homeonews - Farmacia Natural

Transcripción

HOMEONEWS
Edición N° 8
Abril – Mayo -Junio de 2007
Director: Farm. Fernando Estevez Castillo
PUBLICACION BIMESTRAL
DISTRIBUCION GRATUITA
PARA PROFESIONALES DE LA SALUD
Homeonews
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Edición N° 8 – Abril – Mayo - Junio de 2007
Edición n° 8
Abril – Mayo - Junio de 2007
Registro de la Propiedad Intelectual n°: 505276
Director: Fernando Oscar Estevez Castillo
Propietario: Fernando Oscar Estevez Castillo (C.I.: 10.103.605)
Dirección postal: Pte. Quintana 414 – Lanús Oeste – Pcia de Buenos Aires
(B1824NVJ), Argentina
Tel.: (54-11) 4241-4441
E.Mail: [email protected] ó
[email protected]
Director: Fernando Estevez Castillo
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INDICE
1- Editorial, pág. 5.
2- Fitoterapia:
Eficacia de una pomada de extracto de raíz de consuelda en el tratamiento
de pacientes con osteoartritis dolorosa de rodilla: resultados de un ensayo
controlado contra placebo, randomizado, bicéntrico y a doble ciego, pág. 6.
3- Alopatía:
Diclofenac tópico en el tratamiento de la queratosis actínica, pág. 21.
4- Homeopatía:
Efecto de preparaciones homeopáticas en el desarrollo del cáncer de
próstata humano en modelos animales y celulares, pág. 33.
5- Nutrición:
Estudio piloto abierto para medir los efectos de altas dosis de concentrados
de EPA/DHA en los fosfolípidos de plasma y el comportamiento de niños
con déficit de atención e hiperactividad, pág. 52.
6- Recordatorio:
-Prof. Dra. Madeleine Bastide, pág. 66.
-Farm. Arturo Méndez, pág. 67.
7- Novedades:
-Nuevo producto cosmético; pág. 69.
-Libros; pág. 70.
-Nuevo programa radial; pág. 72.
7- Actividades:
-Exposalud; pág. 73.
-II Curso Internacional de Farmacia Homeopática, Lima, Perú; pág. 74.
-Encuentro de Medicinas Alternativas y Complementarias; pág. 76.
-Mercofito III; pág. 78.
8- Cursos, Congresos y Seminarios; pág. 80.
9- Formulario de suscripción, pág. 86.
Homeonews
Foto de tapa: Symphytum officinale L. (Boraginaceae).
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Las opiniones vertidas en los artículos firmados son responsabilidad de sus autores.
EDITORIAL
Estimados colegas del equipo de salud:
Otra vez nos reencontramos con un nuevo número de Homeonews,
demorado en su salida debido a que día a día incorporaba más material y como
consecuencia postergaba su edición, pero espero que esta tardanza no haya
sido en vano y puedan disfrutar de uno de los ejemplares más completos
publicados hasta el momento.
También no quiero dejar de expresar mi tristeza por la pérdida de dos grandes
profesionales y personas, como la Dra. Madeleine Bastide y el Farm. Arturo
Méndez. En el capítulo RECORDATORIO, les contaré como conocí a éstas
dos figuras de la Homeopatía, y algunas características de sus personalidades,
que sólo los GRANDES personajes tienen. Con respecto a los trabajos, todos
muy interesantes y con excelentes posibilidades de aplicación práctica; la
eficacia de la pomada de raíz de consuelda en la osteoartritis de rodilla; el uso
de diclofenac en forma tópica para el tratamiento de la queratosis actínica; una
investigación con preparaciones homeopáticas y su efecto en el desarrollo del
cáncer de próstata y por último un estudio que mide los efectos de altas dosis
de concentrados de EPA/DHA en los fosfolípidos de plasma y el
comportamiento de niños con déficit de atención e hiperactividad. En
NOVEDADES, OMS lanzó un nuevo producto cosmético, BIOCELL FIRM®,
algunos libros muy interesantes para recomendar su lectura y RADIO
PALERMO presenta un nuevo programa, “AMIGOS DE LO NATURAL”. En
ACTIVIDADES, contamos los pormenores de la EXPOSALUD, el II Curso
Internacional de Farmacia Homeopática (Lima, Perú), el Encuentro de
Medicinas Alternativas y Complementarias y el MERCOFITO III, todos con muy
buena repercusión. En CURSOS, CONGRESOS Y SEMINARIOS; distintas
posibilidades para capacitarse, tales como el Curso de Farmacia Homeopática
y el de Control de Calidad micrográfico de Plantas Medicinales y Alimentos de
Origen Vegetal, ambas actividades de la Facultad de Farmacia y Bioquímica
(UBA), el XVIII Congreso Farmacéutico Argentino que se desarrollará en
Mendoza, la Cumbre Mundial de Armonización en Medicina Tradicional,
Alternativa y Complementaria (Lima, Perú) y el Seminario de Obesidad y
Diabetes organizado por la Asociación Argentina de Médicos Naturistas. Por
último quiero agradecer al Dr. Gilberto Pozetti, prestigioso colega y amigo
brasilero, por el envío de trabajos de su autoría con autorización para publicar
en Homeonews, que próximamente podremos disfrutar.
Hasta el próximo número de
tiempo en salir a la luz!!
Homeonews,
que prometo no demorará tanto
Farm. Fernando Estévez Castillo
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Homeonews
FITOTERAPIA
EFICACIA DE UNA POMADA DE EXTRACTO DE RAIZ DE CONSUELDA
(SYMPHYTI OFFIC. RADIX) EN EL TRATAMIENTO DE PACIENTES CON
OSTEOARTRITIS DOLOROSA DE RODILLA: RESULTADOS DE UN
ENSAYO CONTROLADO CONTRA PLACEBO, RANDOMIZADO,
BICÉNTRICO Y A DOBLE CIEGO
B. Grubea, J. Grünwalda, L. Kruga and C. Staigera.
a
Merck Selbstmedikation
Germany.
GmbH,
Rößlerstrasse
96,
64293
Darmstadt,
[Phytomedicine, Vol 14, Issue 1, 10 January 2007: pp. 2-10]
RESUMEN
Este ensayo clínico controlado contra placebo, randomizado, a doble ciego y
bicéntrico, investigó el efecto de la aplicación diaria de 6 g de Kytta-Salbe® f
(3×2 g) durante un período de 3 semanas con pacientes que padecían
osteartritis dolorosa de rodilla.
Los 220 pacientes examinados fueron 153 mujeres y 67 hombres de un
promedio de edad de 57,9 años y con dolencias relacionadas a la osteoartritis
de rodilla durante 6.5 años (promedio). Doscientos veinte pacientes fueron
incluidos en Full Analysis Set (FAS) y ciento ochenta y seis (186) (84.5%) en
Valid Case Analysis Set (VCAS).
Durante el ensayo, el puntaje total de la escala visual analógica (VAS) (valor
primario) en el grupo verum, cayó 51.6 mm (54.7%) y en el placebo 10.1 mm
(10.7%). La diferencia promedio entre los grupos de 41.5 mm (95% de
intervalo de confianza=34.8 to 48.2 mm) o 44.0% es significativa (p<0.001).
Esto se confirma a través de la evaluación diaria, el VCAS y la valoración
separada de los dos centros. Esto también se aplica a la evaluación separada
del puntaje total de VAS, siguiendo el dolor en reposo y en movimiento.
El puntaje total WOMAC (Western Ontario and McMaster Universities) (valor
secundario) mejora de manera similar al puntaje total de VAS. Al final del
ensayo, se registró una reducción de 60.4 mm (58.0%) para el grupo verum y
de 14.7 mm (14.1%) para el placebo. La diferencia promedio entre grupos de
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45.7 mm (95% de intervalo de confianza=37.1 a 54.3 mm) o 43.9% fue
significativa (p<0.001).
La diferencia entre los grupos tratados se incrementa sistemáticamente y
significativamente, en paralelo con la duración del tratamiento. De esta manera,
se demuestra la superioridad del tratamiento con Kytta-Salbe® f con respecto
al placebo, inclusive por medio del análisis multivariado y multifactorial para
medidas repetitivas.
Con respecto a las medidas exploratorias secundarias, SF-36 (calidad de vida),
medida del ángulo (movilidad de la rodilla), CGI (impresión clínica global) y
evaluación global de la eficacia por el médico y el paciente, se demostró una
superioridad significativa (p<0.001 en cada una) del grupo verum sobre el
placebo.
Los resultados sugieren que la pomada de extracto de raíz de consuelda es
apropiada para el tratamiento de la osteoartritis de rodilla. El dolor se reduce,
mejora la movilidad de la rodilla y por ende la calidad de vida.
Palabras clave: Comfrey; Symphytum officinale; Doble ciego; Randomizado;
Ensayo clínico controlado contra placebo; Osteoartritis de rodilla; Eficacia;
Rodilla; Dolor.
ARTICULO ORIGINAL
Introduction
Rheumatic disorders have different causes (inflammatory, infectious,
degenerative, metabolic), are located at different parts of the body (joints,
tendons, muscles, spine) and have different symptoms. Among them are
several chronic tissue diseases and painful disorders of the locomotor system,
including osteoarthritis of the joints.
Osteoarthritis characterises a primarily non-inflammatory, degenerative change
of the structure of the cartilage and bones of one or more joints, involving an
increasing deformation of the joint. On principle, all joints can be affected;
frequently knee and hip joints, hands and the spine are affected. The frequency
of osteoarthritis rises with age, approximately 80% of people over 75 are
affected (Cooper, 1998). Osteoarthritis of the knee is described by the Deutsche
Gesellschaft für Rheumatologie (German Rheumatology Association) as a
disease primarily of the joint cartilage which coincides clinically with pain (pain
upon walking, pain on exercise), limited movement and walking impairment, and
can result in instability, false position and concomitant synovialitis (active
athrosis) (Deutsche Gesellschaft für Rheumatologie, 2000).
The multitude of diseases and complaints is faced by an equally large number
of therapeutic drug-based and non-drug based treatment options (Walker-Bone
et al., 2000, Hunter and Felson, 2006). Due, in particular, to the symptoms:
pain, joint stiffness and restriction of movement, patients seek therapeutical
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advice. As a result, symptomatic improvement represents an important
therapeutic objective. The reduction of pain, the preservation and the
restoration of the joint's function and thus the restoration of quality of life are
therefore important target parameters in clinical trial (Förster, 2005).
The phytopharmaceutical drugs used in Germany are made, for instance, from
willow bark and comfrey root. Since antiquity, the medicinal plant comfrey has
been used both internally and externally in different forms of administration, for
the treatment of a variety of diseases, e.g. bone fractures, wounds and ulcers
(Englert et al., 2005).
