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 INTERNATIONAL JOURNAL OF GERONTO-GERIATRICS
Year 12 Vol. 12 Num. 15 2009 Fundación Ana Aslán-­‐FICO-­‐Research Chronomics Center-­‐BIOCOS-­‐Cronómica at San Diego, California USA Research International Group Members of BIOSPHERE and COSMOS: BIOCOS
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INTERNATIONAL JOURNAL OF G E R O N T O-G E R I A T R I C S
Board of Editors MARIA MAGDALENA IONESCU President of Ana Aslan Foundation Editor in Chief SALVADOR SÁNCHEZ DE LA PEÑA Associate Editors Alfonso López Fiesco, Alfredo Feria Velasco, and Salvador Sánchez-­‐Castro Scientific Advisors Research International Group Members of BIOSPHERE AND COSMOS: BIOCOS (see previous page) ASIA Lin He (China) K. Kitani (Japan) K. Otzuka (Japan) A.Aswin (Indonesia) G.R.Andreus (Australia) EUROPE Anthea Tinker (England) P. Coleman (England) A. Donatas (Greece) Ursula Lehr (Germany) B, Fisher (Germany) Y.N. Berner (Israel) P.Cugini(Italy) A. Scuteri (Italy) Cornelia Rusu (Romania) J.M. Ribera C (Spain) J.P.Mitchel (Switzerland) G Leuba (Switzerland) MEXICO Blanca Mendoza (UNAM) José Waizel Bucay (IPN) Irene Mendoza Lujambio (IPN) Candido E. Guzmán Félix (IPN) RUSIA S. Chibisov G. Katinas V. N. Anisimov Y. Khavinson NORTH AMERICA Franz Halberg Germaine Cornélissen L. Hayflick Novera Spector Hana Hermanova Gloria Gutman SOUTH AMERICA Nelson Marques (Brazil) Design & Format Mónica Leal Morgán Romo Aguirre Jorge Castillo Bermudez Sponsors: Of GERONTO-­‐GERIATRICS: Ana Aslan Foundation and Fundación de Investigación Crono-­‐Oncológica A.C. (FICO) . Semestral publication. Year 11, Volumen 11, Number 14, Decembre 31st 2008; e-­‐ mail: http://www.cronomica.com; Published at Cronómica A.C. México City. ISSNB and ISSN certifications are in process. Permit for parcial or total text reproduction is authorized by Authors and Editor. Address in EUA: CRONÓMICA 119 Pacific Highway Unit 2002. San Diego, California 92101 United States INTERNATIONAL JOURNAL OF GERONTO GERIATRICS
CONTENTS PHYSIOLOGICAL DATA VARIATION IN RABBITS UNDER EXTREME ENVIRONMENTAL CONDITIONS (MAGNETIC STORM) Sergej M. Chibisov, Franz Halberg, Marya Ragulskaya V., Germaine Cornélissen. MODELO DE LA REACCIÓN CARDÍACA HUMANA BAJO LA INFLUENCIA DE AGENTES COSMOGEOFÍSICOS Sergej M. Chibisov, Marya V. Ragulskaya, Salvador Sánchez-­‐de la Peña, A.A. Kirichek. CHRONOBIOLOGICAL PERSPECTIVES IN ENDOCRINE CANCER AND RELATED DISEASES D. W. Wilson+, K. Griffiths, A. P.S. Hungin, H. Simpson, G. Cornélissen and F. Halberg. DÓSIS ÚNICA DE CARBONATO DE LITIO EN PACIENTES BIPOLARES GERIÁTRICOS Roberto Miranda Camacho Year 12
Vol 12
Num 15
Pages 187-­‐190 191-­‐198 199-­‐212 213-­‐216 2009
187
Intl. J. of GERONTO-GERIATRICS, 12 (15) 187-190 , July 2009
PHYSIOLOGICAL DATA VARIATION IN RABBITS UNDER EXTREME
ENVIRONMENTAL CONDITIONS (MAGNETIC STORM)
Sergej M. Chibisov1, Franz Halberg2, Marya Ragulskaya V.1, Germaine Cornélissen2,
Salvador Sánchez-de la Peña3
People’s Friendship University of Russia, Moscow; [email protected] 2Chronobiology Center, University of Minnesota; MMC 8609
1
Chronomic Research Center-Instituto Politécnico Nacional (IPN)-ENMH,México.
1
Abstract
Article is dedicated to experimental study of chronostructure of rhythms of various parameters of cardiovascular system activity and their changes under
influence of environmental factors. It is shown, that
reaction of chronostructure of heart to the stimuli like
fluctuations of a geomagnetic field is monotypical and
it is a specific adaptive stress. The problem of influence of the Earth geomagnetic field distortion on the
chronostructure of morphofunctional conditions of
parameters of heart is discussed. [1,2,3,]. The results
of laboratory researches of animals demonstrate that
geomagnetic storms cause desynchronosis of chronostructure of heart rhythms, appropriate the adaptive
stress, the similar stress under circadian rhythmics
disturbance, occurring under the effect of other extreme factors. This material allows estimating the
mechanisms underlying morphofunctional changes of
heart activity, controlled by the temporary factor. This
study has shown, that there is a displacement of the
periods of circadian rhythms to the infradian area in
intact animals under influence of external stress . At
the same time rhythms of circadian range dominate
among authentic rhythms in intact animals under
quiet conditions. So it is possible to conclude, that in
the majority of intact animals there are inherent circadian rhythms of parameters of acid-basic balance with
internal synchronization by the period of rhythms of
separate parameters with the certain value of MESORs
and amplitudes. Under influence of external stress factors the acid-basic system of animals reorganized its
time structure that was expressed in transformation of
circadian period into acyclic fluctuations or into formation of basically infradian or ultradian rhythmics.
Key words: heart, ultrastructure, a magnetic storm,
biological rhythms.
Background
The organism can be presented as a set of functionally
and spatially allocated oscillators. Frequencies of
radiation and biorhythms are own frequencies of
system. There are bases to consider, that the high-
frequency area of bioeffective frequencies is caused by
mainly compelled resonance of microscale structures
of an organism (ions, amino acids, membranes, etc.),
and low-frequency - a parametrical resonance of
large-scale systems (heart, a brain, blood system,
etc.). Bioeffective frequencies are defined by own
frequencies of corresponding systems of an organism
and can be calculated at knowledge of scale factors
and characteristic speeds in considered system [4].
Objective. To use biorhythmical approach to determine an influence of stress factors upon a circadian
rhythmics of various components of water-mineral
homeostatic system.
Materials and methods
Biological experiment was held on 240 males of
‘’Shinshilla’’ rabbits with weight 2600-3500 g, contained
on a standard diet of vivarium during magnetoquiet
day and during a phase of restoration of moderate
geomagnetic storm С1, an initial phase of a strong
storm А2 following it, the main phase of a big planetary
storm В2 and the first hours of a phase of restoration
С2 of the latter. The increase in characteristics of the
geomagnetic field А2 was registered at 8:00 p.m. the
day after the start of experiment, the active period of
this strong storm was on the next day at 1:00 p.m., and
peak of the main phase В2 was registered at 5:00 p.m.
The data of measurements of an electromagnetic field
of the Earth were obtained in magnetic observatory
IZMIRAN. Acid-basic balance (ABB) of blood and
systolic and diastolic blood pressure (SBP and DBP
accordingly) were measured in animals (n=5) within
the three days of experiment with a 3-h interval, peak
systolic blood pressure was registered in the cavity of
the left ventricle of heart (SBP -LV) after five-second
occlusion of aorta. The same parameter, but with
occlusion of a pulmonary artery was determined for
the right ventricle of heart (SBP-RV), cardiac hystiocytes
of left ventricle (LV) and right ventricle (RV) were
examined by transmission electron microscopy (ТЕМ)
at x6000 and in a JEM-100C microscope at x20,000.
Quantitative analysis of ТЕМ data was performed as
188
described elsewhere [2]. The following parameters
were determined: mitochondrion energetic efficiency
coefficient (MEECX); TEM-determined mitochond­rion
energetic efficiency coefficient (MEECTEM); lysosomal
membrane permeability coefficient (LMPC); peak
systolic intraventricular pressures in undamped LV
and RV; peak systolic pressure in LV and RV after 5-sec
aorta and pulmonary artery occlusion, re­spectively
(near-isometric contraction of heart cham­bers). Serum
content of free fatty acids was measured as described
previously with modifications [3].
Results of research
Comparison of spectra of ABB during the magneto
quiet day shown high similarity of rhythmic structures
of APH, AHCO3, ATCO2, ABEE, ABEIN, ABC, AHB, VHCO3,
VTCO, VBEE, VBEIN, VBC, VHB, SBP and DBP. All these
parameters had the basic maxima from 03 up to 06 h in
circadian range (duration of the period 22-24 h).
Chibisov et al.
The periods close to the second harmonic (10-11 h)
are also revealed. For many parameters maxima of the
spectra found at linear cosinor-analysis have been confirmed by a method of nonlinear cosinor.
Spectra of oxygen and carbonic acid voltage in arterial
and venous blood, and also an arteriovenous difference
of oxygen voltage, besides circadian peak, had maxima
in the period of 16 hours, i.e. ultradian rhythm. During magneto quiet day spectral characteristics of systolic and diastolic blood pressure in rabbits practically
coincided. They were characterized by a precise daily
component (the period of 24 h) and by considerably
less expressed ultradian components (12-13 h in both
spectra and 8 h in a spectrum of SBP). Cosinor-analysis
revealed significant distinctions of daily rhythms of the
tested physiological parameters during magnetoquiet
and magneto distorted days that is well seen on the
figures 1 and 2. These distinctions were especially expressed in parameters of BP (Figures 1 and 2).
