnes. Res. 14, 49-52.

81a. Johnson, D., Gallagher, C., Canavaugh, M., Yip, R. & Mayers, 1. (1993): The lack of effect of routine magnesium administration on respiratory function in mechanically ventilated patients. Chest 104, 536-541.

81b. De Valk, H.W., Kok, P.T.M., Stuyvenberg, A., van Rijn, H.J.M., Haalboom, J.R.E., Kreukniet, J. & Lammers, J.W.J. (1993): Extracellular and intracellular magnesium concentrations in asthmatic patients. Eur. Respir. J. 6, 1122-1125.

82. Sadeh, M. (1989): Action of MgSO4 in the treatment of preeclampsia-eclampsia. Stroke 20, 1273-1275.

83. Cotton, D.B., Janusz, C.A. & Berman, R.F. (1992): Anticonvulsant effects Of MgSO4 on hippocampal seizures: therapeutic implications in pre-eclampsia-eclampsia. Am. J. Obstet. Gynecol. 166, 1127-1134.

84. Skajaa, K., Forman, A. & Andersson, K.E. (1990): Effects of magnesium on isolated human fetal and maternal uteroplacental vessels. Acta Physiol. Scand. 139, 551-559.

85. Alborch, E., Salom, J.B., Perales, A.J., Torregrosa, G., Miranda, F.J., Alaradi, J.A, & Jover, T. (1992): Comparison of the anticonstrictor effect of dihydropiridine (nimodipine and nicardipine) and Mg2+ in isolated human cerebral arteries. Eur. J. Pharmacol. 229, 83-89.

86. Bohmer, D. & Kreyssel, P. (1993): Influence of magnesium to vasoconstriction caused by hyperbaric oxygenation. Magnes. Res. 6, 408-409.

87. Friedman, S.A., Lim, K.H., Baker, C.A. & Reike, J.T. (1993): Phenytoin versus MgSO4 in pre-eclampsia; a pilot study. AM. J. Perinatal 10, 233-238.

88. Guzman, E.R., Stewart, R., Ivan, J., Pitter, M. & Kappy, K. (1993): Phenytoin and MgSO4 effects on fetal heart rate tracings assessed by computer analysis. Obstet. Gynecol. 82, 375-379.

89. Higby, K., Xenakis, E.M.J. & Pauerstein, C. J.. (1993): Do tocolytic agents stop preterm labor? A critical and comprehensive review of efficacy and safety? Am. J. Obstet. Gynecol. 168, 1247-1259.

90. Martin, R.W., Perry, K. G., Wayne Hess, L., Martin, J.N. & Morrison, J. C. (1992): Oral magnesium and the prevention of preterm labor in a high-risk group of patients. Am. J. Obstet. Gynecol. 166, 144-147.

91. Reinhart. R. (1991): Clinical correlates of the molecular and cellular actions of magnesium on the cardiovascular system. Am. Heart J. 121, 1513-1521.

92. Iseri, L.T., Allen, B.J., Ginkel, M.L. & Brodsky, M.A. (1992): Ionic biology and ionic medicine in cardiac arrhythmias with particular reference to magnesium. Am. Heart J. 123, 1404-1409.

93. Gottlieb, S.S., Fisher, M.L., Pressel, M.D., Patten, R.D., Weinberg, R.N. & Greenberg, N. (1993): Effects of intravenous MgSO4 on arrhythmias in patients with congestive heart failure. Am. Heart J. 125, 1645-1650.

94. Eichhorn, E.J., Tandon, P.K., Dibianco, R., Timmis, G.C., Fenster, P.E., Shannon, J. & Packer, M. (1993): Clinical and prognostic significance of serum magnesium concentration in patients with severe chronic congestive heart failure. J. Am. Coll. Cardiol. 21, 634-640.

95. Fanning, W.J., Thomas, C.S., Roach, A., Tomichek, R., Alford, W.C. & Stoney, W.S. (1991): Prophylaxis of atrial fibrillation with MgSO4 after coronary artery by-pass grafting. Ann. Thor. Surg. 52, 529-533.

96. England, M.R., Gordon, G., Salem, M. & Chernow, B. (1992): Magnesium administration and dysrhythmias after cardiac surgery: a placebo-controlled, double-blind, randomized trial. J.A.M.A. 268, 2395-2402.

97. Sager, P.T., Widerhom, J., Peterson, R., Leon, C., Ryzen, E., Rude, R., Rahimtoola, S. H. & Bhandari, A.K. (1990): Prospective evaluation of parenteral MgSO4 in the treatment of patients with reentrant supraventricular tachycardia. Am. Heart J. 119, 308-316.

