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Abstracts of Dr. Durlach's articles


1. Durlach J, Durlach V, Bac P, Bara M, Guiet-Bara. A Magnesium and therapeutics. Magnes Res 1994 Dec;7(3-4):313-28

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.


2. Millart H, Durlach V, Durlach J. Red blood cell magnesium concentrations: analytical problems and significance. Magnes Res 1995 Mar;8(1):65-76

In order to assess total magnesium concentrations in human red blood cells (erythrocytes--ErMg), atomic absorption spectrometry (AAS) provides high accuracy and precise method rapid and amenable to automation. Taking care of eliminating the chronic marginal magnesium deficits, normal values of ErMg evaluated through a direct method and expressed as mmol/litre of packed cells are 2.3 +/- 0.24. Inductively coupled plasma-mass spectrometry (ICP-MS) is a multielemental analytical technique. Particle induced x-ray emission (PIXE) also provides multielemental capability, but is time-consuming and costly. Microelectrodes are the gold standard for intracellular Mg2+ measurements. But microelectrodes and fluorescence probes measure the activity of magnesium ions, not the concentrations. Ionized magnesium content of human intact erythrocyte is mainly assessed with the NMR method and with the zero point titration. The concentration of ionized magnesium as estimated by NMR (31P NMR method) was found to be 0.20 +/- 0.02 mmol/litre cell water and with the zero point titration 0.55 +/- 0.12. The uncertainty concerning the two current used techniques for free magnesium determination is worsened by the fact that magnesium inside red cells continually oscillates in vivo. Free magnesium constitutes a small part of total magnesium. Further studies are necessary to assess the importance of its variations in clinical medicine. Efflux of ErMg is controlled through membranous sodium-dependent and sodium-independent pathways and through genetic and neurohormonal regulations. Variations in the total or ionized ErMg do not necessarily mean that similar changes should exist in the magnesium pool. But it remains the basic static cellular magnesium item. Its value will be subsequently enhanced when it takes place among the clinical and paraclinical data of dynamic magnesium investigations.


3. Rayssiguier Y, Guezennec CY, Durlach J. Editorial policy of Magnesium Research: General considerations on the quality criteria for biomedical papers and some complementary guidelines for the contributors of Magnesium Research. Magnesium Research (1995) 8, 3, 191-206

The quality criteria of biomedical journals--and of 'Magnesium Research' as such--are being given a new insight. This has practical implications for the contributors and the editors.

General considerations on the patterns of evaluation of scientific papers highlight five types of errors, that may be incurred in submitted manuscripts.

1) The information conveyed may remain ambiguous: for example, lack of discrimination between acute and chronic patterns, or confusion between the clinical and toxicological consequences of pharmacological and physiological studies: for example it is a real scientific fraud to identify the absent toxic effects of physiological magnesium supplementation with those of high pharmacological magnesium doses...which in fact may induce toxicity. There should be no confusion between in vitro and in vivo data, with a good understanding of the systemic neuroendocrine metabolic and renal regulations and of the multiple local targets concerned. It is always important to discriminate between the two types of deficit: deficiency due to insufficient intake which merely requires oral physiological supplements and depletion related to a dysregulation which requires more or less specific correction of its causal dysregulation.

2) Insufficient information retrieval, frequently with consultation of one database only. Because of indexing omissions and word usage idiosyncrasies, no literature search can retrieve all papers. Monographs and books of proceedings are rarely mentioned in databases and therefore escape consultation. It is obvious, besides, that some of the quoted references have sometimes not been read, but only the title (and in the best cases also the abstract), occasionally with the remaining misprints. A good specific and general knowledge of the background of the study is necessary.

3) Basic methodological errors. Coexistence does not mean causality. Analogous patterns do not demonstrate an identical aetiopathogenesis. The complexity of biology must not be disregarded just because the present trend focuses on one aspect of knowledge at the expense of many others.

4) Thought processes must be unbiased. Citation of supportive papers to the prejudice of unsupportive constitutes a real ethical fraud. It seems also very important to submit for publication papers with negative results as well as ones with positive results. In studies on pharmacological indications for magnesium, choice of the magnesium salt used ought to be justified and the efficiency must be evaluated vs reference treatment.

5) Observance of the formal regulations is frequently neglected, in the presentation of manuscripts particularly.

Some guidelines should therefore be added to the directions to contributors. Before establishing valuable protocols and in order to write up well structured introductions, discussions and conclusions, the authors should have a comprehensive view of their subjects, that is to say an overall knowledge of the previous general and specific publications related to the topic which must be read. Title, conclusions and abstract ought to be informative and unequivocal. Both supportive and unsupportive data should be taken into account in the discussion. References should be duly consulted or mentioned as 'cited in'. There should be strict observance of the presentation of the manuscripts according to the directions to contributors. Studies resulting in negative results should not be disregarded. Reciprocally, the editorial policy requires that editors and referees ought to be strict as regards the quality criteria. Although editors and peer reviewers are in no position to detect basic fraud they can, however, highlight errors, whether due to simple oversight or to more subtle ethical or scientific pseudo-frauds. Both conclusive and inconcern papers may deserve publication: positive and negative results equally concern public health.

To conclude, the editorial board must be ready to reject dubious manuscripts but must at the same time keep their minds open to consider in a positive light innovative papers. But all opinions may be discussed and the letter to the editor allows permanent debating.