Figure 1. Results of the cosinor-analysis 24-h rhythm SBP in magnetoquiet day (a) in magnetodistorted day (b).
Similar rhythmic structures were found out for AHCO3,
ATCO2, ABEE, ABEIN, ABC, VHCO3, VTCO, VBEE, VBEIN
and VBC during the magnetodistorted day. Some
maxima in ultradian range (with the periods of 7, 9, 1213 and 16 h) were revealed in their spectra. Circadian
rhythm was “spread” - the wide maximum of spectral
density, which exceeded the bounds of circadian range,
was marked. According to results of nonlinear cosinor,
the top limit of a confidence interval achieved 36-37 h.
Spectra of oxygen and carbonic acid voltage and also
pH in arterial and venous blood, considerably differed
from those during the magnetoquiet day. Ultradian
component was expressed to the maximum in them.
Ultradian rhythmics is characteristic for parameters of
blood pressure.
Figure 2. Results of the cosinor-analysis 24-h rhythm
DBP in magnetoquiet day (a) in magnetodistorted day
(b).
Physiological Data Variations in Rabbits Under Environmental Conditions (Magnetic Storm)
Enhanced geomagnetic activity induced pronounced
alterations in cardiomyocyte ultrastructure. During
phase Cl, ultrastructure of mitochondria did not sig­
nificantly differ from that under normal conditions.
The mitochondria were equally distributed in cells,
sometimes they concentrated in the perinuclear zone.
Polymorphism and swelling of organelles and clearcut duplication of the outer mitochondrial membrane
were seen. Some mitochondria demonstrated thicke­
ning of the outer membrane with ruptured fragments.
Cristae were dense and partially fragmented. Matrix in
most mitochondria was dense, although some mito­
chondria were clarified. Mathematical analysis revea­
led a significant (p<0.05) positive correlation between
contractile force developed by LV and RV and mito­
chondrial volume (r=0.76 and r=0.81, correspondin­
gly), which was described by the following formula:
y=b+xm, where b=218 and m=0.05 for LV and b=24.6
and m=9.55 for RV.
Phase A2 was characterized by pronounced chan­
ges in myocardial ultrastructure. The cardiomyocytes
membrane was loosened, and the integrity of its outer
leaflet was disturbed. Arcades filled with mito­chondria
and pronounced intercellular edema were seen. The
cytoplasm demonstrated individual stria­ted lipid
deposits. In most cases, the nuclear mem­brane was
invaginated. Sometimes chromatin margination and
its focal washout were noted. The capil­lary walls were
thickened and sometimes surrounded with a collagen
sheath. The number of lysosomes increased compared
to the previous day. The myofibrils had pronounced
homogenization foci. The intercalated disks were
thickened and their boun­daries were blurred. Myofibrils
were edematous and fibrous. Focal lysis, breaks of
myofibrils, and invaginations of the nuclear membrane
were characteris­tic of phase A2. Most mitochondria
were markedly swollen; the structure of their outer
membrane leaflet was disturbed. Some mitochondria
had vacuolated matrix. Many mitochondria were
destructed and de­graded. The cristae were strongly
fragmented; the number of cristae in a representative
mitochondrion or their total number in a representative
ТЕМ image was 2-fold lower that during phase Cl. MEEC
de­creased 2-fold (from 3.9± 0.8 to 1.9±0.2). Swelling
of mitochondria, fragmentation of cristae, decrease of
their number, vacuolation of the matrix, destruction
and degradation of mitochondria were characteristic
of phase A2. The volume of mitochondria markedly
in­creased compared to phase Cl, and the correlation
between mitochondrion volume and contractile forces
of LV and RV became negative (r=-0.73 and r=-0.81,
correspondingly, both remained significant), which
attested to further increase in the volume of orga­nelles
and the drop in contractile force of the heart.
189
The number of vessels surrounded by collagen
sheaths increased during phase B2 (Figure 3)
Figure 3. Transmission electron microscopy of left ventricle
myocardium of intact rabbit during phase B2 of geomagnetic
storm. x 20,000. The number of vessels surrounded by
collagen sheath (CS) markedly increased. Cell nuclei with
chromatin margination and partial matrix washout were
noted. During the daytime, the number of primary and
secondary lysosomes and glycogen content in cardiomyocytes
increased (Figure 4).
Figure 4. Transmission electron mi­croscopy of left ventricular
myocardium of intact rabbit during phase B2 of geomagnetic
storm. x20,000. Accumulation of secon­dary lysosomes (L).
A char­acteristic feature of this phase was widening of
the sarcoplasmic reticulum. Mitochondrion volume
decreased in compari­son with the initial phase of
magnetic storm, but was higher than during the
abatement phase. No corre­lation was revealed
between mitochondrion volume and contractile force
of the heart, the latter gradually decreased.
Correlation analysis revealed a strong and signi­ficant
positive correlation between mitochondrion volume
and serum content of free fatty acids (r= 0.998, p<0.0l).
Taking into consideration that the correlation coefficient
between the content of free fatty acids and the number
of cristae in an average ТЕМ pattern was r=-0.988,
and that the number of cristae closely correlates with
mitochondrion volume (r=-0.95), one can conclude
that free fatty acids suppress energy production in
mitochondria by in­ducing their swelling and spatial
separation of thcir cristae. The unidirectional character
of changes in living organisms induced by magnetic
190
storm is confirmed by a significant correlation between
myocardial MEEC and LMPC of hepatocytes (r=0.977).
Taking into consideration the reaction of lysosomal
apparatus of cardiomyocytes and cardiac contractile
function to geomagnetic storm, one can conclude
that decrease in EMPC attesting to condensation of
lysosomal membranes, cut down participation of these
orga­nelles in the processes of intracellular regeneration.
Stabilization of lysosomal membrane impedes the
effect of lysosomal hydrolases, which among other
functions initiate the release of mitochondrial DNA and
promote reproduction of mitochondria.
It is noteworthy that in nocturnal and morning hours
during phase C2, the increase in the content of free fatty
acids disturbed permeability of lyso­somal membranes
(correlation coefficient between the content of free
fatty acids and LMPC is 0.949). During phase B2, the sign
of correlation changes (r=-0.929), which means that
lysosomal membranes are stabilized by free fatty acids.
In the periods when free fatty acids produce this effect,
the number of mitochondria drastically decreased,
and most of them degraded. MEEC and МЕЕСTEM
decreased more than 2-fold: from 3.9±0.8 to 1.3±0.4
and from 19.3±4.9 to 8.7±2.1, correspondingly.
Therefore, one of the effects of magnetic storm on living
organisms is stabilization of lysosomal mem­brane. This
conclusion is supported by the existence of a strong
negative correlation between Cp index of geomagnetic
activity and LMPC (r=-0.977). Analysis of correlation
between Cp and LMPC carried out during a period of
one year revealed a non-linear interdepen­dence of
these indices described by a power function: y=bxm,
where 6=31.5 and m=-0.268. Hence, enhancement
of geomagnetic perturbations is accompanied by a
decrease in lysosomal membrane permeability, which
is especially pronounced during strong geomagnetic
fluctuations. Free fatty acids belong to the main inter­
mediaries in the membranotropic effects of electromag­
netic radiation, and their influence undoubtedly de­
pends on the phase of intrinsic physiological rhythms of
entire organism and its target organs. The bond became
negative, being valid and reliability (r=-0,73 and-0,81
accordingly), that testified to the further increase in
volume of organelles and falling of contractile strength
of heart. In experiment it was established, that
amplitude of daily fluctuations of contractile strength
of heart was considerably below during geomagnetic
disturbance (Table 1).
Conclusion
Thus, during the magnetoquiet day in spectra of haemodinamic variables, as well as in spectra of parameters
of ABB, circadian components dominated; alongside
ultradian components - close to the second harmonics
of circadian rhythm - were revealed. The increase in
geomagnetic activity led to significant changes of chronostructure of rhythms of ABB. It was revealed, that
Chibisov et al.
Table 1
Circadian rhythms of a parameter of peak systolic blood
pressure (SBP) in left (LV) and in right (RV) ventricles of
hearts of rabbits during quiet geomagnetic conditions
and during geomagnetic storms.
-----------------------------------------------------------------------------------------Variable
PR
P
Parameters of the Cosinor-Analysis
M±SE
2A±SE
ø (95% CI)
magnetoquiet day
SBR-LV
SBR-RV
26 0.002 167.6 ± 3.0 31.9 ± 8.4
39 <0.001 29.1 ± 0.9 13.5 ± 2.6
magnetodistorted day
-48° (-154, - 79)
-78° (- 57, - 99)
SBR-LV
10 0.002 207.6 ± 2.1 21.3 ± 5.9 -212° (-179, -246)
SBR-RV
5 0.046 40.3 ± 0.7 5.0 ± 2.0
-288° (-236, -340)
-----------------------------------------------------------------------------------------PR-percent of a rhythm: percent of presence of the rhythm, determined by a trial and error method of model (24-hour cosine curve);
P-probability: А=0; М-MESOR (mean value of a rhythm); 2А-the
double amplitude; ø-acrophase expressed in °, and 360°=24 hours
- 00:00; СI-a confidence interval.
------------------------------------------------------------------------------------------
during magnetic storms phenomena of desynchronosis
appeared. Cosinor-analysis revealed significant distinc
tions of structure of circadian rhythms of the examined
physiological parameters in various magnetic conditions. At magnetoquiet state daily rhythms were well
expressed and during a magnetic storm they either
were absent or were “smoothed”, ultradian components among which rhythms with the periods of 15-16
hours were basical. Especially brightly these distinctions were shown in parameters of BP and PO2 in venous blood.
