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.
- Intracerebral Mg2+ varies from one structure to
another, both in normal and in magnesium-deficient rat;
- Intracerebral concentration of magnesium is twice or three
times higher in the control and in the deficient group
respectively compared to the intraerythrocytary magnesium
level;
- Global cerebral magnesium homeostasis is maintained in
magnesium-deficient rat.
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:
- 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 using
most often non or poorly soluble magnesium salts;
- finally, some types of local magnesium therapy:
mucocutancous or cytoprotective.
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:
- 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
- The links between some types of magnesium depletions and
dementias.
- Therapeutical implications.
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