4. Bara M, Guiet-Bara A, Durlach J. Comparative effects of MgCl2 and MgSO4 on the ionic transfer components through the isolated human amniotic membrane. Magnes Res 1994 Mar;7(1):11-6

The effects of MgCl2 and MgSO4 are different on the total transfer through the human amniotic membrane: MgCl2 at low concentration (1 mM) decreases the total conductance Gt and increases it at high concentration (4 mM) on the fetal side (FS) and on the maternal side (MS), while MgSO4 has no effect on the MS and increases Gt on the FS. Moreover, whatever the concentration, MgCl2 increases the flux ration F1/F2 while MgSO4 decreases it to reach a value near to 1. Gt is the sum of various components: three paracellular components (Gp) and nine cellular components (Gc constituted from channels, exchangers, antiporters and cotransporters). All components of Gt, on the two faces, are decreased by 1 mM MgCl2 and increased at 4 mM. MgCl2 also has an effect on all ionic exchangers across the membrane. In contrast, on the MS, MgSO4 (1 mM) decreases GpNa, increases GpK and the antiport Na/H component and has no effect on any of the other components, while at 4 mM, MgSO4 has no effect. On the FS, MgSO4 (1 mM) increases GpNa and GpK, but does not modify the other components. At 4 mM, the effect is the same, except for an increase of GpCl. These data show the importance of the anion-cation association in the ionic exchanges through a membrane: MgCl2 and MgSO4 have a different action--MgCl2 interacts with all the exchangers, while the effect of MgSO4 is limited to paracellular components without interaction with cellular components excepted the antiport Na/H.


5. Durlach J. Present and future of magnesium research. Journal of Japanese Society for Magnesium Research 1993, 12, 2:113-135

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.


6. Durlach J, Durlach V, Bac P, Rayssiguier Y, Bara M, Guiet-Bara A. Magnesium and ageing. II. Clinical data: aetiological mechanisms and pathophysiological consequences of magnesium deficit in the elderly. Magnes Res 1993 Dec;6(4):379-94

Ageing constitutes a risk factor for magnesium deficit. Primary magnesium deficit originates from two aetiological mechanisms: deficiency and depletion. Primary magnesium deficiency is due to insufficient magnesium intake. Dietary amounts of magnesium are marginal in the whole population whatever the age. Nutritional deficiencies are more pronounced in institutionalized than in free-living ageing groups. Primary magnesium depletion is due to dysregulation of factors controlling magnesium status: intestinal magnesium hypoabsorption, reduced magnesium bone uptake and mobilization, sometimes urinary leakage, hyperadrenoglucocorticism by decreased adaptability to stress, insulin resistance and adrenergic hyporeceptivity. Secondary magnesium deficit in ageing largely results from various pathologies and treatments common to elderly persons, i.e., non-insulin dependent diabetes mellitus and use of hypermagnesuric diuretics. Magnesium deficit may participate in the clinical pattern of ageing, particularly in neuromuscular, cardiovascular and renal symptomatologies. The consequences of hyperadrenoglucocorticism-the simplest marker of which is non-response to the dexamethasone suppression test-may include immunosuppression, muscle atrophy, centralization of fat mass, osteoporosis, hyperglycaemia, hyperlipidaemia, atherosclerosis, and disturbances of mood and mental performance through accelerated hippocampal ageing particularly. It seems very important to point out that magnesium deficit and stress aggravate each other in a true 'pathogenic vicious circle', particularly in the stressful state of ageing. The importance of magnesium deficit in the aetiologies of insulin resistance, and the adrenergic, osseous, oncogenic, immune and oxidant disturbances of ageing is still uncertain. Oral physiological magnesium supplementation (5 mg Mg/kg/d) is the best diagnostic tool for establishing the importance of magnesium deficiency. Too few open and double blind studies on the effects of the treatment of magnesium deficiency and of magnesium depletion in geriatric populations have been done. Further study is necessary to assess the true place of magnesium deficit in the pathophysiology of ageing.


7. Durlach J. Death from infancy to older age and marginal maternal magnesium deficiency. How long should the follow-up of the consequences of undernutrition in pregnancy be continued? Magnesium Research (1993) 6, 3, 297-298

Higher incidence rates of sudden infant death syndrome (SIDS) have been observed in infants of diminished birth weight. Several analytical studies, for example the NICHD cooperative study (1) controlling a variety of confounders of birth size have estimated the likelihood of SIDS deaths in relation to the four variables of birth size: birth weight, birth length, head circumference and gestational age. SIDS may be associated with symmetrical intrauterine growth retardation because of reduction in both birth weight and length even after controlling for gestational age and sex of the infant. This suggests that mechanisms responsible for growth retardation in this situation begin early in pregnancy (1). Various subtle morphological differences between SIDS and controls support the notion of early intrauterine injury as playing some part in the genesis of SIDS (2).