It was revealed, that during magnetic storms there are
phenomena of desynchronosis of cardio- vascular system - one of the first attributes of which were changes
of amplitude and the period of biological rhythms contractile strength of heart. There was a phenomenon of
fading of amplitude of a rhythm under the influence
of information stress factor, which is an ultralow frequency magnetic radiation.
Acknowledgment
To Instituto de Ciencia Y Tegnología del Gobierno del
DF for suporting SSP research (PICDS08-82).
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191
Intl. J. of GERONTO-GERIATRICS, 12 (15) 191-198 July 2009
MODELO DE LA REACCIÓN CARDÍACA HUMANA BAJO LA
INFLUENCIA DE AGENTES COSMOGEOFÍSICOS
Sergej M. Chibisov1, Marya V. Ragulskaya1, Salvador Sánchez-de la Peña2, A.A. Kirichek1
1
Departamento de Patología general y Fisiología patológica de la Universidad de Rusia de la Amistad de los Pueblos. Facultad de Medicina,
c / Micluho – Maklaya, 8, C.P. 117198 - Moscú, Rusia. Correo electrónico: [email protected]. Instituto de Magnetismo terrestre, Ionosfera y Difusión de ondas
radioeléctricas de la Academia de Ciencias de Rusia. Moscú, Rusia. Correo electrónico: [email protected].
2
Chronomic Research Center-Instituto Politécnico Nacional (IPN)-ENMH,Mexico.
Este artículo se concibe a sí mismo como un trabajo
dedicado a analizar los modelos teóricos de regímenes
de adaptación responsables de generar y estabilizar
la actividad cardíaca supuesto que se caracteriza por
los parámetros dinámicos punteados y no lineales. El
análisis está limitado por investigar la evolución en el
tiempo de electrocardiogramas (ECG). Para hacerlo
existen varias maneras matemáticas. Se han descrito comparativamente algunos modelos de caracter
dinámico que están correspondientes a la actualidad.
Durante las investigaciones se ha revelado que es preciso que se creara un modelo máximamente general
basado en las leyes físicas que describen los procesos
de la repercusión cardíaca bajo la influencia exterior.
Han mostrado que las perturbaciones insignificantes
del sistema dinámico en el espacio fásico tienen sus
propias modas. Los índices máximos de su crecimiento
se localizan alrededor de unos puntos especiales. Dos
de éstos se encuentran en el intervalo de las ondas T y
P. La conducta cualitativa del sistema, así como su variabilidad bajo la influencia exterior está determinada
consiguientemente por las propiedades evolucionadas
de dichos intervalos.
Palabras clave: electrocardiograma, corazón, estudios
clínicos incesantes, sistema dinámico, adaptación.
es la influencia la que ejercen los factores cosmofísicos
y los atmosféricos sobre el organismo humano había
sido fundado el sistema distribuido de telecomunicación que une los centros científicos localizados en el
territorio de los miembros de la Comunidad de Estados
Independientes, los ex republicas de la antigua URSS.
De esta forma, los científicos han realizado los estudios
clínicos incesantes prolongados de los parámetros fisiológicos de organismo humano y los de medio ambiente. En todos los centros que están respectivamente
en Moscú, San Petersburgo, Kiev, Simferopol y Yakutsk,
han usado la misma instalación y mismo protocolo de
la investigación presupuesto a registrar simultáneamente los datos corrientes mediante el uso conjunto
online de un server de portico único que está en Kiev
(véase el gráfico 1).
Los estudios heliomedicinales incesantes han acabado
principalmente por revelar mediante el método de
análisis estadístico que existen los cambios específicos
de misma dirección de los parámetros de la actividad
cardiaca que se observan alrededor de la tempestad
magnética aislada dándose la circunstancia de que fueron observados simultáneamente por todas las ciudades en diferentes latitudes. El proceso de adaptación
que afecta el estado funcional comprende dos etapas
consigientes que son:
Prólogo
Los autores han discutido en el artículo [7] la tecnología de construcción y resultados primarios de
los estudios clínicos y heliomedicinales incesantes
de telecomunicación de amplia escala llamada “Heliomed”, un proyecto conjunto e interdisciplinario de
la Academia de Ciencias de Rusia y de la Academia Nacional de Ciencias de Ucrania. Para que revelaran cuál
1.a , en la víspera de la tempestad magnética, exactamente a las 24 horas antes de su comienzo,
habían cambiado los regímenes de la dirección de
la actividad cardíaca bajo la influencia del cargamento adicional físico. El régimen normal se sustituyó por el estresante lo que observaba en la mayoría de los casos registrados por el sistema. Este
efecto fue común para todos los grupos los que
192
Chibisov et al.
!
Gráfica 1. Proyecto de los estudios clínicos incesantes heliomedicinales de telecomunicación organizados en los
centros científicos localizados en diferentes latitudes y de la tecnología instantánea del tratamiento de los datos
corrientes usando el espacio de fases.
Mediante el uso conjunto de los métodos de telecomunicación y estudios clínicos incesantes repartieron
así en el espacio como en el tiempo el estudio de influir
biotrópicamente por los agentes locales y globales del
medio ambiente. Los factores locales comprenden la
presión atmosférica, temperatura, duración de período luminoso, nivel de insolación. Entre los factores
planetario-generales distinguen los parámetros de tiempo del Espacio, variaciones del campo geomagnético de la Tierra y rayos cósmicos. No obstante, no pudieron solucionar el problema principal puesto por los
autores los científicos de nuestro grupo ni sus colegas
de otros grupos científicos que concluyera en revelar
un factor único cosmogeofísico que podría ejecutar la
influencia dominante sobre el organismo humano. Lo
dicho anteriormente convierte en un problema debatible básico de la física de hoy de relaciones helioterrestres, provocado por varios agentes. Ante todo los
factores de medio ambiente poseen las amplitudes
mínimas de variaciones. Esos campos podrían ejecutar
la influencia paramétrica mediante el sistema complicado basándose en resonancias no lineales y retrocomunicación. Han propuesto actualmente una serie de
algunos procedimientos de la influencia biotrópica de
los campos naturales [2] entre los cuales pudiera estar el mecanismo verdadero. Por desgracia ninguno de
aquellos procedimientos describió todo el conjunto de
eventos observados no permitiendo hacer el pronóstico incontestable de la conducta individual de ser
vivo bajo la influencia de diferentes agentes de medio
ambiente. Precisamente por lo tanto el proyecto “Heliomed” estaba dedicado a partir de su empiezo a investigar la reacción psicofisiológica conjunta que fuera
común para todos los individuos de una populación
humana bajo las variaciones bruscas de la actividad
solar y de tiempo [1,4].
Todos los factores del medio ambiente de la Tierra los
que caracteriza una concordancia considerable mutual
dependen de los procesos ocurridos en la superficie
del Sol determinando así modo lo esencial del siguiente
problema objetivo que complica las prospecciones de
un agente físico específico que podría ejercer la influencia arriba mencionada. Los fenómenos físicos ocurriods en todas las envolturas de la Tierra incluyendo
la Ionosfera, Atmósfera y Litosfera se caracterizan por
la duración y frecuencia que tienden a cambiar simultáneamente en consecuencia con las modificaciones
Modelo de reacción Cardíaca Humana Bajo la Influencia de Agentes Cosmogeofísicos
de parámetros corrientes del viento solar. La existencia
de la Magnitosfera, un componente del Planeta, determina que el viento solar no consigue la superficie terrestre excepto la area de las caspas polares, es decir,
convierte el viento solar en un factor que no produce
un efecto directo sobre funcionamiento de organismo
humano. De esta forma, si trataramos de apreciar mediante el método del análisis estadístico las relaciones
causales reveladas entre la actividad solar, por una
parte, y el aumento cíclico fuerte de llamadas a una
ambulancia conjunto con el numero de muertos, por
la otra, no podríamos separar un agente único exterior que fuera determinado influyendo realmente sino
solo revelamos el fenómeno de existencia de aquella
influencia.
Finalmente, mientras analizar los datos corrientes obtenidos por el sistema “Heliomed” han de resolver lo
siguiente, el ser vivo se caracteriza bajo la influencia
exterior por duración vasta de reacción que tiene a
veces el caracter no lineal. Los agentes naturales del
medio ambiente influyen en el objeto vivo provocando
la respuesta habitual no lineal que depende adicionalmente de estado íntimo de este objeto y prólogo de
su evolución. Los factores diferentes de medio ambiente pueden provocar las mismas modificaciones de
los parámetros fisiológicos de organismo vivo. Al contrario, los experimentos presupuestos a estudiar la influencia equivalente del agente específico demuestran
que la reacción del organismo humano, su duración y
hasta el signo de esa, lo determina el factor temporal.
El objetivo general de la investigación es de valorar los
modelos teóricos de los regímenes de adaptación responsables de generar y estabilizar la actividad cardíaca partiendo de la suposición que ésa tiene el caracter
dinámico punteado no lineal.
Procedimientos de la investigación y material
sometido a prueba
En el intervalo de los años 2006-2008 en los centros
científicos situados en Moscú, San Petersburgo, Kiev,
Simferopol y Yakutsk organizaban simultáneamente
los estudios clínicos incesantes heliomedicinales que
permitieron recoger por todos los centros los datos
conjuntos registrados en un server de portico único.