In recent times, several clinical trials have proven the efficacy of comfrey in the
treatment of distorsions, strains and sprains and other muscle and joint
complaints (Koll et al., 2004; Predel et al., 2005; Kucera et al., 2005, Staiger,
2005).
In recent observation studies a reduction of pain of approx. 50% in respect of
joint pain and a virtually complete decline of morning stiffness was observed
after approximately two weeks of treatment with preparations containing
comfrey root extract (Klingenburg, 2004; Tschaikin, 2004).
The efficacy of comfrey is essentially due to its anti-inflammatory, analgesic,
granulation promoting and antiexsudative properties (Kommission E, 1990,
Schmidtke-Schrezenmeier et al., 1992). Allantoin, rosmarinic acid and other
hydroxycinamon acid derivatives as well as muco-polysaccharides are likely to
be of critical importance for the pharmacodynamics of the root drug (Andres et
al., 1989; Gracza et al., 1985).
Patients and methods
The clinical trial was performed in accordance with the ICH-GCP guidelines and
the Declaration of Helsinki. The patients were informed prior to commencement
of the trial and provided written confirmation of their participation in the trial.
This double-blind, randomised, bicenter, placebo-controlled trial involved a total
of 220 patients with painful osteoarthritis of the knee. Both ambulatory centres
were located in Berlin, Germany. Principal investigator was Barbara Grube,
Kurfürstendamm 157/158, further investigator was Regina Busch, Weißenseer
Weg 111. The CRO was Dr. Jörg Grünwald, Waldseeweg 6, Berlin, Germany.
Biometry was done by Prof. Dr. Klaus-Dieter Wernecke, Wildensteiner Str. 27,
Berlin, Germany.
The patients were randomly allocated to one of two treatment groups and
received either the commercially available Kytta-Salbe® f or a placebo. Kytta
Salbe® f contains comfrey root liquid extract (1:2, ethanol 60% V/V, 35%), the
holder of the marketing authorisation is Merck Selbstmedikation GmbH,
Darmstadt, Germany (Fachinformation Kytta-Salbe® f 2006). The extract
specification allows an Allantoin content of 0.2–0.5% (m/m). A special
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procedure is applied to remove over 99% of the pyrrolizidine alkaloids contained
in Symphytum officinale (specification: <0.35 ppm in the proprietary medicinal
product).
The criteria for inclusion and exclusion are listed in Table 1. The patients
applied a 6 cm long thread of verum or placebo ointment on the skin covering
the knee joint three times a day and massaged this in. In the event of
osteoarthritis of both knees, both knee joints were treated but only the knee that
was more severely affected on admission to the trial was assessed. Treatment
continued for a period of 21 days. Following a thorough initial examination
during the first visit, clinical controls were performed after 6–8, 13–15 and 20–
22 days (visits 2–4). In addition to the visits, patients logged the course of pain
in a diary.
Table 1.
Inclusion and exclusion criteria
Inclusion criteria
1. Age
18 years (women of reproductive potential should use effective contraceptive
measures throughout the trial)
2. Patients provide their written agreement of their participation in the trial, understand the
objective of the trial and agree to comply
3. Pain intensity of at least 40 mm on the 100 mm visual analogue scale (VAS) on inclusion
Exclusion criteria
1. Intake of steroids within the last 4 weeks prior to the start of the study
2. Intake of analgesics
3. Intake of systemic and/or local anti-inflammatory drugs prior to the start of the trial (
the half-life)
4. Known hypersensitivity reaction to any of the components of the treatment
5. Severe systemic and organ disorder
6. Cancer as well as AIDS (HIV-positive)
7. Pregnancy and lactation
8. Alcohol abuse, addiction to therapeutic drugs and drugs of abuse
double
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9. Currently participating or having participated in another clinical trial in the preceding 6 weeks
10. Compliance with and adherence to the protocol cannot be guaranteed due to language
problems
Primary and secondary target criterion
The primary target criterion was pain relief, namely the reduction of the total
score from pain at rest and on movement, assessed by the patient using a
100 mm Visual Analogue Scale (VAS). The patient scores were measured in
millimetres. Their estimations were rounded up/down to 5 mm.
The secondary target criterion was the improvement of the pain, stiffness and
function symptoms, determined by means of the WOMAC test (Western Ontario
and McMaster Universities). It is recognised as a reliable and valid tool for the
recording of the symptoms and physical function restrictions of patients
suffering from osteoarthritis of the hip and knee and comprises a total of 24
questions. Each question is presented as an analogue scale and answered by
the patient through ticks. (Stucki et al., 1996; EMEA, 1998 CPMP/EWP/787/97).
Further concomitant variables
The restriction of movement of the knee joint was recorded at all visits through
angle measurement (neutral-zero method). Excessive stretching and bending of
the knee joint were measured using a plastic protractor (Hess, 1992; Meinecke
and Gräfe, 2002).
To determine the quality of life, the patients answered the German version of
the SF-36 questionnaire at visits 1 and 4 (Bullinger, 1995).
The investigators assessed the severity of the disease using the CGI
questionnaire. On the basis of the Clinical Global Impression (CGI), the
investigator can execute a benefit-risk assessment of the therapeutic treatment
and determine the severity of the disease, the global change of condition and
the efficacy index (ratio of effect and adverse drug reactions) (Guy, 1976).
In addition, the vital parameters (heart rate, blood pressure) and adverse events
(AE) were registered. All AEs and their possible link with the trial medication
were recorded. Compliance was tested by means of the amount of trial drug not
used. At the end of the study a global assessment of efficacy and tolerance was
made.
The exploratory analysis of the trial was scheduled prospectively, the patient
collective determined prior to unblinding. The assessment was effected
descriptively. The primary endpoint was the pre–post difference in VAS pain
scores. A difference in the comparative branches of the trial (Kytta-Salbe® f
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versus Placebo) was analysed using the non-parametric two-sample test in
accordance with the Mann–Whitney. The diary and the secondary target value
were subjected to the same procedure.
Possible changes of clinical parameters when comparing individual visits were
tested using the Wilcoxon test for related samples. All tests were performed
with a type 1 error α=5% two-tailed or 2.5% one-tailed. The evaluation of results
for the primary and secondary target value was effected both in accordance
with the Full Analysis Set (FAS) principle and in accordance with the Valid Case
Analysis Set (VCAS) principle. All patients for whom a signed informed consent
form was available and who had received the investigational therapy were
included in the FAS collective. The VCAS collective includes all patients treated
per protocol.
Results
General information
A total of 220 patients (153 female, 67 male) were randomised and received
trial medication after providing written agreement of their participation in the trial
(FAS and Safety population). The patients were of an average age of 57.9
years. The complaints relating to osteoarthritis of the knee had on an average
persisted for 6.5 years.
There was no significant group difference with regard to distribution of sex, age,
height, and body weight. 44 of the 220 patients (20%) suffered from
osteoarthritis of the right knee, while in 33 the left knee was affected. A total of
143 patients (65.0%) suffered from osteoarthritis of both knees, while the right
knee was more severely affected in 89 cases and the left knee in 54 cases.
There was no significant difference between the groups.
A total of 34 patients, who did not observe the trial's term of 20–22 days or used
25% more or less of the trial medication, were excluded from the VCAS
collective.
Efficacy
With regard to total pain (total of pain at rest and pain on movement), no
significant difference (p=0.972) between the groups in the FAS collective was
discernible at the outset of the trial. A continual decline of pain was achieved in
both groups; a decline of 51.6 mm (54.7%) in the verum group but only
10.1 mm (10.7%) in the placebo group by the end of the trial. In the verum
group the reduction of pain was therefore five times that of the placebo group.
The average group difference of 41.5 mm (95% confidence interval=34.8 to
48.2 mm) corresponds with 44% and is significant (p<0.001). In accordance
with the primary target value the intensity of pain was reduced considerably in
the verum group from an initial average of “moderate pain” (47.1%) to “mild
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pain” (21.3%). The difference between the treatment groups increased
systematically, in parallel with the term of the treatment (Fig. 1).
Fig. 1. VAS total score (Pain at rest and on movement).
With regard to pain at rest, again no significant difference (p=0.715) between
the groups in the FAS collective was observed at the outset of the trial. In the
course of the trial, however, a significant decline of pain of 20.9 mm (56.6%)
was recorded in the verum group, while the placebo group recorded a decline of
only 4.6 mm (12.2%). The difference between the groups of 44.4% is significant
(p<0.001). The development during the clinical trial is depicted in Fig. 2.
Fig. 2. VAS pain at rest.
With regard to pain on movement, the two groups in the FAS collective again
did not vary significantly (p=0.734) at the outset of the study. At the end of the
trial, however, the verum group had undergone a reduction of pain on
movement of 30.7 mm (53.5%) while the placebo group had only undergone a
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reduction of 5.6 mm (9.9%) (Fig. 3). The group difference to the baseline was
significant (p<0.001).
Fig. 3. VAS pain on movement.
The significant differences are always confirmed by the evaluation of the diary,
the VCAS collective and the separate assessments of the two centres.
WOMAC and SF-36
With regard to the WOMAC total score (secondary target value), an
improvement was found similar to the VAS total score: At the end of the trial, a
reduction of 60.4 mm (58.0%) was recorded for the verum group and a
reduction of 14.7 mm (14.1%) for the placebo group. The average group
difference amounted to 45.7 mm (95% confidence interval for the average value
37.1 to 54.3 mm) or 43.9% and is significant (p<0.001). The significance is also
confirmed by the VCAS assessment and the separate assessment of the two
centres. The division of the WOMAC by pain, stiffness and physical function
also resulted in a significant superiority (p<0.001 each) of the verum over the
placebo.
In the course of treatment a considerable improvement of the quality of life (SF36) of the verum group over the placebo group was observed. The significant
group difference was 33.9% (p<0.001) for physical function and 7% (p=0.006)
for mental function.
Mobility and CGI
With regard to the restriction of movement, patients in the verum group
experienced a significant improvement (p<0.001) of knee flexion — on an
average by 7.5 °C (7.0%). In the VCAS collective the group difference was
7.8 °. The neutral-zero scaling of the knee showed that patients, on an average,
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were unable to fully extend their knee (upper and lower leg form a straight line)
at the outset of the trial. At the end of the trial, the verum group had undergone
an average improvement of 2.0 °, while the placebo group had undergone an
average deterioration of 0.4 °. The group difference is significant (p<0.001), in
the VCAS collective as well.
The Clinical Global Impression (CGI) on the severity of the disease and on the
change of the condition also resulted from the significant superiority (p<0.001)
of the verum over the placebo. In the verum group 29.1% of patients exhibited a
“slight”, 52.7% a “clear” and 10.9% a “comprehensive” improvement, in
compliance with the change of the condition, as expected. 7 patients no longer
required treatment. In the placebo group 82.6% did not experience any
improvement.