8. Goubern M, Rayssiguier Y, Miroux B, Chapey MF, Ricquier D, Durlach J. Effect of acute magnesium deficiency on the masking and unmasking of the proton channel of the uncoupling protein in rat brown fat. Magnes Res 1993; 6:(2) 135-143

The short term regulation of heat production in brown adipose tissue mitochondria (BAT) of acutely Mg-deficient rats was demonstrated by comparing several parameters of mitochondrial energization. Mg deficiency in vivo had absolutely no effect on the BAT uncoupling protein concentration (UCP) which was only modified by thermal conditions. The same high concentration was observed 10 d cold exposed control and Mg-deficient rats. Four days of warm re-exposure at thermal neutrality led to a moderate 26 per cent decrease with both diets which was not modified by cold stress for 1 h. Proton conductance. CmH+, and proton motive force, delta p, were calculated from membrane potential and respiration rate measurements. The same high level CmH+ was observed in cold exposed rats with both diets. Compared to warm re-exposed control rats, CmH+ was threefold higher in the corresponding Mg-deficient group which indicated a much lower masking of the proton channel of UCP with the Mg-deficient diet. This difference was not dependent on the presence of magnesium in vitro. The basal CmH+, independent of UCP, was not altered by magnesium deficiency. These results emphasize that acute regulation of thermogenic BAT activity through the masking and unmasking process is altered when magnesium supply is limited in vivo.


9. Bara M, Guiet-Bara A, Durlach J. Regulation of sodium and potassium pathways by magnesium in cell membranes. Magnes Res 1993 Jun;6(2):167-77

Magnesium plays an important role in a large number of cellular processes by acting as a cofactor in enzymatic reactions and transmembrane ion movements. Magnesium is a modulator of Na,K ion transport systems in numerous tissues. In this study, the interactions between magnesium and Na,K pathways are described. In the paracellular pathway, Na,K transports are generally increased by Mgo. In the cellular pathway, there are various processes: (1) Potassium channels-Mgi blocks the outward currents, first by interfering with the passage of K+ ions and inducing rectification of the channel current-voltage relationship, and secondly by completely blocking the channel pore and reducing the channel open probability: Mgo increases the K+ channel permeability in a leaky membrane. (2) Sodium channels-Mgi blocks outward currents in a voltage- and dose-dependent manner, acts as a fast blocker by screening of surface charges, and produces an open channel block in several Na+ channels; Mgo increases Na+ transport in toad bladder and human amnion at high concentration by acting on the driving force of the sodium pump. (3) Na/K pump-Mgi and Mgo stimulate the Na/K exchange at low concentration and inhibit it at high concentration, by a stabilization of E2 forms of the enzyme which would reduce the rate of turnover of the pump. (4) Na-K-2Cl cotransport increasing Mgo concentration stimulates this system in red cells and human amnion, and the bumetadine-sensitive K+ transport is sensitive to Mgi (5) Kcl cotransport-The increase in Mgi inhibits this cotransport. (6) Na-H antiport-Na/H exchange responds to manipulations of cell magnesium but the effect is probably not a direct one; magnesium is required not for the transport process per se, but for the transduction of the volume stimulus (7) H-K pump Mg activates this system. (8) Na-Ca antiport-The activity of this antiporter is inhibited by Mgo; the inhibition by magnesium is competitive with calcium. (9) Na-Mg exchange-in this system, the Na+ gradient provides the energy for net Mg2+ extrusion. In conclusion, intracellular and extracellular magnesium may be an important physiological regulator of the sodium and potassium pathways in the cell.


10. Bac P, Herrenknecht C, Binet P, Durlach J. Audiogenic seizures in magnesium-deficient mice: effects of magnesium pyrrolidone-2-carboxylate, magnesium acetyltaurinate, magnesium chloride and vitamin B-6. Magnes Res 1993 Mar;6(1):11-9

Magnesium deficiency in mice causes and increases audiogenic seizures. This effect was reversed by oral administration of magnesium acetyltaurinate (ATaMg), magnesium pyrrolidone-2-carboxylate (PCMH), MgCl2. When treatment was discontinued, audiogenic seizures recurred only in the groups treated with PCMH or MgCl2. Following intraperitoneal administration of AtaMg, the mice were protected against audiogenic seizures after 4 h and this protection persisted for up to 72 h after the treatment. With the other magnesium salts (PCMH and MgCl2) maximum protection occurred by 6 h after the injection, but after that time the number of seizures increased sharply. Intraperitoneal taurine alone only reduced the severity of the audiogenic seizures. The length of treatment needed to inhibit audiogenic seizures was reduced by treatment with a combination of vitamin B-6 (a magnesium fixing agent) and PCMH or MgCl2. However this combination of vitamin B-6 and magnesium salts did not prevent the recurrence of audiogenic seizures, which was only achieved by ATaMg. The results suggest that audiogenic seizures in magnesium-deficient mice form a model of magnesium depletion. This depletion is completely inhibited by the combination of an inhibitory neurotransmitter (taurine) and magnesium, in the form of magnesium acetyltaurinate.