La base tiene de 20.000 medidas que reflejan el dinamismo temporal y espacial de las modificaciones de
los parámetros obtenidos por la 1a derivación. Los
parámetros se medieron en el período desde el otoño
193
hasta la primavera, en los días equinocciales. El cuerpo
de todos los grupos era constante. Los datos corrientes
se registraron cotidianamente cuatro veces en cada
grupo: primero, en estado de reposo, luego después
de las pruebas sicofisiológicas estandartizadas, test de
Ruffier y finalmente después de haber reposado por 10
minutos. Los datos corrientes se analizaron comparándolos con los valores correspondientes del Número de
Wolf (también conocido como el International sunspot
number, o Número de Zúrich), que es una cantidad de
que mide el número y tamaño de las manchas solares
indicando el término perturbador del campo geomagnético de momento actual, y de los rayos cósmicos.
Esta información la concedía el Centro de previsión de
ambiente geofísico del Instituto de Magnetismo terrestre, Ionosfera y Difusión de ondas radioeléctricas
de la Academia de Ciencias de Rusia.
Resultados y discusión
Para analizar teóricamente los resultados de los estudios clínicos y heliomedicinales incesantes de telecomunicación “Heliomed” los autores del artículo decidieron resolver el problema principal mediante convertir
los objetos básicos de la investigación. En vez de estudiar la influencia de los factores cosmofísicos sobre el
organismo humano se analizaba el funcionamiento del
sistema circulatorio supuesto que se caracteriza por los
parámetros dinámicos no lineales así como se revelaron
las particularidades de estabilizar y funcionar por este
sistema provocadas por el efecto de una fuerza exterior.
Méritos y faltas de los modelos que describen el dinamismo y reconstrucción de ECG, Al haber analizado
la influencia de los factores de medio ambiente tan
considerables que comprenden las variaciones de los
factores cosmogeofísicos revelamos que fuera posible
omitir las dimensiones del corazón por los parámetros
que fueran dinámicos punteados no lineales y estandartizados caracterizando las fluctuaciones de la actividad cardíaca. Los señales que se transmetían se
caracterizaron por la amplitud que estaba modificándose correspondiente a los cambios observados en
ECG. Así no tendemos a analizar las causas, fuentes y
particularidades de generación que pertenecían a las
fluctuaciones. Se nos salvaba de estimar los procesos
de difusión espacial de ondas producidas por excitar
el miocardo [3]. Entonces teníamos que nuestro trabajo tenía por su objetivo principal investigar los cambios dinámicos de la amplitud y sus regularidades que
pasaron durante el período determinado. Al misno
tiempo estabamos en busca de los parámetros en el
Chibisov et al.
194
espacio de fase que manejaran estos cambios. Naturalmente, si aquellos parámetros se cambiaran bajo
una influencia exterior alguna nos habría interesado
así el fenómeno semejante como sus particularidades.
características “nuevas” son la velocidad de modificaciones de la amplitud y la amplitud misma. Además,
no es preciso que se analizen las regularidades de los
fenómenos físicos y biológicos que se observan.
En estado sano las modificaciones que las tenía la amplitud de señal cardiaco, no tuvieron el caracter rigurosamente cíclico [8,13] sino lo hacen el seudoperiódico.
Este fenómeno lo confirmaron las variaciones de fase y
versiones de configuración de que se caracterizaba el
señal de ECG. El modelo único no describía la conducta semejante. Sería posible que las variaciones de ECG
obtenidas por nosotros, hablando más exactamente la
parte constitutiva incoherente de esas, se debieran a la
acción recíproca entre dos sistemas uno de los cuales
era el circulatorio y el otro, el respiratorio [10, véase
la información detallada]. Según el trabajo científico
mencionado, el espectro de fluctuaciones de sistema
circulatorio tiene las particularidades que pueden
presentarse en concepto de la influencia resultante
de dos osciladores estocásticos responsables de funcionamiento cardiaco y respiratorio respectivamente.
Los datos obtenidos describen de un modo evidente la
reestructuración interior del sistema dinámico gobernada por unos fenómenos endógenos. Está descrito
también el fenómeno de paralización de sistema que la
transforma en las fluctuaciones incoherentes. No obstante, dejan estar discutibles las particularidades de la
conducta de sistema bajo el estímulo exterior.
La serie de los trabajos hecha por un científico ruso
V.S Anischenko está dedicada a investigar las leyes que
tienen las modificaciones de la amplitud del señal cardiaco [11]. El científico consideraba el señal cardiaco
como el fuente punteado y no le interesaba la influencia de una fuerza exterior alguna. El objetivo principal
era de investigar las condiciones de convertir las fluctuaciones reguladas en las incoherentes computando los
grados del Orden y Caos de los sistemas a estudiar. Al
reconstruir el sistema dinámico no lineal a base de los
electrocardiogramas auténticos usando los métodos
matemáticos específicos comprobaron así la configuración de señal cardíaco. Allí a la dependencia funcional se le conocía como un total de unas decenas de polinomios. Los coeficientes correspondientes se ajustaron
tomando en consideración los datos aproximados de
ECGas auténticas. Para reponer las propiedades únicas
del complejo PQRST de señal cardíaco se omitieron
las variaciones incoherentes de ECG construyendo un
modelo estandartizado basado en un principio de las
fluctuaciones constantes por su configuración y fase.
El modelo mencionado se denota por:
FORMULAS
Es favorable analizar y filtrar los electrocardiogramas
usando los modelos dinámicos de caracter no autónomo. En el trabajo científico hecho por G.D. Clifford y
P.E. McSharry [9] se demuestra el uso de esos modelos.
Organizando los programas automáticos de computar
los datos corrientes recogidos por los estudios clínicos
heliomedicinales incesantes “Heliomed” se usaron los
modelos de interpolar creados por L.S.Fainsilberg [6].
El rasgo fuera de lo común consiste en el señal mismo
cuyos variaciones y configuración, en general, se determinan por hacer funciones de los modelos. Dichas
funciones son los resultados de sumar los fuentes deltoides los centros de los cuales convirgen a los períodos específicos de la fase de ECG que comprenden
los máximos y los mínimos del complejo PQRST. Este
procedimiento matemático nos permite automatizar el
proceso del análisis comparativo de ECG. Ahí el sistema
de coordenadas cilíndricas que se usaba anteriormente
y cuyas caractéristicas son la amplitud de señal y el tiempo cede el sitio a un sistema de espacio fásico. Las
en el que la cantidad variable X3 refleja el señal de
ECG, los coeficientes CI1I2I3 se indican en un trabajo de
N. Wessel y H. Malberg llamado “Nonlinear methods
of cardivascular physics and their clinical applicability”
[11]. Este modelo refleja las propiedades generalizadas
de una especie de señal cardíaco en estado reposo.
Bajo un estímulo exterior se cambian los parámetros
dirigidos de sistema dinámico en algunos casos. Para
investigar esos procesos es necesario que se analizen
adicionalmente las reconstrucciones numéricas basadas en los datos recogidos por el ECG en los intervalos diferentes de tiempo, por ejemplo, antes de un
esfuerzo, en el momento inmediato de una influencia
y después de él. Se debe añadir que no han resuelto
este problema.Utilizando los ecuaciones polinomiales
propuestas por N.Wessel y H.Malberg a analizar los
datos auténticos de los estudios clínicos heliomedicinales incesantes revelamos que un modelo puesto por
V.S. Anischenko tenía tanto las cualidades evidentes de
Modelo de reacción Cardíaca Humana Bajo la Influencia de Agentes Cosmogeofísicos
caracter analítico como las imperfecciones indudables
vinculadas con el uso de éste para investigar la influencia de una fuerza exterior. Lo comprobaron las mejores
condiciones para el uso de este modelo que son:
Primera, el voltaje de la onda R es mucho mayor al voltaje de la onda T.
Segunda, el período de aflojamiento entre las fluctuaciones vecinas son comparativas a los períodos de las
fluctuaciones mismas.
Realmente, la experiencia del análisis de los electrocar
195
diogramas auténticas demuestra que ambas condiciones son inaccesibles en los casos de la taquicardia o
los esfuerzos físicos considerables.
Estuvieron calculados los estados fijos de un sistema
dinámico no punteado (1). El parámetro del estímulo
exterior se denomina por una variable B , mientras
que una variable A refleja la firmeza de este sistema.
Tomando los valores de a = 1
, b = 560 este modelo describiera de un modo evidente las propiedades
generalizadas de una clase de un señal cardíaco en
estado reposo.
Figura
2. Reconstrucción de ECG según el modelo (1) en diferentes condiciones de la firmeza: a la izquierda es
!
de a=1, a la derecha es de a=1.2. Arriba representa el señal de ECG, abajo está su reconstrucción en el espacio
fásico de 3 medidas.
La ecuación diferencial (1) expresada en forma lineal
permite descubrir las modas propias que describen
la solución (1) alrededor de unos puntos específicos.
Según el análisis, una modificación relativamente imperceptible del parámetro a que es menor del 10% y
se puede considerarse como un caso particular de las
velocidades integrales de la reacción de un organismo
humano. Aquella modificación puede suceder a las
perturbaciones significantes de los parámetros del crecimiento de soluciones propias alrededor de los puntos
específicos ya mencionados modificando también las
propiedades morfo- y topológicas del sistema (véase
los ejemplos en el gráfico 2). El valor de parámetro a
hace la gran influencia a unas siguientes propiedades
de la onda T: la anchurra, fase de crecimiento, fase de
disminución y correlación de los dos fases.
Tiene de gran importancia revelar los parámetros de
señal cardíaco que sean sensibles máximamente a una
influencia exterior. Permite plantear con eficacia el experimento y entender de las propiedades generales,
que determinan la estabilidad del sistema circulatorio
humano, y capacidades de adaptar. El estado estacionario está calculando por resolver un conjunto de ecuaciones .
El modelo (1) como la ecuación tiene unas posiciones
de equilibrio dos de los cuales convergen en ceros de
la función f perteneciendo a la trayectoria del conjunto
siguiente
.