The assessments of the investigators and patients on global efficacy complied
well with this. In the placebo group no effect was observed in respect of 85.5%
(patient view) or 90.9% (physician's view) of patients, while 77.3% or 80.0% of
patients in the verum group experienced a good effect (Table 2). At the end of
the trial, 8 patients of the verum group were free from symptoms.
Table 2.
Global assessment of efficacy (FAS collective)
In summary, it can be noted that a highly significant superiority of the comfrey
root extract ointment could be proven over the placebo (Table 3) in respect of
both the primary and the secondary target value (VAS, WOMAC) and all
concomitant variables (SF-36, angle measurement, CGI, global assessment of
efficacy).
Table 3.
Summary of the changes achieved after three weeks and the group difference
Efficacy variable
Verum group
Absolute
Relative
(%)
Placebo group
Absolute
Relative
(%)
VAS (mm)
Group
difference
Absolute
%
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Efficacy variable
Verum group
Placebo group
Group
difference
Absolute
Relative
(%)
Absolute
Relative
(%)
Absolute
%
Total score
51.6
54.7
10.1
10.7
41.5
44.0
Pain at rest score
20.9
56.6
4.6
12.2
16.4
44.4
Pain on movement score
30.7
53.5
5.6
9.9
25.1
43.6
Total score
60.4
58.0
14.7
14.1
45.7
43.9
Pain score
12.1
58.2
2.7
12.9
9.4
45.3
Stiffness score
4.8
55.8
1.2
13.2
3.6
42.6
Function score
43.4
58.2
10.7
14.4
32.7
43.8
Physical function score
11.9
38.1
1.3
4.2
10.6
33.9
Mental function score
4.2
9.5
1.1
2.5
3.1
7.0
Knee flexion
7.5
7.0
0
0
7.5
7.0
Extension of the knee (neutralzero)
−2.0
−65.8
0.4
19.6
2.4
85.4
WOMAC (mm)
SF-36 (points)
Angle measurement (°)
Safety
In the course of the clinical trial 22 patients (10.0%) experienced a total of 22
AEs. These related to 7 patients (6.4%) in the verum group and 15 patients
(13.6%) in the placebo group. One patient in the placebo group discontinued
the clinical trial at the third visit at her/his own request, due to ineffectiveness.
All AEs were not serious and did not represent an adverse drug reaction (ADE).
There was no significant difference between the groups (p=0.072).
At the end of the trial (visit 4), a global assessment of tolerance was performed
by the physician and the patient using a scale. Values ranging from “very good”,
“good”, “moderate” and “bad” could be given. Only “good” and “very good”
ratings were issued: In the verum group the “very good” ratings predominated
(73.6%, physician and patient) and in the placebo group, the “good” ratings
(50.9% physician and 53.6% patient).
Discussion
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Osteoarthritis of the knee is among the most frequent degenerative joint
diseases within the rheumatic disorders. This is due primarily to the complexity
of the knee's structure, the high level of stress it is under from body weight but
also to the increasing age of the population of industrialised countries. The
primary, conservative treatment of osteoarthritis of the knee is symptomatic, as
monotherapy or in combination with physical, physiotherapeutical and drugbased measures.
The most important pillars of drug therapy are pain-relieving and antiinflammatory drugs, i.e. non-steroidal anti-inflammatory drugs (NSAID) and, as
a new variant of NSAID the COX-2 inhibitors, which are considered to be more
easily tolerated by the stomach (Sweetman, 2004; Hardman and Limbird,
1996). In severe cases cortisone with a strong antiphlogistic action is injected
directly into the knee. Phytopharmaceuticals such as comfrey root extract
ointment, which are applied topically, have the benefit that they are applied
targetedly and have fewer to no adverse drug reactions. The fact that the active
substance actually reaches the target area when applied topically was proven
e.g. for diclofenac-diethylammonium emulgel (Gondolph-Zink and Gronwald,
1996).
This clinical trial was characterised by the careful selection of patients (strict
observance of the inclusion and exclusion criteria), a high patient number, good
patient management, management of a pain diary and good compliance. For a
good assessment of efficacy of the trial drug in comparison to the placebo, a
homogeneous initial situation in the two groups is important. This condition was
fully met with 220 trial participants with painful osteoarthritis of the knee in this
comparative trial.
The primary target criterion was fully met. In the pre/post comparison (1st/4th
visit), the VAS total score for the verum group dropped by an average of 54.7%
over three weeks. In observational studies with Kytta-Salbe® f or Kytta-Balsam®
f, involving patients with painful joints and muscles, Tschaikin (2004) and
Klingenburg (2004) noticed a reduction of pain of approximately 46% (patient
query) after an average treatment time of 12 days. In a clinical trial with
diclofenac emulgel (over Ibuprofen oral) that is comparable with this clinical trial
with regard to patient age, duration of therapy and VAS initial situation, patients
from the diclofenac group with an activated osteoarthritis of the finger joints
achieved a reduction of pain (VAS total score) of 41.6% (Zacher et al., 2001).
The result achieved in this clinical trial relating to the primary target value is at
least comparable with the above results.
In the pre/post comparison (1st/4th visit) an average group difference of
16.4 mm (44.4%) was determined in respect of pain at rest and a value of
25.1 mm (43.6%) in respect of pain on movement. A change of 20 mm is
considered to be clinically relevant (Biegert, 2003). With an average change of
20.8 mm (an average of pain at rest and on movement or VAS total score
divided by 2) this criterion is met, i.e. not only has a statistically relevant trial
result been achieved but one that is also clinically relevant (Kelly, 1998).
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The extent of pain reduction is, on top of that, at least comparable with the
results of other trials. In a clinical trial with orally administered willow bark dry
extract and diclofenac (daily dose 1.36 g or 100 mg) to patients with
osteoarthritis of the hip and knee (Biegert, 2003), an average difference
between diclofenac and the placebo of 18.4 mm (patient assessment) or
7.6 mm (physician assessment) was achieved over a trial period of 42 days; the
effect of willow bark dry extract was not different to that of the placebo. In a
clinical trial in which comfrey root extract was compared with diclofenac in the
treatment of ankle distortions, the clear reduction of pain under topical therapy
was again confirmed (Predel et al., 2005). It was additionally proven that the
plant-based active substance was at least as effective as the chemical
substance; there were even clear indications of the superior efficacy of the
phytotherapeutic topical agent.
In this trial, the percentage of change of the WOMAC total score (secondary
target value) was analogue to that of the primary target value. In the pre/post
comparison the verum group experienced a reduction of 58.0%, while the
placebo group experienced a reduction by 14.1%. The group difference (43.9%)
is significant (p<0.001). Thus, the secondary target criterion is fully met.
In the Biegert trial (Biegert, 2003) a reduction of pain of 16.3% was achieved
with willow bark dry extract after 28 days of the trial, of 44.0% with diclofenac
and of 10.0% with the placebo, while only the difference between diclofenac
and the placebo was significant (p<0.001). Although, the application in this
clinical trial was topical and not oral, a result was achieved that was at least
comparable with that achieved by diclofenac. On division of the WOMAC total
score into the sub-scores pain, stiffness and physical function it was additionally
proven that the sub-scores changed equally.
With regard to the primary and secondary target value, particular attention
should be paid to the fact that a continual pain reduction was achieved in the
course of the trial. As early as from the second visit onwards there was a
significant group difference (p<0.001) of the verum group to the baseline. At the
end of the trial, the level of pain reduction achieved in the verum group was 5
times (in respect of VAS) or 4 times (in respect of WOMAC) higher than the
level of pain reduction achieved in the placebo group. With regard to the
primary and secondary target value, a multivariate covariance analysis and a
VCAS assessment were performed additionally and checked for centre effect.
In all cases the statements on the significance of the results did not change.
Regarding SF-36, the patients of the verum group displayed a significant
improvement of quality of life over the placebo group at the end of the trial. The
group difference with regard to “physical function” and “mental function” of
33.9% or 7.0% is significant (p<0.001 or =0.006). In respect of “physical
function”, Biegert (2003) describes the following group differences in
comparison with the placebo (in %) after 42 days: willow bark dry extract 7.6
(p=0.236), diclofenac 25.8 (p<0.001). With regard to “mental function” no
therapeutic effect was proven. The results of this clinical trial in respect of SF-36
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are thus at least comparable with those of the Biegert trial concerning
diclofenac.
In this clinical trial the Clinical Global Impressions (CGI) and the global
assessments of the investigators and patients underscore the VAS, WOMAC
and SF-36 results on efficacy. In all cases a significant superiority (p<0.001
each) of the verum over the placebo was proven: with regard to the
improvement of the level of severity and the condition of the disease, with
regard to the efficacy index and in the view of both the investigator and the
patient. Eight patients of the verum group were symptom-free at the end of the
trial, seven no longer required treatment. These results must be rated highly as
osteoarthritis of the knee is a chronic disease (Towheed and Hochberg, 1997).
The comfrey root extract ointment proved to be very well tolerated and free of
adverse effects; the application of Kytta-Salbe® f did not result in any adverse
drug reactions. This confirms the results of previous studies (Predel et al., 2005;
Koll et al., 2004; Tschaikin, 2004; Klingenburg, 2004; Staiger, 2005). There was
only one discontinuation of the trial due to ineffectiveness among the 22 AEs (7
VG, 15 PG) that occurred and this occurred in the placebo group. Clinical
parameters (vital parameters) were not affected by the clinical trial. On the basis
of the results achieved, it can be deduced that Kytta-Salbe® f is well suited for
the therapy of osteoarthritis of the knee. Such therapy reduces pain, improves
mobility of the knee and increases quality of life.
Conclusions
The fact that the verum medication is significantly superior to the placebo
medication with regard to all target values proves the therapeutic efficacy of the
comfrey root extract ointment in the treatment of painful osteoarthritis of the
knee.
At the end of the trial, pain in the verum group had, on an average, reduced five
times more than in the placebo group. The primary target value (VAS total
score) improved by 54.7% in the verum group, but only by 10.7% in the placebo
group.
With regard to the secondary target value (WOMAC total score) verum proved
to be four times more effective than the placebo. In the verum group the
improvement was 58.0%, in the placebo group, however, it was only 14.7%.
The intensity of pain, when applying Kytta-Salbe® f, on an average reduced
from “moderate pain” initially to “mild pain” at the end of the trial. This related
both to pain at rest and pain on movement.