11. Rayssiguier Y, Gueux E, Bussiere L, Durlach J, Mazur A. Dietary magnesium affects susceptibility of lipoproteins and tissues to peroxidation in rats. J Am Coll Nutr 1993 Apr;12(2):133-7

Magnesium (Mg)-deficient and control diets were pair-fed to weanling Wistar rats for 8 days. Plasma lipoproteins were separated into various density classes by sequential preparative ultracentrifugation. The extent of lipid peroxidation was measured in terms of thiobarbituric acid reactive substances in lipoproteins and tissue homogenates before or after iron-induced lipid peroxidation. Hyperlipemia in Mg-deficient rats was accompanied by increased oxidation of very-low-density lipoproteins and low-density lipoproteins. Moreover, very-low-density lipoproteins and high-density lipoproteins from Mg-deficient rats were more susceptible to oxidative damage following iron incubation. Mg deficiency increased lipid peroxidation in liver, heart and skeletal muscles. Their homogenates were more susceptible to in vitro peroxidation. Mg deficiency has been discussed as a possible contributory factor in the development of cardiovascular disease and was associated with tissue damage and membrane alteration. These results demonstrate for the first time that Mg affects the susceptibility of lipoproteins to peroxidation and suggest that the mechanism responsible for the pathological consequences of Mg deficiency may be mediated by lipid peroxidation products.


12. Durlach J, Durlach V, Rayssiguier Y, Bara M, Gueit-Bara A. Magnesium and blood pressure. II. Clinical studies. Magnes Res 1992 Jun;5(2):147-53

Magnesium deficit may be considered as a cardiovascular risk because of its aetiopathogenic role in the genesis of atherogenous dyslipidaemias and the so-called "idiopathic" mitral valve prolapse. It does not, however, constitute a major antihypertensive factor, though it may sometimes be an accessory co-factor. Plasma magnesium is generally normal in untreated hypertensive patients and normotension is the rule during magnesium deficit. An inverse relationship between magnesium and renin in the plasma of hypertensives has not been confirmed. In practice, plasma magnesium seems to be related to the evolution of the disease. An inverse correlation between blood pressure and erythrocyte total and free magnesium levels has been observed in diverse selected populations but no adjustment has been made in these studies for important covariables. A weak positive association between blood pressure and erythrocyte free magnesium was lost in a multivariate regression analysis. As a rule there is no difference between erythrocyte, leucocyte, and lymphocyte magnesium in hypertensives and controls. More often no relation between urinary magnesium and blood pressure is observed. Daily urine magnesium may be increased with increased excretion of urine adrenaline. Epidemiological data on dietary magnesium, particularly in drinking water, should be carefully scrutinized: these studies do not establish a major role for magnesium as an antihypertensive factor but confirm the importance of magnesium deficit as a nephrocardiovascular risk factor and sometimes gives support for a role of magnesium as an antihypertensive cofactor. The use of magnesium-depleting drugs in hypertensive patients may induce magnesium depletion which must be palliated. In none of the double blind placebo-controlled studies of magnesium therapy in hypertensive patients was a significant fall in systolic or diastolic blood pressure observed. Monotherapy with oral magnesium cannot be considered as an efficient treatment of hypertension or be used as a substitute for drugs of proven efficacy. However, in some hypertensive patients with magnesium deficit, its deleterious effects on the nephrocardiovascular apparatus must be controlled. The well known pharmacological hypotensive action of parenteral magnesium may be used in hypertensive patients --in pre-eclampsia particularly--but the pharmacological mechanisms are observed irrespective of magnesium status. Such effects should not beused as a diagnostic tool in the investigation of magnesium deficit.


13. Durlach J, Durlach V, Rayssiguier Y, Bara M, Guiet-Bara A. Magnesium and the cardiovascular system: II. Clinical data. A critical review. In: Molecular biology of atherosclerosis. Proceedings of the 57th European Atherosclerosis Society Meeting. Edited by MJ Halpern. John Libbey & Company Ltd. Ch 114, pp 513-521.

Magnesium is an important factor in physiology of the cardiovascular apparatus, and the pathogenesis of cardiovascular diseases. However several methodological errors are definitely misleading. Extrapolation from pharmacological effects to physiological properties is obviously erroneous. Many papers consider as a proof of the importance of magnesium deficit in the pathogenesis of cardiovascular diseases the effects of parenteral magnesium or of high oral doses of magnesium (greater or equal to 2 Mg RDA, i.e. 12mg/kg/d) which are only pharmacological data. The physiological properties of magnesium can only be demonstrated by the occurrence of symptoms due to in vivo magnesium deficiency subsequently followed by its specific control with supplementation through physiological oral doses of magnesium (usually 5 mg/kg/d, always less than 2 Mg RDA, i.e. 12 mg/kg/d)(1,2,3). The physiopathological role of magnesium deficit is shown by the parallel correction of this magnesium deficit and of its related symptomatology.

Control of magnesium deficit depends on the nature of the magnesium deficit(1,2). The difference between magnesium deficit, magnesium deficiency and magnesium depletion should not be overlooked. In the case of magnesium deficit it is very important to distinguish between magnesium deficiency where the disorder corresponds to an insufficient magnesium intake and which merely requires simple oral physiological magnesium supplementation, and magnesium depletion where the disorder is related to a dysregulation of the control mechanisms of magnesium metabolism and which requires appropriate correction(1,2).

The main expression of primary magnesium deficit is closely linked with the consequences of long term chronic magnesium marginal deficiency. Experimental and clinical forms of chronic magnesium deficiency are better and better identified and differ from overt signs of acute deficiency(1,2,3).