Sustituyendo el
Chibisov et al.
196
espacio fásico por el espacio de coordenados usamos
los parámetros de la duración y el tiempo registrándolos en los ECG auténticos. Los puntos estacionarios de
ecuación (1) pertenecen a unos extremos de las ondas
P y T (véase el gráfico 3).
una especie “asiento-foco” situado en fronteras de las
ondas P y Q. Para entender más de este efecto tendremos que conseguir esa investigación analizando por
métodos computadoros una serie extensiva de ECG
de pacientos correspondientes. Actualmente queda
desconocido hasta qué punto conserven aquellas especies de estados estacionarios para distintos clases de
ECG.
!
El gráfico 3. Trayectorias del sistema dinámico alrededor de los puntos especiales de estados estacionarios
de una especie “asiento – foco”.
Resulta que los puntos estacionarios situados a principios de la onda P y a fines la onda T son de una especie
llamada “foco”. Al mismo tiempo los puntos estacionarios localizados a principios de las ondas Q y T son de
la otra clase llamada “asiento”. Queda bien sabido que
la existencia de los estados estacionarios pertenecidos
a una especie “asiento - foco” fija las propiedades del
dinamismo caótico de sistema no lineal. Los trabajos
científicos [5, 12] representan la discusión y el análisis
de estos problemas. Según los resultados, podemos
proponer que el sistema cardíaco de fluctuaciones funcionadas normalmente y a la vez controladas lo tenga
por un signo diagnóstico que pueda revelar los cambios de funcionamiento circulatorio bajo la influencia
de un estímulo exterior las propiedades inestables
de las ondas P y T que está en contradicción con una
hipótesis expuesta anteriormente sobre la mayor importancia de los intervalos R-R y su inclinación a las
variaciones diferentes. La justicia de nuestra teoría la
demuestran varios fenómenos científicos. Por ejemplo,
el retrato fásico de intervalos R-R de un cíclo cardíaco
es de una especie titulado “centro” cuya frecuencia no
depende de unas propiedades de un agente exterior
sino de las modificaciones que sufren los parámetros
a dirigir interiores apropiados. El gráfico 3 representa
unas clases generalizadas de trayectorias de sistema
dinámico alrededor de los puntos especiales. Es posible que los infartos Q-dependientes tengan una correlación desconocida con unas propiedades específicas
de dinamismo de un punto excepcional pertenecido a
Deducción
Al hacer la investigación, hemos revelado que los modelos de ECG no lineales principales, los más usados en
trabajos, se basan en un principio de sustituir iterativamente un señal lo que estamos observando por un
conjunto alguno de funciones matemáticas. Este paso
ofrece beneficios simplificando la implantación de los
métodos de cómputo en el tratamiento de los datos
corrientes. Al mismo tiempo, no permite revelar lo
esencial de los procesos a investigar. Finalmente, está
limitado en un caso de describir por separado 1 o 2
fenómenos de todo el conjunto de los procesos que
se observan realmente. Para describir un efecto más
tendremos en disposición un modelo nuevo que sea el
mejor en condiciones correspondientes. Está revelado
un nuevo efecto y el ciclo empieza de novo. Disponemos de una serie de modelos que están propuestas
por varios científicos [6, 9-11]. Al utilizarlos con datos
auténticos hemos considerado que para describir los
procesos a investigar con maxima eficacia mientras
estudia la influencia de unos agentes exteriors sobre
la actividad cardíaca tenemos que trivializar considerablemente las ecuaciones dinámicas primarias construyendo adicionalmente un modelo a base de los
principios no matemáticos sino físicos de describir los
fenómenos.
Después de haber investigando la firmeza del sistema
(1), consideramos que las perturbaciones insignificantes y pequeñas, que lo sufría el sistema dinámico
en un espacio fásico, tenía unas modas propias. Los valores más altos del crecimiento estaba alrededor de los
puntos especiales dos de los cuales estaban situados
en un intervalo de las ondas T y P.
Partiendo de lo dicho anteriormente, la conducta cualitativa de sistema y el nivel de su variabilidad bajo los
estimulos cosmogeofísicos exteriors se deben así a las
propiedades de dichos intervalos derivadas de la Evolución como a la corespondencia de períodos correspondientes de reposo de sistema.
Los autores dan las gracias al señor V.N.Obridko, el doc-
197
Modelo de reacción Cardíaca Humana Bajo la Influencia de Agentes Cosmogeofísicos
tor en Ciencias Físicas y Matemáticas, por sus consultas
y apoyos. El trabajo lo han hecho con la ayuda monetaria de una subvención concedida por el Fondo de Rusia de Investigaciones Fundamentales (Russian Foundation for Basic Research) № 09-02-90471 Ukr_f_a.
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Reconocimiento
Al Instituto de Ciencia Y Tegnología del Gobierno
del DF por el apoyo económico para la investigación
cronómica de SSP (PICDS08-82).
autores
Chibisov Sergey Mikhailovich
Doctor en Ciencias Médicas (M.D.).Professor del Departamento de Patología General y Fisiología Patológica
de la Universidad de Rusia de la Amistad de los Pueblos, Moscú. Rusia. Correo electrónico: [email protected]
Ragulskaya Mariya Valer’evna
Candidato a doctor en Ciencias Físicomatemáticas (Cand.Fis.&Math.Sci.), el colaborador científico jefe del Departamento de Conexiones Solareterrestres del Instituto de Magnetismo terrestre,
Ionosfera y Difusión de ondas radioeléctricas
de la Academia de Ciencias de Rusia, Moscú.
Interés Científico: La Fisica y su aplicación en conexiones
solareterrestres; el análisis sistémico y tratamiento de
198
datos corrientes en biomedicina; la radiofísica cuántica.
Correo electrónico: [email protected]
Salvador A. Sánchez de la Peña
Doctor en Ciencias (D.C.) en Biofísica y Fisiología Comparativa y Doctor en Médicina.
Director del Centro de Investigación CronómicaLaboratorio de Cronobiología Médica de la Escuela
Nacional de Medicina y Homeopatía del Instituto Politécnico Nacional.
CorreoS electrónicos:
[email protected],
[email protected].
Kirichek Andrey Andreyevich
Estudiante de la Facultad de Medicina de la Universidad de Rusia de la Amistad de los Pueblos.
Correo electrónico: [email protected]
Chibisov et al.
199
Intl. J. of GERONTO-GERIATRICS, 12 (15) 199-212 July 2009
Chronobiological perspectives in endocrine cancer
and related diseases
D. W. Wilson+, K. Griffiths1, A.P.S. Hungin2, H. Simpson*, G. Cornélissen++ and F. Halberg++
+
School of Medicine and Health, Wolfson Research Institute, University Durham, Stockton on Tees, TS17 6BH, *University of Glasgow,
++
Chronobiology Laboratories, University of Minnesota, Mayo Building, Rooms 715, 733-735, Minneapolis Campus,
Mayo Clinic Code 8609, 420 Delaware Street SE, Minneapolis, MN 554455,USA.
A Tribute to our Father Figure:
It is indeed appropriate, that in the year 2009, as the
world pays tribute to the ‘Father of Evolution’ in recognising the bicentenary of Charles Darwin’s birth, we can also
celebrate the 90th birthday of the ‘Father of Chronobiology’, the very eminent Professor Franz Halberg. Whereas
Kant’s view of the cosmos [1] predated Darwin’s Theory
of Evolution [2], Darwin clearly distinguished variability
within life forms, as was also recognised by Halberg [3],
from the direction of evolutionary change. Halberg, like
Bernard [4], arguably the 19th century Father of Experimental Medicine, recognised and discussed the constancy of the internal environment, but nevertheless, realised that that temporal changes within life forms were
necessary in order to accommodate the impact of the
exterior milieu, both geophysical and cosmological, that
could prejudice the continued good health and well-being of organismic life. The concept of homeostasis taken
too literally is, in principle, fallacious, although Cannon’s
viewpoint [5] was less literal, rather one of steady state.
Thus it seems not illogical that within this conflict, where
neural, cellular and humoral variations interact in healthy
forms of life, a ‘consensus partium in tempore’, there is
genetic adaptation, possibly through processes involving
the methylation of DNA and the consequent changes in
gene expression and regulation.
Although it is well recognised that knowledge of
biological rhythms has been documented through past
centuries [6-8], it has been most certainly, the intellect
and experimental genius of Franz Halberg, through 60 or
more years devoted to his investigations, that developed
1
2
the hypotheses, principles and methodologies of
chronobiology [9] and he continues to do so. Thus were
created the procedures by which, inter alia, they could be
exploited in the detection of pre-clinical disease and to
more effectively treat overt disease than other traditional
forms of therapy [10, 11]. Any considerations of health
and disease, must embrace biocosmology, in evolutionary
and recent social time [12, 13] and in near-Earth and
organismic space, wherein physical and biological
interactions take place. It is fascinating to reflect on the
(pre-) adaptive radiation that probably initially began
with the evolution of prokaryotes and their subsequent
association, to form, with mitochondria and chloroplasts,
the early endosymbiotic, autotrophic eukaryotes [14].
Through the years, Franz Halberg has reflected on their
evolution through changing chemical, physical, and
cosmological environments and a myriad of factors such
as solar luminosity, geomagnetics, temperature, marine
and atmospheric composition, the Earth’s rotation [1],
to form complex, multi-cellular organisms. Some of
these changes, facilitated perhaps by haploid and diploid
switching, may have been reflected in RNA earlier and in
DNA [15-17] in very much more recent evolutionary time
and following geophysical imprinting.