Compared to information and clinical trials described in literature, the trial
results achieved are of clinical relevance. In comparison with the results of this
clinical trial, clinical trials with willow bark dry extract and diclofenac showed that
the results achieved by comfrey root extract were at least as good if not better
19
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than those with diclofenac and clearly superior to the results achieved with
willow bark dry extract.
The good benefit-risk ratio also bears particular emphasis, as not only the
excellent and high-level of efficacy are of particular importance to users but also
the lack of adverse drug reactions.
This clinical trial has proven that the application of topical comfrey root extract is
a sensible treatment option in osteoarthritis of the knee.
References
Andres, 1989 P. Andres, R. Brenneisen and J.T. Clerc, Relating antiphlogistic
efficacy of dermatics containing extracts of symphytum-officinale to chemical
profiles, Planta Med. 55 (1989), pp. 66–67.
Biegert, 2003 Biegert, C., 2003. Eine randomisierte, kontrollierte klinische
Studie zur Wirksamkeit und Verträglichkeit eines standardisierten
Weidenrindenextraktes in der Behandlung von Cox- und Gonarthrosen. Ph.D.
Thesis. Faculty of Chemistry and Pharmacy, University of Tübingen, Germany.
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Gondolph-Zink and Gronwald, 1996 B. Gondolph-Zink and U. Gronwald,
Wirkstoffkonzentrationen in artikulären und periartikulären Geweben des
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Rosmarinsäure aus Symphytum officinale und ihre anti-inflammatorische
Wirksamkeit in einem In-vitro-Modell. Über biochemisch-pharmakologische
Untersuchungen pflanzlicher Arzneistoffe, Arch. Pharm. 318 (1985), pp. 1090–
1095.
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Manual for Psychopharmacology, National Institute of Mental Health, Rockville,
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Hrsg.: G. Rompe u. A. Erlenkämper, 2. überarbeitete und erweiterte Auflage,
Georg-Thieme-Verlag, Stuttgart (1992).
Hunter and Felson, 2006 D.J. Hunter and D.T. Felson, Osteoarthritis, BMJ 332
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Kelly, 1998 A.M. Kelly, Does the clinically significant difference in visual analog
scale pain scores vary with gender, age, or cause of pain?, Academic
Emergency Medicine 5 (1998), pp. 1086–1090.
Klingenburg, 2004 S. Klingenburg, Wärmendes Topikum mit Symphytum
officinale, Erfahrungsheilkunde 6 (2004), pp. 350–354.
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B. Giannetti, S. Klingenburg and C. Staiger, Efficacy and tolerance of a comfrey
root extract (Extr. Rad. Symphyti) in the treatment of ankle distorsions: results
of a multicenter, randomized, placebo-controlled, double-blind study,
Phytomedicine 11 (2004), pp. 470–477.
Kommission, 1990 Kommission E, 1990. Monographie Symphyti radix
(Beinwellwurzel). Bundesanzeiger 318.
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Meinecke and Gräfe, 2002 R. Meinecke and K. Gräfe, Bewegungs-, Längenund Umfangsmessungen. Neutral-Null-Durchgangsmethode, Lau-Verlag
GmbH, 4.überarbeitete Auflage, Reinbeck (2002).
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Efficacy of a comfrey root extract ointment in comparison to diclofenac in the
treatment of ankle distortions: results of an observer-blind, randomized,
multicenter study, Phytomedicine 12 (2005), pp. 707–715.
Schmidtke-Schrezenmeier et al., 1992 G. Schmidtke-Schrezenmeier, R. Reck
and G. Gerster, Behandlung der nichtaktivierten Gonarthrose. Besserung durch
ein Phytotherapeutikum, Therapiewoche 42 (1992), pp. 1322–1325.
Staiger, 2005 C. Staiger, Beinwell – eine moderne Arzneipflanze, Z. Phytother.
26 (2005), pp. 169–173.
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Dick and R. Theiler, Evaluation einer deutschen Version des WOMAC (Western
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pp. 40–49.
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Reference (34th ed), Pharmaceutical Press, London (2004).
Towheed and Hochberg, 1997 T.E. Towheed and M.C. Hochberg, A systematic
review of randomized controlled trials of pharmacological therapy in
osteoarthritis of the knee, with an emphasis on trial methodology, Semin.
Arthritis Rheum. 26 (1997), pp. 755–770.
Tschaikin, 2004 M. Tschaikin, Extrakt aus Symphytum officinale. Wirksamkeit
und Verträglichkeit bei topischer Anwendung, Naturheilpraxis 57 (2004), pp.
576–578.
Walker-Bone et al., 2000 K. Walker-Bone, K. Javaid, N. Arden and C. Cooper,
Medical management of osteoarthritis, BMJ 321 (2000), pp. 936–940.
Zacher et al., 2001 J. Zacher, K.J. Burger, L. Färber, M. Gräve, H. Abberger
and K. Bertsch, Topisches Diclofenac Emulgel versus orales Ibuprofen in der
Therapie der aktivierten Arthrose der Fingergelenke (Heberden- und/oder
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Rheumatol. 26 (2001), pp. 7–14.
ALOPATIA
DICLOFENAC TOPICO EN EL TRATAMIENTO DE QUERATOSIS ACTINICA
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Hans F. Merk, Prof. Dr. Med
Department of Dermatology and Allergology, Medical Faculty, RWTH Aachen,
Aachen, Germany
[International Journal of Dermatology 46 (1) 12-18]
ARTICULO ORIGINAL (sin resumen)
Introduction
A privilege for dermatologists is the capability to observe fundamental biological
processes through the diagnosis and treatment of skin diseases, for example,
the possibility to observe premalignant lesions and how they develop into a
malignancy. Actinic keratosis (AK) is one such skin lesion, which is caused by
excessive exposure to ultraviolet (UV) radiation and can progress into
squamous cell carcinoma (SCC). It is therefore of serious clinical concern. The
American Academy of Dermatology estimates that 60% of predisposed
individuals aged 40 years and over have at least one AK, making it the most
common form of precancerous skin lesion. 1 The prevalence of AK is higher in
men than in women, increases with age, and is more frequently observed in
fair- rather than dark-skinned individuals. Other predisposing factors include
immunosuppression, papillomavirus infection, and certain genetic conditions
such as xeroderma pigmentosum. 1,2 Skin tumors, including SCC, basal cell
carcinoma (BCC), and malignant melanoma (MM), are the most frequent types
of malignant tumor. Together, these skin tumors account for the highest rate of
mortality amongst heart and kidney transplant patients. 2
AK occurs as intraepidermal lesions, primarily on areas exposed to sunlight,
such as the face and arms. The physical appearance may vary from 1–2-mm
papules to larger plaques, pigmented or erythematous, with a rough
hyperkeratotic surface and occasional horn formation. 1
The clinical rationale for treating AK lies in its strong association with SCC, both
histologically and cytologically. AK should be regarded as an early step in the
progression to SCC. 3 The rate at which AK progresses to SCC has been
estimated to be up to 20% per year. 4 The treatment goal is to eliminate AK in
the premalignant phase and to prevent progression to more invasive disease.
Deciphering How AK Develops
AK occurs as one distinct stage in the stepwise development of a specific type
of nonmelanoma skin cancer. The first step is initiation, in which a carcinogen
causes a mutation in a target gene. This step is followed by promotion, during
which exposure to a carcinogen, such as phorbol esters, causes
proinflammatory promoter agents to expand the clone of damaged cells into,
this case, an AK. Further exposure to a carcinogen will induce the final
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conversion step in which the neoplasm develops into an invasive malignancy
(Fig. 1). Studies have shown that UV radiation acts as an inducer as well as a
promoter, and that it is the main reason for the formation of skin cancer on a
cellular and molecular level.
Figure 1 Early events in human skin cancer (adapted from Ziegler et al. 3)
UV radiation from exposure to natural sunlight is believed to be the predominant
trigger for the development of AK and, subsequently, SCC. The
pathophysiologic mechanisms by which AK develops have been studied
extensively in animal models and human studies, and include changes in the
expression of oncogenes and tumor suppressor genes, altered apoptotic and
proliferation activity, suppression of interferons (IFNs), and modifications to
cyclooxygenase (COX) isoenzyme expression.
Changes to chromosome and tumor suppressor genes
In normal cells, the p53 tumor suppressor gene is induced in response to
exposure to a carcinogen, such as UV radiation, chemical agents, or
oncogenes. When activated, p53 is capable of inducing DNA repair and
triggering apoptosis of damaged cells. UV-mediated mutations in the p53 gene
reduce its tumor suppressor effect and render cells susceptible to clonal
expansion into a neoplasm when exposed to a promoting agent, such as further
UV radiation. 6
Mutations in the p53 gene that are indicative of UV exposure have been found
in over 90% of SCCs and, interestingly, the same "UV-signature" mutations
have been identified in AKs, thus providing evidence of the causal relationship
between AK and SCC, with UV radiation acting as both initiator and promoter,
even at a molecular level. 3
A further genetic target shown to play a role in the development of AK is the ras
oncogene. Activated ras genes promote aberrant cell growth and, analogously
with p53, have been found in both AK and SCC. 7
Reduced apoptosis and increased cell proliferation
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Maintaining a homeostatic balance between apoptosis and cellular growth is
vital to preserve the function and integrity of the epidermis and to prevent cells
from undergoing malignant transformation. Studies in mice have shown that
inactivation of the p53 gene reduces the rate of apoptosis, as shown by the
appearance of sunburn cells, which are apoptotic keratinocytes generated by
UV exposure. 6
Other epidermal apoptosis-regulating agents whose function is altered by UV
exposure include CD95 (Fas) ligand, tumor necrosis factor (TNF)-related
apoptosis-inducing ligand (TRAIL), and flice inhibitory protein (FLIP). 8,9 In AK,
aberrant expression of these proteins may prevent apoptotic elimination of
mutated keratinocytes. The reduced rate of apoptosis results in more cells with
damaged DNA available for clonal expansion into AKs, and hence increases the
likelihood of malignant conversion into SCC.
Suppression of IFN
Another mechanism by which UV radiation may cause AK lesions to progress to
SCC is by suppressing the host's immune defense against the tumor cells. This
effect is mediated by systemic immunosuppression, together with a local
tumorigenic effect. 5 The underlying mechanism is complex and involves
several pathways; the agent that has attracted the most attention as a potential
therapeutic is IFN type 1.