Coexistence of a symptomatology and a marker of magnesium deficit even though it was correlated should not be mistaken for a causality link. Parallel control of both is necessary to prove this connection. This shows the importance of the magnesium oral loading test(1,4,5). At a physiological dose level (5 mg/kg/day) of a well absorbed salt for at least 1 month, oral magnesium is totally devoid of the pharmacodynamic effects of parenteral magnesium. Correction of biological and clinical symptoms checked after 1 month constitutes the best proof that these were due to magnesium deficiency. Reversely it is ineffective in magnesium depleted patients(1,6,7,8,9). The more delicate diagnosis of magnesium depletion rests on the control of the magnesium metabolism dysregulating factors(1,4,5).

We will firstly discuss epidemiological data, secondly the role of magnesium deficit in cardio-vascular risk, its correlation with blood pressure and dyslipidaemias particularly, lastly its role in the physiopathology of some cardio-vascular diseases.


14. Poenaru S, Aymard P, Durlach J,Manicom R, Poenaru L, Rouhani S, Rayssiguier Y, Emmanouilidis E, Gueux E, Nkanga N, Soulairac A. Regional distribution of magnesium in the cerebral tissues in normal and magnesium deficient rat. Magnesium Research 1991, 4, 3/4, 246.


15. Durlach J, Durlach V, Rayssiguier Y, Ricquier D, Goubern M, Bertin R, Bara M, Guiet-Bara A, Olive G, Mettey R. 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 1991 Sep-Dec;4(3-4):137-52

The sudden infant death syndrome (SIDS) remains a leading cause of death during the first year. The common epidemiological and pathological data which characterize SIDS include the curve for age at death (with 3 months as modal age), the stigmata of early maternal intrauterine injury, the seasonal predominance in winter, and the absence of an adequate cause of death at autopsy. Some data characterize risk factor subgroups: for example low socioeconomic level, environmental pollution, stress, and mistakes in baby care. Symptoms before death may be lacking, they may be common and non-specific, or rarely they may be acute, corresponding to apparent life-threatening events (ALTE). SIDS may be a magnesium-dependent disease of the transition from chemical to physical thermoregulation. This theory originates from a synthesis of our present knowledge of SIDS, maternal magnesium status, and thermoregulation in the baby. It is consistent with all the epidemiological and pathological prerequisites characterizing SIDS. It eliminates the hiatus between relatively minor thermal stress and induced lethal thermal stroke. Logical scepticism about the role of an implausible lethal superacute magnesium deficiency is no longer justified with regard to well established chronic marginal magnesium deficiency. Further experimental and clinical research will be interesting, i.e. ex vivo studies on brown adipose tissue (BAT) and magnesium deficiency under various conditions of thermal exposure. But even now the theory leads to three therapeutic consequences: (1) the need to define the importance of magnesium deficiency in diagnosis and treatment of ALTE; (2) an assessment of the use of new techniques of rewarming (i.e. extracorporeal circulation) in hypothermia cases to distinguish cot death from apparent death; (3) investigation of the prevention of SIDS with magnesium through a blinded and randomized multicentre prospective cooperative study of magnesium supplementation in pregnant and lactating women, followed not only in the mother, fetus, and neonate at birth, but also through the first year of life.


16. Durlach J. Magnesium depletion and pathogenesis of Alzheimer's disease. Magnesium Research (1990) 3, 3, 217-218

Mg depletion, particularly in the hippocampus, appears to represent an important pathogenic factor in Alzheimer's disease. It is associated with high aluminium incorporation into brain neurones. This type of Mg deficit cannot respond to mere Mg supplementation, but requires correction of the dysregulation inducing this Mg depletion. Further research should seek to control the alterations of albumin, which may induce this brain Mg depletion.


17. Durlach J. Magnesium and Its Relationship to Oncology. In Metal ions in biological systems. Vol. 26. Compendium on magnesium and its role in biology, nutrion and physiology H. Sigel and A. Sigel, eds Marcel Dekker Inc. New York-Basel 1990: 744 p.

Relationships between magnesium and cancer are complex: both Mg load and Mg deficit may produce either carcinogenic or anticarcinogenic effects. Carcinogenesis modifies the Mg status inducing Mg distribution disturbances which may frequently associate a tumor Mg load with Mg depletion in nonneoplastic tissues (1-3).

The aim of this chapter is first to review the consequences of the cancerous state on Mg metabolism and those of the disturbances of Mg status on carcinogenesis, to analyze the cellular and systemic bases of these relations, and to appreciate their theoretical and practical implications. We will then present some new personal data on the membranous relationship between magnesium and various anticancer or carcinogenic agents. We will attempt as a conclusion to show how these data may bring about new promising developments in cancer research as well as in Mg and anticancer treatment.