Professor Cornélissen [18] has considered the influence
of environmental, multifrequency radiations, such as geomagnetic and non-photic signatures. Some frequencies
have been translated into, and expressed by the human
chronome. Some are akin to heterochrony [19], categories of which include pera- and paedo-morphosis, a very
important concept in evolution since it involves changes
Formerly, Professor of Cancer Research, Tenovus Institute for Cancer Research, University of Wales College of Medicine, Cardiff.
Dean of the School of Health and Medicine with programmes directed towards clinical research, human development and health promotion.
200
in the chain of development not seen in ancestors [20]
and is invoked to explain, through the existence of variation in development, the exceptions to recapitualisation
theory.
Halberg has independently sought to scientifically identify, characterise, and use biological variation, in terms of
rhythmic change, chaos and intrinsic variation, through
investigations into a vast array of biological and physical
environmental impacts on a raft of biological systems.
Massive care was taken to unravel the endogenous and
environmental components that can cause masking and
difficulties in the interpretation of data [21].
Investigations directed to endocrine cancer have embraced a most challenging and rewarding field of research
endeavour that has challenged the intellect and expertise of Franz Halberg. Predisposition, protopathology and
data on the initiation, detection and treatment of breast
and prostate cancer have been part of his sphere of interest in issues of health [22, 23]. Early work on blood pressure and cardiovascular disease [25-27] by Halberg and
others were important contributions to the field which
have expanded enormously. These areas of research and
those relating to duodenal melatonin [24] are also of
particular interest to two of the authors within the University of Durham. The authors of this presentation have
been concerned with multifarious individual and collective approaches to the study of biorhythmicity and disease, usually in close relationship with Minnesota. These
studies established to try to better understand endocrine
cancer used the available resources at the Tenovus Institute for Cancer Research, at the University of Wales
College of Medicine, in Cardiff, to undertake particular
chronobiological investigations using, for example, sensitive and specific assays for steroids in saliva, well established statistical techniques, and the availability of
excellent support of schools in the U.K. and Thailand [28,
29]. The following outlines, somewhat briefly, some of
the studies.
Some principles of chronobiology and the adrenal gland:
Research in the Institute centred on the essential relationship between the adrenal gland, the ovary and
cancer of the breast. Early studies were directed to the
Wilson et al
elucidation of the integrated control mechanisms that
regulated the hypothalamic-pituitary- gonadal network
and the influence the pineal gland might exercise. Epidemiological studies of lifestyle factors such as diet and
physical exercise, were explored using assays for steroids
in both plasma and saliva. The clinical relevance of oestrogen [30-33] and androgen [34] receptor levels were
assessed, together with molecular studies on the mechanism of action of the steroid-receptor complex on gene
expression. The capacity of breast tumours to synthesise
oestrogens from potential precursors such as DHA-sulphate and androstenedione were particularly of interest. After the identification of prognostic factors for both
breast cancer [32] and prostate cancer [35,36], there followed the establishment of clinical trials co-ordinated by
the Institute [37]. Chronobiology was always recognised
as a vital aspect of the work, although circumstances
such as inadequate funding and limited sampling made
practical progress difficult to achieve. During the late
1950s and early 1960s at the University of Minnesota,
the pioneering work of Halberg in the continued development of chronobiology and circadian adrenal rhythmicity [38] stimulated the interest of Griffiths, a Fulbright
scholar from the University of Edinburgh and Glick [39]
in understanding the functional zonation of the adrenal
and the steroid biosynthetic activity of the glomerular,
fascicular and reticular zones, using ultramicro-analytical
techniques developed by David Glick in Minnesota.
Subsequently, in Cardiff, the Institute sought to understand the relationship between the biosynthetic
pathways to produce cortisol and DHA-sulphate from
17alpha-hydroxypregnenolone in the adrenal gland and
determine the urinary androsterone, aetiocholanolone
and 17-hydroxycorticosteroids levels in healthy women,
and in those with either benign breast disease, or primary, or advanced breast cancer. The aim of the Institute work [40-42] was to confirm and extend the work
of Bulbrook [43] whose studies suggested the use of a
discriminant function might indicate which women with
advanced breast cancer might respond to endocrine
ablation. The notable outcome from these Cardiff studies was, using regression techniques, that low values of
androsterone and aetiocholanolone were indeed asso-
201
Chronobiological Perspectives in Endocrine Cancer and Related Disease
ciated with advanced localised disease, primarily in the
chest wall, regional nodes and pleural cavities, metastatic
spread generally associated with a poor clinical response
to endocrine ablation.
Epidemiology:
Several strands of development allowed a better understanding of breast cancer aetiology [31,44], with the pioneering work of Halberg, summarised in a Glossary [9]
and elsewhere [45] which emphasised that single-samples were not necessarily representative of the endocrine status of healthy women, nor of those with breast
disease. Sensitive and specific immunoassays were developed for salivary steroids. Little difficulty was encountered in obtaining ethical approval for multiple sampling
in school children, or adults with endocrine-related disease. It was readily recognised that failure to take into
consideration hormone rhythms, circadian [46-48], circaseptan, circatrigintan [49], or circannual rhythms [4951] or indeed could lead to erroneous conclusions and
a major publication by Franz Halberg and team [52] focussed on chronoepidemiology, to explain international
geographic variation in some endocrine cancers. Assays
for adrenal and gonadal salivary steroids were successfully established [53], supported by the contemporaneous development of high-resolution specific ion monitoring mass-spectrometry and innovative quality control
techniques [54,55]. Moreover, biological rhythms could
then be characterised using time series analysis developed by Halberg and his team [56-58] in the University of
Minnesota and also by De Prins [59] in the Free University of Brussels. International chronoendocrinological differences were identified in populations at differing risk of
breast cancer, implicating differences in the ‘spring’ and
‘autumn’ of the potential reproductive lifespans. Early
menarche is associated with early ovulatory cycles [60]
and these issues will be influenced by immunological
load, diet, exercise and pregnancy, as indicated from evidence gained from epidemiologically-orientated studies
of these authors [44,61] and those currently being conducted by Professor Gillian Bentley at the University of
Durham.
Epidemiological studies, including those of migrants,
have shown substantial systematic variation in the incidence of breast and prostate cancer in the world. From
an anthropological viewpoint, hard physical exercise and
nutritional intake are of interest with regard to human
development, as seen in Bangladeshi women [62], in Iruri
women in Zaire [63] and in Thai schoolgirls [64] shedding
light on lifestyle factors that influence breast cancer risk.
Preneoplastic breast disease:
Oestrogens [65] have long been implicated in mammary
carcinogenesis, supporting the earlier work by Beatson
[66] on the restraint of metastatic breast cancer growth.
Risk factors implicating oestrogens were also recorded by
MacMahon et al [67] and Stasewski [68] and oestrogens
were thought to act by the promotion of cell proliferation in the breast, although possibly as procarcinogens,
initiating genetic change [69-71]. The development of a
sensitive assay for oestradiol was found difficult despite
considerable technical expertise and the availability of
optimisation techniques [72]. However, oestradiol assays were developed and together with those for progesterone, were applied to studies of human development [63,73] that continue at the University of Durham
[74,75].
Detecting the breast at risk of cancer is a primary goal; a
doubling exercise on a calculator intuitively and simplistically indicates a palpable primary breast tumour of 1cc
has ‘doubled’ 30 times since initiation, where intervention, even prevention by use of an ‘anti’- oestrogen like
tamoxifen, or dietary phyto-oestrogens [[76-78] is inappropriate. Different incidence rates between the West
and Asia may relate to differences in blood levels of phyto-oestrogens for which assays were developed [79-81].
Even the small just palpable 1cc tumour has a 27% chance
of being associated with metastatic spread [82] and Gullino [83] considered that breast cancer was systemic for
two-thirds of its total time course. It was Simpson and his
co-workers, [84] who reported pre-cancerous lesions associated with cancer, hyperplasia with a ‘constellation of
cysts, papillary ingrowth and apocrine metaplasia’, in the
region as the foci of cancer’. These observations provided
good evidence of active breast cell hyperplasia and preneoplasia just after the initiation of menarche
202
Wilson et al
and revived the concept [85] of an early transition from
mammary gland preneoplasia to neoplasia [86,87]. Cancer appeared to develop by a series of epithelial cell
changes [88,89] and not a focal dysfunctional event [90].
Moreover, intraductal hyperplasia may form an integral
part of breast neoplasia [91]. Simpson et al [84] examined 164 mastectomy specimens from the Glasgow Royal
Infirmary series (1976-1977) for hyperplastic epithelial
lesions, or epitheliosis , as a function of chronological
age. The incidence of epitheliosis is high near the menopause [92,93] but declines in postmenopausal years thus
possibly implicating ovarian change with the genesis of
epitheliosis. The studies of Bulbrook may be relevant
with respect to low androgen production, related to adrenal DHA-sulphate secretion and paracrine effects [94]
and the capacity of breast cancer to synthesise oestrogens from blood prohormones. The question was raised
as to how a ‘precancerous’ breast can be identified. The
concept that rhythmns of breast temperature was initiated by Simpson and colleagues [95,96] with the close
support of Franz Halberg.
The Chronobra and breast temperature rhythmns:
Surface heat has, for a long time, been implicated in the
functional activity of the breast [97] and heat changes
through the menstrual cycle have been documented using thermography [98]. Of interest to those practising
natural family planning, was the pre-ovulatory rise in
temperature [99]. Using Cosinor Analysis developed by
Halberg and his colleagues [100,101], a circadian rhythm
was observed, a variation of the de Gorter [102] signal,
recognised by Halberg [103,104], of the breast skin temperature pattern overlying a breast tumour. There is a
reduced amplitude and an advanced phase, when compared to a similar site on the contralateral breast. This
pattern was confirmed by Gautherie and Gros [105] and
later, with qualification, by Wilson and his colleagues
[106,107].