98. Viskin, S., Belhassen, B., Sheps, D. & Laniado, S. (1992): Clinical and electrophysiologic effects of MgSO4 on paroxysmal supraventricular tachycardia and comparison with adenosine triphosphate. Am. J. Cardiol., 70, 879-885.

99. Gullestad, L., Birkeland, K., Mostad, P., Hoyer, M.M., Vanberg, P. & Kejksus, J. (1993): The effects of magnesium versus verapamil on supraventricular arrhythmias. Clin. Cardiol. 16, 429-434.

100. Leone, A., Biondo, L., Fabiano, P., Mori, L Bertoncini, G., Battaglia, A. & Bertanneli, F (1993): Low dose lidocaine combined with MgSO4 in warming ventricular arrhythmias. Jap. Heart J. 34, 23-28.

101. Perticone, F., Ceravolo, R., De Novarra, G., Torchia, L. & Cloro, C. (1992): New data on the antiarrhythmic value of parenteral magnesium treatment: magnesium and ventricular arrhythmias. Magnes. Res. 5, 265-272.

102. Rogiers, P., Vermeier, W., Kesteloot, H. & Stroobandt, R. (1989): Effect of the infusion of MgSO4 during atrial pacing on ECG intervals serum electrolytes and blood pressure. Am. Heart J. 117, 1278-1283.

103. Suleiman, M.S. & Chapman, R.A. (1993): Calcium paradox in newborn and adult guinea-pig hearts. Changes in intracellular taurine and the effects of extracellular magnesium. Exp. Physiol. 78, 503-516.

104. Arsenian, M.A. (1993): Magnesium and cardiovascular disease. Prog. Cardiovasc. Dis. 35, 271-310.

105. Homer, S.M. (1992): Efficacy of Intravenous magnesium in acute myocardial infarction in reducing arrhythmias and mortality: meta analysis of magnesium in acute myocardial infarction. Circulation 86, 774-779.

106. Thogersen, A.M., Johnson, O. & Wester, P.O.. (1993): Effects of magnesium infusion on thrombolytic treated patients with acute myocardial infarction. International. Cardiol. 39, 13-22.

107. Galloe, A.M., Rasmussen, H.S., Jørgensen, L.N., Balslov, S., Cintin. C., Graudal, N. & McNair, P. (1993): Influence of oral magnesium supplementation on cardiac events among survivors of an acute myocardial infarction. Br. Med. J. 307, 585-587.

108. Hatashita, S. & Hoff, J.T. (1990): Brain edema and cerebrovascular permeability during cerebral ischemia in rats. Stroke 21, 582-588.

109. Izumi, Y., Roussel, S., Pinard, E. & Seylaz, J. (1991): Reduction of infarct volume by magnesium after middle cerebral artery occlusion in rats. J. Cereb. Blood Flow Metab. 11, 1025-1030.

110. Wolf, G., Keilhoff, G., Fischer, S. & Hass, P. (1990): Subcutaneously applied magnesium protects reliably against quinolate-induced NMDA-mediated neurodegeneration and convulsions in rats: are there therapeutical implications? Neurosci. Lett. 117, 207-211.

111. Wolf, G., Fischer, S., Hass, P., Abicht, K. & Kelhoff, G. (1991): MgSO4 subcutaneously injected protects against kainate-induced convulsions and neurodegeneration: in vivo study on the rat hippocampus. Neuroscience 43, 31-34.

112. Rothe, F., Wolf, G., Fischer, S., Hass, P., Keilhoff, G. & Abicht, K. (1993): Quinolate and kainate facilitate magnesium penetration into brain tissue. Neuro. Report 4, 205-207.

113. Fischer, S., Wolf, G., Kellhoff, G. & Hass, P. (1993): Mg2+ antagonize β(-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid induced brain damage and convulsions. Eur. J. Pharmacol. 232, 121-124.

114. Collery, P., Coudoux, P. & Geoffroy, H. (1982):Magnesium and thrombosis: interrelations with latent tetany, cirrhosis and cancer. In: Nutrition and heart disease, Vol. 21, ed. H.K. Naito, pp. 325-334. New York: S.P. Med. Books.

115. Aldrete, J. A. (1987): Magnesium physiology and pharmacology in anesthesia. Anestesiol. Rev. 14, 33-39.

116. Gambling, D.R., Birmingham, C.L. & Jenkins, L. C. (1988): Magnesium and the anesthesist. Can. J. Anesth. 35, 644-654.