18. Rayssiguier Y, Guezennec CY, Durlach J. New experimental and clinical data on the relationship between magnesium and sport. Magnes Res 1990 Jun;3(2):93-102

Exercise under certain conditions appears to lead to Mg depletion and may worsen a state of deficiency when Mg intake is inadequate. Whereas hypermagnesaemia occurs following short term high intensity exercise as the consequence of a decrease in plasma volume and a shift of cellular magnesium resulting from acidosis, prolonged submaximal exercise is accompanied by hypomagnesaemia. Discordant findings on the effect of physical exercise on erythrocyte concentrations have been reported. A mechanism for the observed decrease in plasma magnesium concentration after long term physical exercise could be a shift of Mg into the erythrocyte. However, in several studies the decrease in plasma Mg was not accompanied by an increase in RBC Mg, but a decrease in cellular Mg was observed. Urinary Mg losses during an endurance event could play a role in this depletion but are often reduced, reflecting renal compensation. Loss of Mg by sweating takes place only when there is a failure in sweat homeostasis, a situation which arises when exercise is made in conditions of damp atmosphere and high temperature. Stress caused by physical exercise is capable of inducing Mg deficit by various mechanisms. A possible explanation for decreased plasma Mg concentration during long endurance events is the effect of lipolysis. Since fatty acids are mobilized for muscle energy, lipolysis would cause a decrease in plasma Mg. In developed countries Mg intake is often marginal and sport is a factor which is particularly likely to expose athletes to Mg deficit through metabolic depletion linked to exercise itself, which can only aggravate the consequences of a frequent marginal deficiency. Mg depletion and deficiency therefore play a role in the pathophysiology of physical exercise. Experiments on animals have shown that severe Mg deficiency reduces physical performance and in particular the efficiency of energy metabolism. These data, however, do not correspond to those of marginal deficiency most commonly observed in humans. Clinical symptomatology, both in athletes and in other patients, is dominated by the symptomatology of neuromuscular hyperexcitability. Medical authorities in sport have enforced obligatory tests for latent tetany in athletes, with ionic assessment. The effects of the correction of magnesium deficiency are judged from clinical signs, Chvosteck sign, electromyogram and echocardiogram findings and plasma Mg, erythrocyte and urine analysis. These may also be complemented by cardiac and respiratory investigations after exercise. The positive effects (analysis after a minimum period of one month) of a simple oral supplement administered in physiological doses (5 mg/kg body weight/day) provides evidence for the existence of a deficiency.(ABSTRACT TRUNCATED)


19. Kubena KS, Durlach J. Historical review of the effects of marginal intake of magnesium in chronic experimental magnesium deficiency. Magnes Res 1990 Sep;3(3):219-26

After the discovery of magnesium as an essential nutrient in 1926, research focused upon the identification of effects of an acute deficiency state and determination of the requirement for the mineral for normal growth and reproduction. In this early work, marginal intakes of magnesium were reported to result in alterations of tissue composition. Since the 1970s, research has shown that the ability to adapt to a marginal intake of magnesium, which is commonplace in developed countries, is limited. In fact, a low intake of the mineral for an extended period of time may be associated with abnormalities in reproduction, growth, and development and may be a factor in the pathogenesis of disorders of neuromuscular, cardiovascular, renal, and immune function. Problems related to the use of pharmacological agents or to trace metals, such as aluminium, may be worsened in the presence of a low intake of magnesium. Evidence presented illustrates that, although physical signs of magnesium deficiency may be absent, that is to say in cases of latent clinical forms, a marginal dietary inadequacy of the mineral over a long period of time could result in significant problems.


20. Bara M, Guiet-Bara A, Durlach J. A qualitative theory of the screening-binding effects of magnesium salts on epithelial cell membranes: a new hypothesis. Magnes Res 1989 Dec;2(4):243-8

A theoretical explanation is given of the screening-binding effects of various magnesium salts on the ionic permeability of epithelial amniotic cell membranes. It is suggested that the 'screening process' induces an increase in the electrical membrane resistance and in membrane stability which is a unique action at low concentration. At high concentration, the binding process induces a reduction or an increase in these parameters as a function of the magnesium salt present. The different effects are due to changes in the distribution and in the repartition of the fixed charges on the cell membrane.


21. Durlach J. Recommended dietary amounts of magnesium: Mg RDA. Magnes Res 1989 Sep;2(3):195-203

In developed countries, the recommended dietary amounts of magnesium have been set at 6 mg/kg day. The magnesium requirements for optimal health in the adult population depend on mesological and constitutional conditioning factors. They may intervene at every stage of magnesium metabolism: absorption, circulation, storage and excretion. The influence of other nutrients is more significant on magnesium absorption than on urinary excretion. Among the multiple interactions it is important to emphasize the maintenance of a Ca/Mg ratio close to 2 in the intake. Magnesium deficit and stress reinforce each other in a pathogenic vicious circle. The Bw35 allele of HLA typing and behavioural type A discriminate two constitutional factors increasing magnesium requirements. The effective passive regulatory mechanism for magnesium overload, the lability of the active regulatory mechanisms for magnesium deficit and the considerable need for exchangeable magnesium are factors which attribute special importance to balance studies in determining the magnesium intake which prevents negative magnesium balance and magnesium deficiency.

Marginal primary magnesium deficit affects a large proportion of the population (15 to 20%), in keeping with a daily mean magnesium intake slightly over 4 mg/kg day versus the Mg RDA of 6 mg/kg day. A physiological oral magnesium load test, evaluated through non-specific and specific clinical and paraclinical items, constitutes the best proof that the clinical pattern depends on an insufficient magnesium intake, confirmed after one month of supplementation. Further research appears necessary. It would be advisable to carry out long-term magnesium balance studies in European countries on the self-selected diets of adults, together with comparisons of direct evaluation of magnesium in the diet with data obtained from tables of food composition. Magnesium intervention trials should be planned to determine whether magnesium supplements decrease the pathogenic consequences of magnesium deficit and particularly to evaluate the efficiency of magnesium supplements in latent tetany (hyperventilation syndrome, "idiopathic" Barlow's disease). Supplementation should consist of a high magnesium density nutrient such as magnesium in water, which has better bioavailability than magnesium-fortified foods.