A 4-pronged research programme was launched by the
Glasgow-Minneapolis-Cardiff group:
(i)
To characterise, from manually collected
data, circadian and circatrigintan breast skin
temperature rhythms in healthy premeno-
pausal women. Minors and Waterhouse,
in the University of Manchester, provided
some initial valuable computational assistance.
(ii)
To continue manual 30 minute measurements of breast skin temperatures in women with benign breast disease, or primary
breast cancer, the latter involving different
sizes and histological grades of tumour.
(iii)
To build an automatic device, named the
Chronobra, for automatically monitoring
breast skin temperatures [108].
(iv)
To use this device ultimately to detect the
breast at risk of cancer.
Wilson used serial section analysis [106], extended cosinor models [107,109] and cusum techniques [110] for
characterising measurements of manual and chronobra
breast skin temperatures. The data clearly indicated that
the infertile post-ovulatory rise in temperature could be
detected; daily salivary progesterone and oral temperatures were also measured. These studies involved ambulatory individuals going about their everyday routine,
so no attempt was made to study environmental masking, but the experiments provided valuable information
on circadian and circatrigintan breast skin temperature
rhythms and proved the technical (electronics and fabric)
feasibility of developing a more advanced version of the
Chronobra.
Benign breast disease and primary breast cancer:
Circadian breast skin temperature rhythms were characterised in patients with overt or occult benign breast
disease, and overt or occult primary breast cancer
[110,111] using an extended 2-component model (12h
& 24h). In overt benign breast disease or occult primary
breast cancer, no consistent highly significant differences
were observed in rhythm parameters for sensors located
over the tumour site compared with a similar site on the
contra-lateral breast (pairs of sensors were also located
in spatially paired locations elsewhere on each breast);
there appeared to be, however, a reduction in the ini-
Chronobiological Perspectives in Endocrine Cancer and Related Disease
203
tial variance and the percentage variation explained by
the model. In general, overt primary cancer was associated with an increased mesor and decreased amplitude
of the fundamental harmonic, and an advanced acrophase of the same. The reason for the advance in phase,
which resembles deep body temperature, may be due to
the hyper-vascularity of the tumour deflecting more of
the deep body temperature rather than the breast tissue itself. This work indicated the potential of thermorhythmometry to identify the breast at risk, the ‘golden
chalice’. Simpson and his colleagues [112] pursued the
notion that the chronobra could become the ‘elecro-cardiogram’ of the breast. In a substantial series of studies
earlier Griffiths [118] had suggested over a century ago,
that secretion of a substance by the testes may maintain
the male characteristics and Zondek and Ashheim [119]
indicated that this was under pituitary control. So it was
logical to study the androgens and oestrogens in male
human development. Measurements of testosterone in
saliva allowed human pubertal development to be more
fully characterised in terms of their progressive increase
in circadian amplitudes and mesors as one traversed the
genital-pubic hair stages of development [120]. Testosterone and cortisol levels in saliva were used to study
circadian rhythms in continuous daylight and physical
stress [121,122], assays that may prove valuable, along
of premenopausal women, with ‘normal’ or high cancer
risk, breast skin temperatures were measured using the
Chronobra and ovarian function monitored using daily
samples of saliva for progesterone assay. Döring [113]
had found that the maximum volume of the breast was
about d25 of the menstrual cycle, the proliferative phase,
which is comparable to the maximal ‘count’ for mitoses
[114], implying a time of ‘growth’ and of metabolic activity: it is also a time when the Chronobra data gave maximal temperatures suggesting that the Chronobra can be
seen as a chronobiological barometer of such events, a
potential bioassay.
with oestradiol, in occupational medicine, for example in
rotating shift work where one report of increased prostatic cancer risk has been documented [123].
Prostate disease:
In accordance with the events in the USA after the launch
of the Nixon Cancer Plan, Griffiths and his co-founders
set up the British Prostate Study Group, to integrate the
scientific and medical research endeavours in the UK.
Long recognised was the pioneering studies of the Nobel
Laureate, Professor Charles Huggins at the Ben May Institute in Chicago demonstrating the androgen dependence
of prostate cancer [115,116], in accord with the classical
investigations of Hunter [117]. Griffiths and his team and
his wide range of scientific colleagues, have developed
major programmes orientated towards unravelling the
biological and time-qualified components the life history
of prostatic disease.
The endocrine similarities between breast and prostate
cancer were recognised, with both oestrogens and androgens playing an important role in their aetiologies. An
Time-qualified reference ranges, called chronodesms [124] may now take the place of ‘normal ranges’, without sylleptic ambiguity [125],
but they should be compiled separately for
chronological age, sex, weight, height, activityrest, hospitalised-domiciled, ambulant, supine
[126,127]. However, even a time-qualified
measurement in a ‘distant’ pool such as blood,
urine or saliva, may not directly relate to a system pathology [128]. This is because the parameters governing secretion, transfer rates, and
disposal rates from pools, either chemical or
anatomic, do not necessarily reflect the organ
itself, but may be a surrogate for exposure in
certain situations. In the human male, as andropause looms, there is an increased oestrogen
to testosterone ratio in blood and within the
prostate gland, as testicular function declines.
Oestrogens react with receptors in the stromal
elements of the prostate. These oestrogens are
formed from C19-steroids such as DHA and androstenedione in adipose and muscle tissue, by
the aromatase enzyme system. Oestrogens also
increase the synthesis of sex-hormone binding
globulin, which also affects the free steroid moieties in blood and reflected in saliva.
It is pertinent that saliva concentrations of neutral ster-
204
reflect the free non-protein bound moiety which is likely
to diffuse other organs such as the prostate but which
may, if the intra-cellular concentrations are low, not obey
classical enzyme kinetics and thereby, receptor-hormone
interaction [129]. Even more complicated are the physico-biochemical properties of free radicals which appear
to be involved in the genesis of cancer through complex intracellular mechanisms. They have redox-active
properties which may covalently alter target molecules
to effect signal induction and these may be affected by
geomagnetic fields - Franz Halberg often discusses geomagnetics.
Thus, gene imprinting by transplacental transmission of
an oestrogen signal [130] or in neonatal life, may, though
methylation of specific nucleotides, restrain the expression of certain genes. There is good evidence that this can
lead to dysfunctional growth later in life. Such gene imprinting may be removed during pubertal development
or later on in adolescent years [131-133]. This dysfunctional growth may be manifest in proliferative inflammatory atrophy, which may be a forerunner of preneoplasia,
prostatic intraepithelial neoplasia and cancer [134].
Current research focuses on the aetiology of proliferative inflammation atrophy and how this may possibly
lead to preneoplasia and to cancer [133]. Inflammation
generates free radicals [134,135] that cause tissue and
protein damage, the nitric oxide radical for example,
forming peroxynitrite, or the hydroxyl radical reacting
with guanine to form 8-hydroxy guanine and thence
8-hydroxy–2-deoxyguanosine, a mutagenic agent that
causes DNA damage. The superoxide anion leads to peroxidation of lipids and microvascular epithelial damage.
Membrane damage causes the release of arachidonic
acid, which is converted by cyclo-oxygenases to various
compounds such as leukotrienes and prostaglandins, the
latter enhancing pain receptor activity. Macrophage and
neutrophil infiltration to an inflammatory lesion, also
produces NO through the induction of NO-synthase, although these are removed by the superoxide dismutase
enzyme system, with the hydrogen peroxide produced
being removed by the glutathione-S-transferase-π and
glutathione peroxidases.
Wilson et al
Glutathione-S-transferase-π expression may be under
the control of oestrogens [136]. Of relevance to inflammatory processes, though not expanded further here, is
the role of nitric oxide, formed from L-arginine by nitric
oxide synthase, in enhancing COX activity that produces
proinflammatory prostaglandins [137]. It would appear
that inflammatory lesions are associated with both epithelial secretory disruption and focal atrophy, and cellular proliferation. This undoubtedly involves the interplay
between tumour necrosis factor (TNF) and corticosteroids, with the transforming growth factor (TGF-β) family
inhibiting growth, and the Cox-1 and Cox-2 expressed by
different genes.
Furthermore, Hungin and his team of researchers at
the School of Medicine and Health at the University of
Durham, has an active interest in hormonal regulation
or influence of inflammatory bowel disease and related
disorders. Some of this work is being conducted using
the General Practice Research Database (GPRD). This is
the world’s largest known computerised system of anonymised longitudinal primary care medical records comprising 3.6 million active patients. Although retrospective
case-control studies have been carried out to investigate
a possible association between prostatitis and cancer
[138], with recall and detection biases and difficulties
that arise in diagnosis, perhaps it is timely to revisit this
problem with a large database, subject to clinical criteria [139], hormonal information such as chronobiological exposure to androgens and oestrogens and adequate
post-prostatitis follow-up, since the inflammatory lesion
characteristic of prostatitis could well constitute a premalignant lesion [133].