IFN consists of types α and β, which are immune mediators whose normal
function is to defend the cell from viral infection. The therapeutic benefit of
intralesional injections of IFN in patients with AK is well established. 10 The
mechanism by which the suppression of IFN occurs in AK lesions, however, has
only recently been shown to include the down-regulation of IFN-stimulated
signal molecules and a subsequent decreased response to endogenous IFN. 11
Modifications to COX-2 expression
COX is a key mediator in the proinflammatory cascade in which arachidonic
acid is converted to prostaglandins and other eicosanoids. In humans, COX
exists in three isoforms: COX-1, COX-2, and COX-3. Firstly, COX-1 is
expressed constitutively in normal cells and is involved in regulating a range of
physiological processes. In contrast, expression of COX-2 is only induced in
response to inflammatory and mitogenic stimuli, and triggers the production of
prostaglandins in the target tissue. Elevated COX-2 levels have been found in
several types of premalignant tissues and tumors, including AK and SCC. 12 16
COX-3 is only expressed in the cells of the central nervous system and
paracetamol is a ligand of this enzyme.
It has been shown that COX-2 levels increase in response to UV radiation. 17,18
Data suggest that this increase is due to mutations in p53: in normal cells, COX2 transcription is subject to p53 suppression; this control mechanism is absent
in cells with mutated p53. 19,20
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The carcinogenic potential of COX-2 is mediated by its ability to augment
pathophysiologic mechanisms, such as angiogenesis, and to alter apoptosis
and cell proliferation. Recent studies in animal models have shown that
increased COX-2 expression is associated with increased production of
vascular growth factors and the formation of new blood vessels. 14,15,21 Cells
containing elevated COX-2 levels have also been shown to resist butyrateinduced apoptosis and to exhibit increased amounts of the antiapoptotic protein
Bcl2. 12 In addition, overexpression of COX-2 has been linked to altered
xenobiotic metabolism, attenuated immunosuppression, and increased
invasiveness of malignant cells. 22
Management of AK
As discussed, the treatment goal for AK is to eliminate the premalignant cells
before the condition can progress to SCC. 1 To achieve this goal with a
minimum of adverse effects, the treatment of choice should ideally address the
pathophysiologic mechanisms that contribute to the development of AK.
A wide range of treatment options are available for AK, which are effective, but
are associated with unwanted side-effects. These include destruction of the AK
with cryosurgery or curettage, dermabrasion, or chemical peels, photodynamic
therapy, laser treatment, or topical treatment with agents such as 5-fluorouracil
(5-FU), imiquimod, or 3% diclofenac in 2.5% hyaluronic acid gel. 1 The efficacy
of these topical agents in the complete clearance of AK lesions is summarized
in Table 1.
Table 1 Efficacy of topical treatments for actinic keratosis
Treatment
Reference
Duration of treatment
and follow-up
Patients with complete
clearance (%)
Vehicle
Active
3% diclofenac in 2.5%
Wolf et al.
hyaluronic acid gel
5-Fluorouracil 0.5% &
5.0% creams
Imiquimod 5% cream
28
Loven et al.
90 days + 30 days
24
4 weeks + 4 weeks
Lebwohl
et al. 26
16 weeks + 8 weeks
50
43
45
20
–
3
5-FU is a prodrug that inhibits the enzyme thymidylate synthase, and thereby
prevents DNA synthesis in tumor cells. 23 Topical 5-FU is effective in the
treatment of AK lesions, demonstrating a complete clearance rate of 43% for
both the 0.5% and 5% cream formulations; 24 however, 5-FU is often associated
with significant side-effects, such as skin inflammation and ulceration. 23 As it is
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applied until there is incipient ulceration and necrosis, it causes discomfort and
cosmetic problems for most patients. In some cases, it is necessary to use
topical corticosteroids to control the inflammation.
One topical treatment in development, but not licensed in Europe, is imiquimod,
which is an immune modulator that has been proposed to augment the
endogenous immune response by promoting the release of cytokines such as
IFN. Clinical studies have demonstrated the efficacy of imiquimod in the
treatment of AK lesions. 25,26 A 16-week, randomized, double-blind study
showed a complete clearance rate of 45.1% (vs. 3.2% with placebo) with
imiquimod 5% cream in 436 patients with AK lesions. 26 Like 5-FU, imiquimod is
associated with severe local skin reactions, such as erythema, edema, erosion,
ulceration, and scabbing. 25,26 Severe erythema was reported in 17.7% of
imiquimod-treated patients compared with 2.3% of patients treated with vehicle.
26
These adverse events may affect the acceptability of the treatment to patients
and, ultimately, patient compliance.
Recent insights into the relationship between COX-2 and carcinogenesis have
provided a rationale for the use of nonsteroidal anti-inflammatory drugs
(NSAIDs) for the treatment of AK. To date, the most thoroughly documented
topical NSAID treatment is 3% diclofenac in 2.5% hyaluronic acid gel
(Solaraze™, Shire Pharmaceuticals, Basingstoke, UK). Several studies have
provided convincing evidence for the use of topical 3% diclofenac in 2.5%
hyaluronic acid gel for the treatment of AK. 27 31
Topical Diclofenac in the treatment of AK
Diclofenac is a potent NSAID with a selectivity ratio for COX-2 over COX-1 of
3 : 1. 32 It has been proposed that COX-2 inhibition is one of the mechanisms by
which 3% diclofenac in 2.5% hyaluronic acid gel eliminates AK. Other
mechanisms by which diclofenac is hypothesized to act are via the induction of
apoptosis (programmed cell death), alteration of cell proliferation, and inhibition
of angiogenesis, either via COX-2 inhibition or independently. 33 36
In a study by Seed et al., 33 it was shown that daily treatment of mice, seeded
with 106 colon-26 tumor cells, with topical 6 mg/kg diclofenac in 2.5% hyaluronic
acid resulted in a complete cessation of tumor growth, thus decreasing the
resulting tumor mass. This was accompanied by a retardation of vascular
development and a reduction in blood vessel density. In these experiments,
topical application of diclofenac in 2.5% hyaluronic acid dramatically reduced
prostaglandin synthesis in the skin overlying the tumors. The investigators also
looked at the cellular proliferation rate of the colon-26 cancer cells in vitro. In
these experiments, diclofenac inhibited cell proliferation in a dose-dependent
manner, as well as inducing apoptosis. An increased apoptotic index was also
observed in the in vivo experiments.
The effect of diclofenac, as well as other NSAIDs, on apoptosis has also been
reported when these agents are administered to transformed chicken embryo
fibroblasts (CEFs) in vitro. When morphological changes were assessed,
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diclofenac was reported to be one of the most potent NSAIDs for eliciting
morphological effects and inducing apoptosis. 34
Further to the study by Seed et al., 33 the effect of diclofenac on angiogenesis
has also been assessed in a mouse model of chronic granulomatous
inflammation. Angiogenesis, the development of new blood vessels that supply
nutrients and oxygen to a tumor, is vital for the growth and metastasis of
tumors. The application of diclofenac (0.18%) formulated in gel containing
hyaluronic acid (2.5%) resulted in a significant inhibition of vascular
development in the granulomatous tissue compared with the control. 35
Another mechanism by which diclofenac could alter cell proliferation is via the
nuclear hormone receptors, peroxisome proliferator-activated receptors
(PPARs). PPARs play an important role in many cellular functions, including
lipid metabolism, cell differentiation, and apoptosis. Activation of PPAR-γ, in
particular, has also been shown to inhibit cancer cell growth. NSAIDs, such as
diclofenac, have been shown to activate PPAR-γ, and diclofenac has been
shown to have a higher affinity than other NSAIDs for PPAR-γ. Indeed,
diclofenac has been shown to be a partial agonist for PPAR-γ in in vitro studies,
and further experiments are required to determine the effect of diclofenac on
PPARs in AK. 36
The hyaluronic acid vehicle is an important component of this topical AK
treatment, as it retains and controls the release of diclofenac in the epidermal
layer of the skin. This may be the result of specific binding to hyaluronic acid
receptors, such as CD44, the receptor for hyaluronan-mediated motility, termed
RHAMM, and intercellular adhesion molecule-1 (ICAM-1). 33,37,38
Clinical efficacy
When topically applied, 3% diclofenac in 2.5% hyaluronic acid gel has been
shown to effectively clear AKs, and is well tolerated by patients. The published
clinical documentation for 3% diclofenac in 2.5% hyaluronic acid gel comprises
two open-label studies and three randomized, multicenter, double-blind, vehiclecontrolled studies, involving a total of 470 patients with AK. 24 31
The first small open-label study included patients with at least one AK, who
applied 3% diclofenac in 2.5% hyaluronic acid gel twice daily for up to 180 days.
27
Treatment efficacy was assessed using a seven-point scale ranging from
"complete response" to "much worse", as well as a four-point assessment of
efficacy and tolerability (poor to excellent), lesion severity, and lesion count. The
results of the study showed that a total of 81% of patients scored a "complete
response," with an additional 15% showing a marked clinical improvement,
providing an early indication of the clinical value of 3% diclofenac in 2.5%
hyaluronic acid gel for the treatment of AK. 27
An important feature of the three randomized studies was the 30-day follow-up
period after treatment had ended. This design was chosen based on
observations made in the open-label study that the optimal treatment effect of
28
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3% diclofenac in 2.5% hyaluronic acid gel was observed up to 4 weeks after the
last application. 27 In the three randomized studies, patients, with five or more
AKs in one to three 5 × 5-cm treatment areas, applied the topical treatment
twice daily to each treatment area.
The primary efficacy parameters in the randomized studies included quantitative
measures of the change in the number of lesions during treatment, as well as
qualitative assessments of the change in lesion severity. In studies by Wolf
et al. 28 and Rivers et al., 29 the primary efficacy variable comprised the target
lesion number score (TLNS) and cumulative lesion number score (CLNS). In a
study by Gebauer et al., 30 the primary efficacy variables consisted of the overall
lesion count and the proportion of patients with complete resolution of lesions
and 50% reduction in lesions. All three randomized studies demonstrated
significant differences in favor of 3% diclofenac in 2.5% hyaluronic acid gel over
vehicle alone in the primary efficacy parameters at the end of the follow-up
period. The proportion of patients achieving complete resolution of AK lesions
was approximately 50%, compared with approximately 20% for vehicle. 28 30
The efficacy observed with 90 days of treatment and a 30-day follow-up period
is shown in Fig. 2.
Figure 2 Efficacy of topical 3% diclofenac in 2.5% hyaluronic acid gel with 90 days of
treatment and 30 days of follow-up
Recently, an open-label study assessed the efficacy of 3% diclofenac in 2.5%
hyaluronic acid gel, specifically investigating a clearance rate of 75% or better.
31
Patients applied the topical treatment twice daily for 90 days, followed by a
30-day follow-up period. At day 120, 85% of patients experienced clearance of
better than 75% AKs based on the TLNS, with 58% of patients experiencing
100% clearance. The results of the four trials are summarized in Table 2.
Table 2 Summary of efficacy with topical 3% diclofenac in 2.5% hyaluronic acid gel
Reference
and follow-up
Complete resolution of all target
lesions TLNS = 0 (% of patients)
Active
Resolution of all target lesions and
new lesions CLNS = 0 (% of
patients)
Vehicle
Active
Vehicle
29
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Wolf et al.