22. Durlach J, Bara M, Guiet-Bara A. Magnesium level in drinking water: its importance in cardiovascular risk. In: Magnesium in Health and Disease. Y. Itokawa and J. Durlach eds. John Libbey. London, 1989; 173-182.

Of all the cardiovascular risk factors, magnesium now takes first place as judged by the accumulation of epidemiological, pathophysiological, clinical and experimental data, both pharmacological and therapeutic. The "water story" began in 1957 when, after observing a geographical correlation between stroke-associated mortality and river water acidity Kobayashi inferred a possible relationship between the composition of drinking water and cardiovascular diseases. Schroeder checked the validity of the Japanese data statistically and then examined the implications of the phenomenon in the USA. He suggested an inverse relationship between various types of heart diseases and drinking water hardness: drinking soft water increases cardiovascular risk and this effect is reciprocally reduced by hard water consumption (23-26). Numerous studies in all the continents have been devoted to this negative correlation with hardness, involving many statistical units of observation (states, districts, towns), diversification of causes of mortality (general, cardiac, vascular) and multiplications of observed variables (climatic and geographical factors, analytical data on water). This inverse relationship has been confirmed in the majority of the studies and in particular in those done on the largest geographical scale. However, the variable relating to water hardness cannot be considered a constant risk since in some studies its effect may be completely absent, the statistical significance of the other ecological variables involved in the water story should not be underestimated (23-26, 34), and other confounding aetiological and atmospheric co-factors (ie amount of rainfall, salt-consumption) which are associated with hardness may play a role. However the most important aim must be to define clearly the factors in drinking water which may be involved in maintaining the cardiovascular apparatus in satisfactory condition. It is therefore necessary to have an accurate definition of hardness. Hardness is defined by hydrotimetry, ie a measurement which determines the presence of encrusting properties which antagonize vegetable cooking and soap lathering. The bulk of total hardness is made up by Ca and Mg compounds but in some areas salts of other metals are also present in significant amounts : Al, Ba, Fe, Mn, Sr. Carbonate (or temporary) hardness denotes the proportion of hardness chemically equivalent to the concentration of carbonate-bicarbonate and is thus an index of water alkalinity and buffer capacity. Non carbonate (or permanent) hardness denotes the proportion of hardness attributable to anions such as sulphate or chloride (9, 20, 41, 54). The variables involved in hardness are of three types: (1) Several metals, but mainly Ca and Mg determining total hardness; (2) The buffer capacity and alkalinity of CO3H-CO3 in carbonate hardness; (3) In non carbonate hardness, some of the numerous factors involved in the aggressive and mainly corrosive properties of the water, such as SO4-2 and Cl- (20, 41). The beneficial and deleterious effects of the multiple macro and trace cations and anions concerned in the measurement of water hardness should be assessed first on the basis of their own properties, then through their reciprocal interactions with Mg (23-26, 54). These water factors only need to be taken into account when they represent quantitatively a significant part of the Recommended Dietary Allowances or if, qualitatively, they constitute a higher bioavailable intake.


23. --


24. Rayssiguier, Y., Gueux, E., Durlach, V., Durlach, J., Nassir, E., Mazur, A. Chapter 113, Magnesium and the cardiovascular system: I. New experimental data on magnesium and lipoproteins.Molecular biology of atherosclerosis, Proceedings of the 57th European Atherosclerosis Society Meeting. Edited by M.J. Halpern. © John Libbey & Company Ltd, pp. 507-512.

Systematic intervention studies in humans that document a cause-effect relationship between Mg status and atherosclerosis have not yet been performed. With this reservation in mind, the following discussion will examine indirect evidence in experimental animals that will strongly suggest a role of magnesium in the aetiology of dyslipidaemia and atherosclerosis.


25. Durlach, J., Durlach, V., Bara, M., Guiet-Bara, A. Part Five, Chapter 1, Section B. Diverse Applications of Magnesium Therapy.

I. INTRODUCTION

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 or for its sedative and antispasmodic properties parenterally.

Today, constantly increasing knowledge of the clinical forms of magnesium deficit in human beings (Durlach, 1988) has made it possible to know under which circumstances and in what ways chronic primary magnesium deficiency can be remedied 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 ameliorate insufficient magnesium intakes. Their indications rest on well-founded epidemiological trials (Durlach et al., 1992a).

Conversely, parenteral 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 (Durlach, 1988).

In this review of the diverse applications of magnesium therapy, we will successively consider:

(i) The uses of physiological oral magnesium - the main form of magnesium therapy involving, first and foremost, an adequate knowledge of the sole indication of chronic magnesium deficiency. The technique of oral physiological magnesium supplementation will be analyzed.

(ii) The indications for, and techniques of, several pharmacological applications of magnesium:

As a conclusion, we will contrast the dangers of using the pharmacological properties of iatrogenic magnesium overload with the atoxicity of oral magnesium supplementation at physiological doses palliative of magnesium deficiencies.