Conclusion:
In conclusion, this report demonstrates the immense
impact that Professor Franz Halberg has had on the
development of the chronobiology in general, but to that
applied to the studies of the authors in particular. The
report presents a flavour of how chronobiology has had
and continues to have a vital role in health and medicine as
it relates to studies of cancers of the breast and prostate,
conducted at the erstwhile Tenovus Institute-Cardiff
University- University of Minnesota axis and on current
studies at the University of Durham. It is most certainly not
205
Chronobiological Perspectives in Endocrine Cancer and Related Disease
a comprehensive report, as the hypothalamic-pituitary
feedback mechanisms would stretch easily to volumes,
as would the intracellular signalling, epidemiological,
pathological,
oncological,
immunological
and
physiological areas wherein chronobiological principles
are fundamental. The UK authors, applaud and pay
tribute to the colossal contribution Professor Halberg
has made to chronomics. It is he, most ably supported
by Profesor Germaine Cornélissen, who has been, and
continues to be, the pioneer of this research, uncovering
what nature has laid down, and using it in the service of
man and other occupants of this planet. As Durham takes
its place as a world university, embracing the challenging
educational needs of the present and future, beautifully
stated by its Vice Chancellor on the 15th July 2009, the
increased accommodation of chronobiology into health
and medicine in research projects, and into student
education constitutes yet an associated challenge, well
recognised by its Dean of Medicine, one of the authors
of this report. Better therapeutic approaches that
capitalise upon chronotolerance and chronoefficacy
and challenge of the concept of clinical equipoise are
necessary, but better still, must be a focus on disease
prevention and potential intervention approaches
through chronobiological health monitoring. An ounce of
prevention is worth a pound of cure, once said Professor
Tarquini [140]. We look forward most eagerly to the next
decade of our Father Figure’s scientific achievements,
well supported by Professor Germaine Cornélissen, but
not as spectators but as active participants. Ten years
from now, we shall return to hear a little of their exploits
and pray that for some time yet, ‘rain will not stop play’
as the English would say.
An acknowledgement:
DW is sincerely indebted to Professor Franz Halberg for
the sharing of his extraordinary insight into the biology of
the Cosmos over the past three decades, and to Professor Germaine Cornélissen, for her thinking and research
skills that have been so helpful.
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Intl. J. of GERONTO-GERIATRICS, 12 (15) , 213-216 July 2009
DÓSIS ÚNICA DE CARBONATO DE LITIO EN PACIENTES BIPOLARES GERIÁTRICOS
Roberto Miranda Camacho1
Sociedad Mexicana de Psiquiatría, A.C. Mexico.
Resúmen
El litio es una de las armas terapéuticas mas importantes
y revolucionarias dentro de la psicofarmacología
psiquiátrica. Las sales de litio tienen un sitio único en el
tratamiento de mantenimiento a largo plazo de pacientes
con una diversidad de trastornos graves y recidivantes de
la afectividad.
El litio se utilizo en el siglo XIX como sedante y
anticonvulsivante. La solubilidad del urato de litio
condujo a J.F. Cade en Australia, a dar a animales
de experimentación una sal de litio para disminuir
la nefrotoxicidad del acido úrico, con el que estaba
experimentando en su búsqueda de una conexión entre
el metabolismo de las purinas y la conducta.
Casualmente, noto que la sal de litio producía un
efecto sedante en los animales y se decidió en ensayar
el litio clínicamente en humanos. El 1949 describió
varias anécdotas sorprendentemente favorables en
pacientes maniacos agudos este informe dio lugar a
una investigación intensa de las acciones biológicas y
clínicas.
En 1950 el Dr. Schou fue el primero que observo en la
necesidad de tener niveles plasmáticos constantes de
litio entre .5 y 1.5 meq/lt para tener un efecto terapéutico
adecuado. Estos niveles son muy importantes para
mantener al paciente en una estabilidad clínica y de
mantenimiento.
Hasta el momento actual se ha dicho que el litio va a actuar
sobre el sodio, potasio, magnesio, calcio así como varios
neurotransmisores como son serotonina, dopamina,
norepinefrina, Gaba y otros como son el A.M.P cíclico y
hormonas. Sin poder precisar el mecanismo de acción
sobre la modificación cerebral que se realiza la cual lleva
a ejercer un efecto clínico beneficioso y/o estabilizador
del trastorno afectivo.
Se sabe que el litio tiene un efecto inibitorio sobre la
enzima adenil ciclasa cerebral que como se conoce es un
enzima marcapaso que provoca una serie de reacciones
en cascada y como ultimo paso va a provocar un
decremento de la fosforilaza A y de esa manera provoca
una disminución en la glicogenolisis. Además esta
demostrado que el litio disminuye el recambio de glucosa
y fosfato solamente durante el periodo que los niveles
de litio se encuentran elevados y asi posteriormente hay
un equilibrio en la concentración de la glucosa y fosfato
este mismo fenómeno sucede con el glucógeno cerebral
por lo tanto los efectos terapéuticos de litio no son
dados en un nivel constante sanguíneo lo cual produciría
un medio interno adecuado y estable en el cerebro si
no que por medio de cambios bruscos neuroquímicos
se desencadenan después de la administración de
litio y durando posiblemente hasta 72hrs. Debido a las
reacciones en cascada provocadas inicialmente por el
litio.
Tomando en cuenta estas consideraciones bioquímicas y
además de los frecuentes efectos indeseables colaterales
provocados por la ingesta del carbonato de litio,
consideramos una única dosis de 300mg a 600mg. Pero
no la suma de dosis administradas durante el día de tal
manera que si un paciente tomara la dosis fraccionada
de 300mg 3 veces al día seria cambiado el esquema
terapéutico inicial por 300mg.y 600mg en la noche como
actualmente se aconseja tomar el litio cada 12hrs. Para
mantener los niveles estables así como el cuadro clínico
214
Roberto Miranda Camacho
posteriormente únicamente administraremos de 600mg
a 300 mg por la noche y tratando de continuar con los
niveles cericos adecuados y con este esquema observar
clínicamente si aumentábamos o disminuíamos la dosis
según el caso tomando en cuenta los efectos colaterales
y terapéuticos.
normal (0.5meq/lt-1.2meq/lt) para posteriormente con
la disminución en la toma de 600mg bajaron los niveles
séricos en un promedio de .6 a .8 meq/lt sin existir
exacerbación de su cuadro clínico, así como tampoco en
los efectos secundarios, e incluso en algunos pacientes
se pudo disminuir la dosis a 300mg de litio por la noche.
Material y Métodos
Los efectos colaterales mas representativos fueron:
Se estudiaron a 16 pacientes geriátricos de edades entre
45 y 60 años de edad de ambos sexos con diagnostico
de trastorno bipolar tipo 1 de los cuales se excluyeron 7
pacientes masculinos por:
Aumento de peso
+++
Fatiga y desgano
++
Tristeza
++
Polidipsia
+
Irritabilidad
+
Nausea
+
3 pacientes se perdieron durante el estudio.
2 por la irregularidad en la toma de su dosis del carbonato
del litio.
2 por presentar exacerbación en los síntomas colaterales,
ya que no pudieron controlarse con la dosis única de
600mg y al administras 900mg por la noche se provoco
un estado nauseoso llegando al vomito constante. Y
suspendiendo voluntariamente la toma de litio con la
consecuente aparición de la sintomatología maniaca, por
lo cual se les tuvo que administrar 300mg por la mañana
y 600mg por la noche con lo que se estabilizo el cuadro
clínico.
Los nueve pacientes restantes de sexo femenino se les
estudio desde el punto de vista terapéutico de efectos
colaterales, control de niveles plasmáticos, cada 15
días, con la aplicación con una escala propia de efectos
colaterales y la toma de sérica de litio 12hrs después
de la toma del medicamento durante un promedio
de 6 meses y consulta psiquiátrica de control de
sintomatología maniaca inicialmente cada 5 días por 45
días y posteriormente cada 15 días por el resto de los 6
meses.
Resultados
En este estudio preliminar; con los 9 pacientes podemos
observar que la eficacia del carbonato de litio manejada
con una única dosis por la noche mostro que su
sintomatología no se exaservó y que además los efectos
secundarios disminuyeron notablemente. Por un mes se
dio la dosis única de 900mg por la noche, observando
que sus niveles séricos se conservaron en un promedio
Los efectos colaterales disminuyeron considerablemente
ya que el aumento de peso disminuyo en 5 de las pacientes
así como la irritabilidad y la polidipsia, y únicamente
aumento el signo neurológico de la rueda dentada en 6
pacientes ,así como el dolor localizado principalmente en
la espalda en 5 pacientes y el temblor distal localizado en
miembros superiores(manos en 4 pacientes )
Concluciones
En este estudio preliminar podemos observar que la
eficacia de el carbonato de litio manejada en pacientes
geriátricos con trastorno bipolar tipo 1 manejados con
una dosis única de litio de 600mg a 300mg por la noche
mostraron que su sintomatología clínica no se exacerbo
y que además los efectos colaterales indeseables
disminuyeron y otros fueron controlados fácilmente por
los pacientes.
Además se pudo observar que si alguno de los pacientes
estudiados olvidaba o dejaba de tomar el medicamento
por uno o mas noches el cuadro clínico se instalaba
rápidamente pero también se controlaba rápidamente
al volver a tomar su dosis única de litio por lo que se
considero que el efecto terapéutico es a corto plazo y
posiblemente este aspecto sea debido a la inhibición que
efectúa el litio sobre la enzima adenil ciclasa cerebral la
Dósis Única de Carbonato de Litio en Pacientes Bipolares Geriátricos
cual provoca reacciones bioquímicas en cascada y que
cataliza la formación de la AMP cíclico en A.T.P, asi mismo
la liberación disminuida de norepinefrina y nuevamente
la inhibición de la adenil ciclasa cerebral pueden contribuir
a producir un bloqueo adrenérgico que beneficiaria en la
sintomatología afectiva en estos pacientes con una sola
pequeña dosis de litio.
Aquí cabe preguntarnos que tanta influencia tendrán los
cationes monovalentes y otros divalentes sobre la enzima
adenil ciclasa cerebral.
Por otro lado se demostró con este estudio que la dosis
única de litio administrada por la noche es efectiva desde
el punto de vista clínico como el de disminuir los efectos
colaterales indeseables así como evitar que el paciente
abandone el tratamiento medico.
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