28
90 days + 30 days
50*
20
Complete resolution of all target
lesions TLNS = 0 (% of patients)
Reference
Nelson et al.
31
Resolution of all target lesions and
new lesions CLNS = 0 (% of
patients)
and follow-up
Active
Gebauer
et al. 30
19
47
Vehicle
Vehicle
Active
84 days + 28 days
38*
10
–
90 days + 30 days
58
–
45
–
–
*Significant difference to vehicle.
As the clinical evidence is specific for 3% diclofenac in 2.5% hyaluronic acid gel,
and the experimental data have shown that the hyaluronic acid vehicle
enhances epidermal drug delivery and retention, it is important not to
extrapolate the clinical data to other topical formulations of diclofenac.
Tolerability
Overall, treatment with 3% diclofenac in 2.5% hyaluronic acid gel has been well
tolerated in all studies. In the three randomized trials, the most frequently
reported adverse events were pruritus, rash, dry skin, and application site
reactions. 28 30 No treatment-related serious adverse events were reported.
Figure 3 summarizes the skin-related adverse events observed in Phase III
clinical studies. 39 An open-label comparison study has recently compared the
tolerability of 3% diclofenac in 2.5% hyaluronic acid gel with that of 5-FU. The
results showed that, although lesion clearance rates were comparable with
those of 5-FU treatment, a higher percentage of patients given 5-FU
experienced moderate to severe erythema, compared with those treated with
3% diclofenac in 2.5% hyaluronic acid gel, with a higher percentage of patients
also satisfied with 3% diclofenac in 2.5% hyaluronic acid gel (79%) than with 5FU (68%). 40
Figure 3 Summary of incidence of selected skin-related adverse events with 3%
diclofenac in 2.5% hyaluronic acid gel. DHA, 3% diclofenac in 2.5% hyaluronic acid gel;
HAV, hyaluronic acid vehicle.
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30
Conclusions
Although the main causative agent for AK is UV radiation from sunlight, the
pathophysiologic mechanisms by which the condition develops and progresses
are more complex. Recent experimental studies have indicated that mutations
in specific tumor suppressor genes and oncogenes, as well as overexpression
of COX-2, play central roles in the initial stages of UV-induced epidermal
change, attenuating a wide range of carcinogenic pathways, including
angiogenesis, altered apoptosis, and cell proliferation. The availability of an
effective, well-tolerated treatment, such as 3% diclofenac in 2.5% hyaluronic
acid gel, that targets the pathways contributing to the development of AK is a
rational choice for the early treatment of AK, in order to minimize any
progression to SCC.
Acknowledgments
I have received honoraria from Shire Pharmaceuticals for consulting activities
and for speaking commitments.
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14 Williams CS, Tsujii M, Reese J, et al. Host cyclooxygenase-2 modulates
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17 Buckman SY, Gresham A, Hale P, et al. COX-2 expression is induced by
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18 Tripp CS, Blomme EA, Chinn KS, et al. Epidermal COX-2 induction following
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19 Subbaramaiah K, Altorki N, Chung WJ, et al. Inhibition of cyclooxygenase-2
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20 Leung WK, To KF, Ng YP, et al. Association between cyclo-oxygenase-2
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21 Masferrer JL, Leahy KM, Koki AT, et al. Antiangiogenic and antitumour
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23 http://www.valeant.com/fileRepository/products/PI/Efudex40_Cream_5_Solution_2-5_PI_March05.pdf 5-Fluorouracil International Data
Sheet (IDS) .
24 Loven K, Stein L, Furst K, et al. Evaluation of the efficacy and tolerability of
0.5% fluorouracil cream and 5% fluorouracil cream applied to each side of the
face in patients with actinic keratosis. Clin Ther 2002; 24: 990–1000.
25 Stockfleth E, Meyer T, Benninghoff B, et al. A randomized, double-blind,
vehicle-controlled study to assess 5% imiquimod cream for the treatment of
multiple actinic keratosis. Arch Dermatol 2002; 138: 1498–1502.
26 Lebwohl M, Dinehart S, Whiting D, et al. Imiquimod 5% cream for the
treatment of actinic keratosis: results from two Phase III, randomized, doubleblind, parallel group, vehicle-controlled trials. J Am Acad Dermatol 2004; 50:
714–721.
27 Rivers JK, McLean DI. An open study to assess the efficacy and safety of
topical 3% diclofenac in a 2.5% hyaluronic acid gel for the treatment of actinic
keratoses. Arch Dermatol 1997; 133: 1239–1242.
28 Wolf Jr JE, Taylor JR, Tschen E, et al. Topical 3.0% diclofenac in 2.5%
hyaluronan gel in the treatment of actinic keratoses. Int J Dermatol 2001; 40:
709–713.
29 Rivers JK, Arlette J, Shear N, et al. Topical treatment of actinic keratoses
with 3.0% diclofenac in 2.5% hyaluronan gel. Br J Dermatol 2002; 146: 94–100.
30 Gebauer K, Brown P, Varigos G. Topical diclofenac in hyaluronan gel for the
treatment of solar keratoses. Australas J Dermatol 2003; 44: 40–45.
31 Nelson C, Rigel D, Smith S, et al. Phase IV, open-label assessment of the
treatment of actinic keratosis with 3.0% diclofenac sodium topical gel
(Solaraze™). J Drugs Dermatol 2004; 3: 401–407.
32 Riendeau D, Percival MD, Brideau C, et al. Etoricoxib (MK-0663): preclinical
profile and comparison with other agents that selectively inhibit
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33 Seed MP, Brown JR, Freemantle CN, et al. The inhibition of colon-26
adenocarcinoma development and angiogenesis by topical diclofenac in 2.5%
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34 Lu X, Xie W, Reed D, et al. Nonsteroidal antiinflammatory drugs cause
apoptosis and induce cyclooxygenases in chicken embryo fibroblasts. Proc Natl
Acad Sci USA 1995; 92: 7961–7965.
35 Alam CA, Seed MP, Willoughby DA. Angiostasis and vascular regression in
chronic granulomatous inflammation induced by diclofenac in combination with
hyaluronan in mice. J Pharm Pharmacol 1995; 47: 407–411.
36 Adamson DJ, Frew D, Tatoud R, et al. Diclofenac antagonizes peroxisome
proliferator-activated receptor-gamma signaling. Mol Pharmacol 2002; 61: 7–12.
37 Freemantle C, Alam CAS, Brown JR, et al. The modulation of granulomatous
tissue and tumour angiogenesis by diclofenac in combination with hyaluronan
(HYAL EX-0001). Int J Tiss React 1995; 17: 157–166.
38 Brown MP, Hanpanitcharoen M, Martin GP. An in vitro investigation into the
effect of glycosaminoglycans on the skin partitioning and deposition of NSAIDs.
Int J Pharm 2001; 225: 113–121.
39 Solaraze Prescribing Information.
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206.pdf July 2005 .
40 Smith SR, Morhenn VB, Piacquadio DJ. Bilateral comparison of the efficacy
and tolerability of 3% diclofenac sodium gel and 5% 5-fluorouracil cream in the
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156–159.
HOMEOPATIA
EFECTO DE PREPARACIONES HOMEOPATICAS EN EL DESARROLLO
DEL CANCER DE PROSTATA HUMANO EN MODELOS ANIMALES Y
CELULARES
Brian W. MacLaughlin, BS, Babett Gutsmuths, PharmD, PhD, Ewald Pretner,
MD,Wayne B. Jonas, MD, John Ives, PhD, Don Victor Kulawardane, MD, DTH,
DCH, and Hakima Amri, PhD1
1
BWM and HA are at the Department of Physiology and Biophysics,
Georgetown University Medical Center, Washington, DC. BG and EP are at the
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34
Department of Cell Biology, Georgetown University Medical Center,
Washington, DC. WBJ and JI are at the Samueli Institute for Information
Biology, Alexandria, VA.DVK is at the Homeopathic Clinic, Jayawardane Place,
Dehiwala, Sri Lanka.
[Integrative Cancer Therapies 5(4); 2006 pp. 362-372]
RESUMEN
El uso de suplementos dietarios goza en estos momentos de una popularidad
sin precedentes. Como parte de esta moda, el Sabal serrulata (saw palmetto),
constituye el tratamiento complementario de elección para temas prostáticos.
En homeopatía, el Sabal serrulata generalmente se prescribe para problemas
prostáticos que van desde la hiperplasia prostática benigna hasta el cáncer de
próstata. El trabajo de los autores evaluó los efectos antiproliferativos de los
medicamentos homeopáticos Sabal serrulata, Thuja occidentales y Conium
maculatum, in vivo, en ratones desnudos, e in vitro, en líneas celulares PC-3 y
DU-145 (cáncer de próstata humano) y MDA-MB-231 (cáncer de mama
humano). El tratamiento in vitro con Sabal serrulata redujo a las 72 horas un
33% la proliferación celular de PC-3 y un 23% las DU-145, a las 24 horas. (P <
0.01). La diferencia en la reducción se debe probablemente al tiempo de
duplicación específico de cada línea celular. No se observó ningún efecto en
las células humanas de cáncer de mama MDA-MB-231. Thuja occidentalis y
Conium maculatum no mostraron ningún efecto sobre la proliferación de células
humanas de cáncer de próstata. In vivo, el tamaño del tumor de próstata
(células de cáncer de próstata humano implantadas en ratones desnudos) se
redujo significativamente en los ratones tratados con Sabal serrulata con
respecto a los controles no tratados (P<0.012). No se observó ningún efecto en
el desarrollo del tumor de mama. Nuestro estudio demuestra claramente una
respuesta biológica al tratamiento homeopático, puesto de manifiesto por la
proliferación celular y el crecimiento tumoral. Este efecto biológico fue (i)
significativamente mayor para el Sabal serrulata que para los controles y (ii)
específico para el cancer prostático humano. El Sabal serrulata debería ser
investigado como un medicamento homeopático específico para las patologías
prostáticas.
Palabras clave: cáncer de próstata; Sabal serrulata, Thuja occidentalis,
Conium maculatum, líneas celulares de cáncer de mama y próstata humana;
ratones desnudos.