117. Sutton, D.N., Tremlett, M.R., Woodcock, T.E. and Nielsen, M.S. (1990): Management of autonomic dysfunction in severe tetanus: the use of MgSO4 and clonidine. Intensive Care Med. 16, 75-80.

118. Drolet, P. (1993): L'utilisation du sulfate de magnésium pendant la chirurgie du phéochromocytome: à propos de 2 cas. Can J. Anaesth. 40, 521-525.

119. Viskin, S., Belhassen, B. & Laniado, S. (1992): Deterioration of ventricular tachycardia to ventricular fibrillation after rapid intravenous administration of MgSO4. Chest 101, 1445-1447.

120. Fassler, C.A., Rodriguez, R.M., Badesch, D.M., Stone, W.J. & Marini, J.J. (1985): Magnesium toxicity as a cause of hypotension and hypoventilation. Occurrence in patients with normal renal function. Arch. Intern. Med. 145, 1604-1606.

121. Frisch, P.W. & Anders, G. (1991): Uber den Einfluss des Mgs auf die menschliche Blutgerinnung. Magnesium Bull. 13, 10-20.

122. Hankins, G.V.D., Hammond, M.T.L. & Yeomans, E.R. (1991): Amniotic cavity accumulation of magnesium with prolonged MgSO4 tocolysis. J. Reprod. Med. 36, 446-449.

123. Hallak, M., Berry, S.M., Madincea, F., Evans, M.I. & Cotton, D.B. (1993): Fetal serum and amniotic fluid magnesium concentrations with maternal treatment. Obset. Gynecol. 81, 185-188.

124. Holcomb, W.L., Schackelford, G.D. & Petrie, R.H. (1991): Magnesium tocolysis and neonatal bone abnormalities: a controlled study. Obstet. Gynecol. 78, 611-614.

125. Smith, L.G., Burns, P.A. & Schandler, R.J. (1992): Calcium homeostasis in pregnant women receiving long-term MgSO4 therapy for preterm labor. Am. J. Obstet. Gynecol. 167, 45-51.

126. Wester, P.O. (1993): Magnesium and hypertension (abs). Magnes. Res. 6, 83.

127. Clanzer, K. & Stolberg, D. (1993): High doses of oral potassium/magnesium therapy in chronic stable ventricular ectopy (abs). Magnes. Res. 6, 86.

128. Ganguli, M., Tobian, L. & Sugimoto, T. (1990): Deleterious effects of high magnesium diets in hypertensive stroke-prone rats. Magnes. Res. 3, 25-61.

129. Kinnunen, O., Karpanen, H. & Salokannel, J. (1989): Safety and the effects on electrolytes of magnesium hydroxide and a bulk laxative in diuretic treated elderly patients. Magnesium Bull. 11, 68-74.

130. Kinnunen, 0. & Salokannel, J. (1989): Comparison of the effects of magnesium hydroxide and a bulk laxative on lipids, carbohydrates, vitamin A and E and minerals in geriatric hospital patients in the treatment of constipation. J. International Med. Res. 17, 442-454.

131. Gonella, M. & Calabrese, G. (1989): Magnesium status in chronically hemodialysed patients: the role of dialysate magnesium concentration. Magnes. Res. 2, 259-265.

132. Harris, J. C. & Rumack, R.H. (1981): Comparative efficacy of injectable Ca and Mg salts in the therapy of hydrofluoric acid bums. Clin. Toxicol 18, 1027-1032.

133. Steidl, L. & Ditmar, R. (1990): Soft tissue calcification treated with local and oral magnesium therapy. Magnes. Res. 3, 113-119.

134. Brown, P.S., Holland, F.W., Parenteau, G.L. & Clark, R.E. (1991): Magnesium ion is beneficial in hypothermic crystalloid cardioplegia. Ann. Thorac. Surg. 51, 354-367.

135. Ziegler, B., Wilke, B., Woltanski, K.P., Knospe, G. & Hahn, H.J. (1983): Protections of insulin secretion by magnesium during islet culture: independence of cyclic AMP or Insulin accumulation. Exp. Clin. Endocrinol. 82, 199-207.

136. Murakami, M., Ishizuka, J., Sumi, S., Nickols, G.A., Cooper, C.W., Towsend, Jr., C.M & Thompson, J.C. (1992): Role of extra-cellular magnesium in insulin secretion from rat insulinoma cells. Proc. Soc. Exp. Biol. Med. 261, 490-494.


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