26. M. Bara, A. Guiet-Bara, P. Moretto, L. Razafindrabe, Y. Llabador, M. Simonoff, J. Durlach Bara, M., Guiet-Bara, A., Moretto, P., Razafindrabe, L., LLabador, Y., Simonoff, M., Durlach, J. Nuclear microanalysis of the monovalent ion distribution in the human amnion. I. Effect of magnesium Magnesium Research (1995) 8, 3, 207-214

Summary: The effect of the addition of MgCl2 on the Na+, K+, and Cl- concentration and distribution in epithelial and compact layers of the human amniotic membrane was investigated using the Bordeaux nuclear microprobe. Particle-induced X-ray emission and Rutherford backscattering spectrometry techniques were used to provide quantitative measurements. In physiological medium (Hanks' solution), the monovalent ion concentrations were identical in both layers. The addition of Mg2+ ions in Hanks' solution induced a decrease of, K+, and Cl- concentration in both layers and Na+ concentration in the compact layer. The results obtained from nuclear microanalysis might be explained from electrophysiological data which indicate that the addition of Mg2+ ions results in an increase in the cellular, paracellular and exchanger ion pathways.


27. Durlach, J.Commentary on recent clinical advances: Magnesium depletion, magnesium deficiency and asthma Magnesium Research (1995) 8, 4, 403-405

To sum up, the dramatic decrease in pn Mg observed in two thirds of the cases of an asthmatic group constitutes a marker or a pathophysiological factor in these particular cases. The mechanism of this magnesium depletion being unknown, it does not involve any therapeutic consequences for the time being. Conversely, when chronic primary magnesium deficiency coexists with asthma it constitutes a decompensatory factor whose control with simple oral physiological magnesium supplementation must help in asthma therapy.


28. Durlach, J., Durlach, A., Durlach, V. Commentary on recent epidemiological and clinical advances:Antioxidant dietary status and genetic cardiovascular risk, or how an adequate intake of a-tocopherol, selenium, taurine, magnesium and various other natural antioxidants may overcome the deleterious metabolic consequences related to the E4-4 type of apolipoprotein E Magnesium Research (1996) 9, 2, 139-141

To sum up, when a genetic risk factor linked with the Apo E 4-4 genotype is involved in hypercholesterolaemia, its harmful effects can be counteracted by nutritional means. The low cardiovascular mortality observed in the Lapp group does not seem to be connected with the type of dietary fats they consume, since lowering the total fat and cholesterol intake and increasing the polyunsaturated/saturated fat ratio is ineffective10,11. It seems, rather, to be related to a rich natural antioxidant intake14. Since we can hardly found our staple diet on reindeer meat and a daily fish catch, we may at least try to prevent such dyslipidaemias not only by a larger intake of vitamin E, selenium, taurine and magnesium14-17,19-21 but also with numerous other natural vitamin, metabolic and mineral antioxidants15,16,23,24 that are equally important in nutritional prophylaxis of atherosclerosis.


29. Ibrahim, B., Guiet-Bara, A., Leveteau, J., Challier, J.C., Vervelle, C., Durlach, J., and Bara, M. Contribution to the physiology of the human placental vessels: effects of Mg2+ on membrane potential of smooth muscle cell vessels Current Research in Magnesium edited by M.J. Halpern and J. Durlach (1996) John Libbey & Company Ltd./7th International Magnesium Symposium, pp. 197-198

A wide range of data has been collected concerning the effect of extracellular magnesium ions on the blood vessel smooth muscle tone and reactivity. The aim of the present study was to contribute to the physiology of the human placental vessels, investigating the influence of magnesium ions (MgCl2 and MgSO4) on membrane potential of the smooth muscle cells of the human placental chorionic arteries with endothelium and without endothelium (endothelium-free).


30. Durlach, J., and Bac, P. Mechanisms of Action on the Nervous System in Magnesium Deficiency and Dementia Mineral and Metal Neurotoxicology, ed. M. Yasui, M .J. Strong, K. Ota, & M. A. Verity, CRC Press: Boca Raton, New York, London, Tokyo, 1997, Chapter 20

INTRODUCTION

Whatever the age, nervous forms of magnesium deficit represent the most commonly seen form in clinical practice.1 First of all, it seems very important to discriminate 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 perturbating factors of the magnesium status. Magnesium depletion requires more or less specific correction of its causal dysregulation.1 It should not be permitted today to extrapolate from physiological data observed in overt acute magnesium deficiency to physiological consequences of chronic magnesium deficiency. Although acute and chronic magnesium deficiencies are specifically reversible through oral magnesium supplementation with physiological doses, the experimental and clinical symptoms may differ. The typical pattern of chronic magnesium deficiency is latent whereas overt signs are observed in acute magnesium deficiency. The discrepancy between the patent and latent nervous forms of magnesium deficiency suggests that in the latent form there are compensatory factors which antagonize the nervous hyperexcitability observed in the overt form.

The aim of this review is to study:

  1. The mechanisms of action of magnesium deficiency on the nervous system as demonstrated by
    • Electrophysiological data testifying to diffuse nervous hyperexcitability (NHE)
    • Biochemical data showing the mechanisms which may induce overt and latent NHE
    • Neuromuscular and neurotic psychiatric data
  2. The links between some types of magnesium depletions and dementias.
  3. Therapeutical implications.

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