ARTICULO ORIGINAL
Introduction
Prostate cancer remains the second leading cause of cancer-related deaths in
men in the United States, with an estimated 30 350 deaths and 232 090 new
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35
cases in 2005 alone. 1The worldwide incidence of prostate cancer deaths has
been estimated at 204 000 per year. 2In the European Union, approximately
100 000 new diagnoses and 40 000 deaths are reported annually. 3Various
molecular mechanisms are involved in the pathogenesis, proliferation, and
metastasis of prostate cancer, and significant controversy surrounds the
management of this major public health problem. Although detection of the
disease is possible at an early stage using either serum prostate specific
antigen measurements or biopsies, screening has not been shown to improve
survival. 4Conventional treatments for earlystage disease involve watchful
waiting, radiotherapy, and prostatectomy, depending on patient age and
comorbidities. In the case of metastatic prostate cancer, androgen suppression
remains the treatment of choice after more than 50 years. Orchiectomy or
hormonal therapy, such as LH-RH agonists and antiandrogens, is used as
systemic therapy designed to prevent access of androgens to the prostate
cancer cells. The major complications of this therapeutic approach are
osteoporosis and osteoporosis-related fractures, with approximately 2000 cases
per year in the United States alone. 5Many factors, such as peptide and steroid
hormones, growth factors, and cytokines, appear to be involved in the
pathogenesis, the aggressiveness, and the metastatic potential of prostate
cancer. 6Scientists are investigating possible causes at the dietary, genetic, and
molecular levels in an attempt to identify new avenues to prevent, detect,
diagnose, and treat this disease. 7Phytotherapy has long constituted an
important component of medical treatment in most societies.
The pharmaceutical industry used medicinal herbs to isolate and characterize
active ingredients, relegating the natural compounds to prototypes for a variety
of synthetic molecules designed for enhanced specificity and efficacy. About
25% of prescription drugs contain at least one active ingredient derived from
plant material. 8Unfortunately, in many cases the dream of a “miracle drug” did
not materialize and left health care providers struggling with adverse effects and
toxicities. As a consequence, the medical, pharmaceutical, and scientific
communities are reconsidering the merits of herbal therapies, which have
continued to play a significant role in many parts of the world.
Medicinal herbs are used either in toto or as parts of a plant (eg, roots, flowers,
fruit) in a decoction, infusion, or cataplasm form, as is the case in traditional
Chinese medicine, Greco-Unani medicine, or homeopathy.
The latter is among the most widely accepted complementary and alternative
medicine (CAM) modalities in Western Europe. A survey assessing the extent
of CAM teaching at European Union Universities revealed that the topic of
homeopathy is the number 1 subject, followed by acupuncture and
phytotherapy. 9In India and Latin America, homeopathy remains a widespread
and popular form of medical treatment. In contrast, homeopathy in the United
States continues to lag behind other CAM modalities, which are considered less
controversial.
“Similia similibus curentur” or treating “like with like” is the central therapeutic
principle in homeopathy. It means that a patient favorably responds to a
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36
particular homeopathic remedy capable of eliciting his or her symptoms in a
healthy individual. These homeopathic medicines are administered in very
highly diluted preparations. As these “ultra-molecular” dilutions seemingly defy
the principles of pharmacology, 10the allopathic medical community remains
skeptical and demands scientific evidence supporting their use.
With regard to homeopathic scientific evidence, laboratory research has
focused on the cellular immune response to inflammation and on toxicologybased in vivo models. A series of experiments conducted by French scientists
demonstrated the degranulation of human basophils by a very dilute anti-IgE
antiserum. 11The study led to a wave of criticism and triggered significant
controversy in the scientific community, as other researchers were unable to
duplicate the group’s findings. 12However, recent investigations confirm that
basophil degranulation is indeed modulated by homeopathic histamine
administration. 13,14With regard to the above-mentioned toxicology-based
approach, a number of research models have managed to demonstrate a
homeopathic therapeutic effect. Heavy metal toxicity induced in laboratory
animals was alleviated with homeopathic dilutions of arsenic and bismuth (7c)
via an increase in urinary heavy metal elimination. 15,16Bildet and colleagues
showed a protective effect of carbon tetrachloride (7c) and phosphorus (7c and
15c) on carbon tetrachloride-induced hepatitis in rats. 17,18Similarly, mortality of
mice due to mercuryinduced nephrotoxicity was reduced when treating with 9c
and 15c Mercurius corrosivus. 19Yet an additional experimental setting
successfully demonstrated the protective and curative properties of Apis (7c
and 9c) on x-ray-induced erythema in albino guinea pigs. 20,21Homeopathic
dilutions of cadmium and cisplatin applied to cultured kidney cells confer
protection against these same substances when administered in
pharmacological concentrations. 22Furthermore, neuroprotective effects of ultralow-dose glutamate in the context of glutamate-induced primary rat spinal,
cortical, and cerebellar neuronal toxicity have also been reported. 23In the field
of cancer research, a very limited number of reports addressing homeopathy
are found in the scientific literature. Ruta graveolens selectively induces cell
death in brain cancer cells while promoting proliferation in normal peripheral
blood lymphocytes. 24Amelioration of p-dimethylaminoazobenzeneinduced
hepatocarcinogenesis in mice treated with homeopathic Chelidonium either
alone 25or in combination with carcinosin was reported. 26A complex
homeopathic remedy frequently prescribed by Brazilian physicians for
immunodeficiency disorders was tested on sarcoma 180-bearing mice.
Significant tumor regression was noted in the treatment group, indicating the
remedy’s anticancer effect. 27In spite of the disease’s increasing significance, no
in vitro or in vivo studies on the use of homeopathy for prostate cancer have
been reported. Anecdotal clinical evidence collected from homeopathic
treatment centers supports the beneficial effects of homeopathy in alleviating
and curing prostate problems, including cancer. The most commonly prescribed
remedy for prostate pathology is Sabal serrulata (synonym to Serenoa repens
[W. Bartram] Small, family Arecaceae, commonly known as saw palmetto).
Depending on the patient’s individual symptomatology, other remedies, such as
Thuja occidentalis, Conium maculatum, and carcinosin, are at times added to
the regimen. In Western Europe, Sabal serrulata is a popular phytotherapeutic
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37
agent for the treatment of uncomplicated prostatism of middle and later life. The
favorable European experience has been the major impetus for the current
interest in the United States. Despite some limitations, there is increasing
evidence that herbal Sabal serrulata extract exerts beneficial effects by
improving a number of urological symptoms and flow measures. 28,29Urologists
thus increasingly consider Sabal serrulata extract for men with symptomatic
benign prostate hypertrophy (BPH). In a recently published review of clinical
trials, Gerber and Fitzpatrick reported the significant effect of Sabal serrulata in
reducing the symptoms of BPH, increasing urinary flow, and improving the
quality of life. They concluded that Sabal serrulata extract might well be
considered a viable first-line therapeutic modality in the treatment of prostate
disorders. 30However, a more recent randomized, double-blind clinical trial
investigating the effects of Sabal serrulata showed no benefits over placebo and
no improvement of BPH symptoms. 31Thus, reports about its efficacy remain
controversial. Although frequently prescribed by homeopaths, no studies or
published research on Thuja occidentalis, Conium maculatum, or carcinosin
pertaining to prostate pathology are available. In this study, we used a series of
homeopathic preparations commonly prescribed to patients suffering from
prostate pathology ranging from benign prostatic hyperplasia to prostate cancer.
We therefore sought to investigate the effects of these above-mentioned
homeopathic preparations on the proliferation of human prostate cancer cell
lines in vitro and on tumor growth in nude mice bearing prostate tumors and
breast tumors as control.
Materials and Methods
Homeopathic Treatments
Mother tinctures and homeopathic preparations of Sabal serrulata, Thuja
occidentalis, Conium maculatum, and carcinosin, as well as homeopathically
succussed deionized water, were prepared by Hyland’s (Paoli, PA). Mother
tinctures were stored in 67% alcohol, and homeopathic solutions were prepared
at minus 5 of final potentization and stored in 87% alcohol. All potentizations up
to 200 CH were performed in Hahnemannian method (Hahneman used a fresh
vial for each step of the potentization) and Korsakovian method beyond 200
(300-1000 CK) (Korsakoff used the same vial that he emptied between each
potentization step). Only the final 5 potentizations of homeopathic treatments
were performed in our laboratory.
Cell Cultures
The androgen receptor negative human prostate cancers DU-145 and PC-3,
and human breast cancer MDAMB-231 cell lines were obtained from the
Lombardi Cancer Center Tissue Culture Shared Resources. All cell lines were
cultured as monolayers in Dulbecco’s modified Eagle’s medium (DMEM)
supplemented with 10% fetal bovine serum (FBS) and penicillin/streptomycin,
all obtained from Biosource (Rockville, MD) and incubated at 37°C in a 6%
carbon dioxide humidified atmosphere. Doubling times of each cell line were
assessed prior to treatments.
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Cell Treatments
Cells were subjected to trypsin digestion for 1 minute (Sigma, St. Louis, MO),
counted with a hemacytometer, and seeded at a density of 104 cells per well in
96-well plates. Cells were seeded for 12 hours in DMEM without FBS to
synchronize cell cycles, and medium was changed to DMEM with FBS 12 hours
prior to first treatment. A variety of treatment regimens were tested, varying
from 1 to 3 treatments (1 every 4 hours) for 1 to 3 days, followed by 1 to 3 days
recovery period.
A range of succussed remedies were tested on each cell line, from 12 CH to
1000 CK potentization. Four of the final potentizations were performed in
deionized ultra-filtered water (DiUF) from Fisher Scientific (Hampton, NH), with
the final potentization prepared in cell culture medium. The alcohol content was
by then minimized to 0.1 parts per billion. Controls included succussed and
unsuccussed medium as well as DiUF vehicle in cell culture medium. Data are
reported as percentage of unsuccussed medium used as control.
Crystal Violet
Crystal violet protein stain was performed on treated cell cultures for
assessment of cell proliferation by total protein content. Briefly, cells were fixed
and stained for 10 minutes with crystal violet (0.5%) from Fisher Scientific and
then solubilized with citrate buffer (0.1 M). Color intensity was measured using a
96-well plate reader at 570 nm with a reference reading at 655 nm.
MTT
Cell viability was assessed using the MTT (3-(4,5-dimethylethiazol-2-yl)-2,5diphenyltetrazolium bromide) assay. MTT was purchased from Invitrogen
(Carlsbad, CA). Cells were incubated for 5 hours with 5 mg/mL MTT in
phosphate buffered saline (PBS) at 37°C, 6% CO2. The resulting formazan
crystals were resuspended in dimethyl-sulfoxide from Fisher Scientific. Light
absorption was measured using a 96-well plate reader at 570 nm with a
reference reading at 655 nm.
Animal and Homeopathic Regimen
All animal procedures were carried out in accordance with the Georgetown
University Department of Comparative Medicine guidelines. In vivo studies were
performed in male nude BALB/c numice from Charles River (Boston, MA). Mice
were housed 5 per cage in ambient temperature with controlled air, subjected to
a 12-hour light-dark cycle, and received standard food and water ad libitum. The
animal facility personnel handling the animals had no information about the
experiments. Four- to five-week-old mice were allowed to adapt to animal
facility conditions for 1 week prior to subcutaneous inoculation with 106 cells of
either PC-3 human prostate or MDA-MB-231 human breast cancer cell lines in
100 µl PBS on both sides of the abdomen. Two days postinoculation, mice were
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39
divided into 5 groups of 10 animals each, except for the untreated group that
had 6 animals. The treatments were administered as follows:
Untreated control (UT) – inoculated mice left untreated and only handled for
weight and tumor measurements
200 CH succussed water (DiUF 200 CH) – mice treated with 100 µl of 200 CH
potentized water
Homeopathic Sabal serrulata (SS 200 CH) – mice treated with 100 µl of a 200
CH succussion (potentization) of Sabal serrulata
Homeopathic multitreatment (MT) – mice treated with 100
doses of various remedies on a 7-day cycle
L of homeopathic
Days 1 and 4 – Thuja occidentalis 1000 CK
Days 2 and 5 – Conium maculatum 1000 CK
Days 3 and 6 – Sabal serrulata 200 CH
Day 7 – carcinosin 1000 CK
The potencies used are based on unpublished experiments performed on rats.
Starting 2 days postinoculation, mice received daily treatment by gavage. The
final 5 potentizations for succussed treatment were prepared daily in deionized
water prior to gavage. Treatment continued for 5 weeks for a total of 35
treatments. Animals were followed up for an additional 5 weeks after final
treatment, and weight measurements were recorded once per week.
Tumor Measurement
Once tumors were of a palpable volume, 3-dimensional measurements were
recorded with a Vernier caliper by a veterinary technician blinded to the
experiment.
Animal weights were also recorded at the time of tumor volume measurements.
The volume formula (LxWxH) was used to estimate relative tumor volume.
In addition, all tumors were weighed upon dissection.
MRI
A representative mouse from 3 of the treatment groups was subjected to
imaging procedures for visualization of tumors. Mice were anesthetized with
1.4% isoflurane and scanned using a Brookline 7 telsa MRI with a 7 cm coil,
following a T1 weighted protocol with fat suppression. Twenty-four abdominal
images per scan were obtained at 0.7 mm thickness, and tumor volume
analysis was performed with ImageJ software available from the National
Institutes of Health (Bethesda, MD) by summing the average of 3 handtraced
regions (tumor area) per tumor image.
Statistics
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Following analysis of variance, Student’s t test was performed to analyze the in
vitro data. Repeated measures for analysis of variance (ANOVA) was used to
test the significant difference between treatments in vivo. To assess the
significant difference between treatments at each day point, ANOVA method
was used. Statistical significance was considered only for P values less than
0.05.
Results
In vitro
Both human prostate and breast cancer cell lines were subjected to a battery of
treatments with Sabal serrulata, Thuja occidentalis, or Conium maculatum at
different dilutions. After the last treatment, the cells were tested for proliferation
either after 24 or 72 hours of recovery time. The proliferation was assessed
using both crystal violet and MTT tests. The human prostate cancer cell lines
responded differently to the various treatment settings. Following a 1-day
regimen of 100 CH Sabal serrulata, PC-3 cells showed reduced proliferation
after a 72-hour recovery period. Cell proliferation was not significantly affected
after 24 hours, but it was reduced by 33% after 72 hours. In contrast, DU-145
cells responded to an identical treatment after just a 24-hour recovery period
(Figure 1). A 23% reduction was observed after 24 hours, whereas no
significant effect was noted after 72 hours. This difference is likely due to the
specific proliferation rates—DU-145 cells grow faster than PC-3 cells—as tested
by doubling time assessment (data not shown). Interestingly, when increasing
potencies of Sabal serrulata ranging from 12 CH to 1000 CK were used, no
significant cell proliferation inhibitory effect was observed on the human breast
cancer cell line (Figure 2). Taken together, these findings indicate the specificity
of Sabal serrulata to prostate cells. Neither Thuja occidentalis nor Conium
maculatum had an effect on cell proliferation of prostate cancer cells in vitro
(Figures 3 and 4), or on breast cancer cells. Traditionally, these remedies are
used to alleviate other distress-related symptoms that the patient may
experience while suffering from prostate disturbances or prostate cancer.
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41
In vivo
The mice were subjected to a regimen reflecting a homeopathic treatment that
could potentially be recommended clinically by homeopaths to patients suffering
from prostate problems including cancer.
It is important to note that in this pilot study, 10 animals were used in each
group except for the untreated control group, which was composed of only 6
animals. The smaller number of animals in the latter may have resulted in the
observed intragroup variability. The tumor incidence rate for the prostate cancer
Homeonews
42
untreated control group was at 100% by the end of the experiment, whereas it
remained at 75% for the SS 200 CH, 94.5% for the MT, and 83% for the DiUF
200 CH.
In the breast cancer group, the tumor incidence was between 90% and 100% in
all animal groups. The treatments did not affect the body weights, as they
remained the same throughout the experiment (Figure 5), and no toxicity due to
the remedies was noticed. Sabal serrulata showed a more pronounced
inhibitory effect on prostate cancer tumor growth than the combined regimen
including Thuja occidentalis, Conium maculatum, and carcinosin (Figure 6).
When compared to the untreated control group, tumor growth in
serrulata treatment group was at 42% (P<0.012), but this effect was
significant when Sabal serrulata was administered biweekly as
regimen including Thuja occidenatlis, Conium maculatum, and
(P<0.07).
the Sabal
marginally
part of a
carcinosin
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43
Animals treated with potentized deionized water showed reduced tumor growth
as well when compared to untreated controls (P<0.048). The fact that no effect
on breast cancer tumor growth was observed using the same treatments
(Figure 6B) indicates a certain prostate tissue specificity of Sabal serrulata’s
effects. To capture tumor sizes by MRI, 1 representative animal from each
group bearing the average size tumor underwent imaging. The smallest tumor
size was observed in the prostate cancer animal group treated with
homeopathic saw palmetto (Figure 7).
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44
Discussion
Complementary and alternative therapies are used to prevent illness or side
effects caused by conventional medical treatments, reduce stress, and control
or cure disease. It is therefore not surprising that use of CAM therapies by
cancer patients is on the rise. In a study published by Richardson and
colleagues, 83% of 453 cancer patients had used at least one CAM therapy in
their treatment. 32Another survey reported that 37% of 46 patients with prostate
cancer had used one or more CAM modalities. 33These consisted mostly of
herbal remedies, vitamins, and dietary measures.
Although the German Commission E states that Sabal serrulata relieves
symptoms associated with prostatic hypertrophy without reducing the
enlargement itself, 34homeopaths prescribe it to treat conditions involving both
the female and male reproductive systems including prostate hypertrophy or
atrophy accompanied by ulceration and bleeding. Using dilutions of 10–400, 10–
2000
, and 10–20000, Vozianov and Simeonova as well as Pecherskii and
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45
colleagues studied the effects of homeopathic remedies on prostate adenoma
and BPH. They suggested the interaction of the homeopathic medicine’s
informative energy imprint with the bioholographic human organism. Short- and
long-term effects on both the target organ and higher regulatory centers
indicated a definite therapeutic effect.35,36 It is a challenge to understand and
explain the mechanisms underlying the beneficial effects of homeopathic
treatments. Therefore, most studies have focused on proving the biologic
effects caused by homeopathic preparations in vitro and in vivo. Our work
demonstrates the inhibitory effect of homeopathic Sabal serrulata on human
prostate cancer cell line proliferation and on tumor growth.
By testing Sabal serrulata on human prostate cancer cell proliferation and
comparing its effect to that on human breast cancer cell lines, we demonstrated
that Sabal serrulata specifically inhibits prostate cancer cell proliferation. No
effect was observed on the human breast cancer MDA-MB-231 cell line.
Interestingly, the 2 prostate cancer cell lines PC-3 and DU-145 responded
differently to Sabal serrulata treatment. PC-3 cells were not significantly
affected after 24 hours, but their proliferation had been reduced by 33% at 72
hours. In contrast, a 23% reduction of DU-145 cell proliferation was observed
after 24 hours whereas no significant effect was noted at 72 hours. This
difference is likely due to the specific doubling times—DU-145 cells grow faster
than PC-3 cells (data not shown)—and/or to the different ontogenic
environments of the 2 cell lines, meaning that different cell-line-specific
molecular mechanisms might have been triggered. Furthermore, the cell lines
were also treated with homeopathic solutions of Thuja occidentalis and Conium
maculatum with no significant effect on either human prostate or breast cancer
cell lines.
Thuja occidentalis, also known as white cedar, has been traditionally used in
folk medicine for various health conditions such as cystitis, prostate
hypertrophy, urinary incontinence, uterine carcinoma, psoriasis, rheumatism,
and condylomata.37 Today, it is primarily used by homeopaths to treat a wide
array of health problems ranging from warts to headaches, vertigo, emotional
distress, depression, polydipsia, dysphagia, abdominal cramps, and so on. Its
use for prostatitis is advised only if the symptoms are accompanied by urinary
frequency, foam-covered cloudy urine, insomnia, and/or fever with chills that
worsen in the evening.
Several studies have identified various pharmacological properties of Thuja
occidentalis as an herbal preparation. When applied to freshly infected MT-2
cells, Thuja occidentalis polysaccharides inhibit HIV-1-specific antigen
expression in a dose-dependent manner.38 Noteworthy among its
immunopharmacological properties is its mitogenic potential triggering T-cell
induction of CD4-positive T-helper/inducer cells with enhanced interleukin-2 (IL2) production. In this case, Thuja occidentalis was shown to promote
proliferation and differentiation of functional T-helper cells, an effect that was
not observed with B cells.39 Used with mouse macrophages, Thuja occidentalis
induced an increase in IL-1, IL-6, and tumor necrosis factor-alpha (TNF-α). In
addition to its effects on cytokine secretion, a stimulation of NO2– production
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46
was reported. The immunomodulatory potential of Thuja occidentalis has also
been supported by animal studies.40 In mice subjected to radiation, Thuja
occidentalis treatment revealed protective properties against radiation toxicity.41
Recently, Iwamoto and colleagues reported a potential antitumor effect of
diterpenoids isolated from the stem of Thuja standishii.42 Homeopathic tinctures
of Thuja occidentalis have been evaluated for their genotoxic effects using the
Salmonella/mammalianmicrosome test and the induction of β-galactosidase,
indicative of DNA damage. No mutagenic effects have been noted.43
Conium maculatum, commonly known as poison hemlock, is one of the most
toxic species of the plant kingdom. Due to the narrow boundary between its
therapeutic and toxic effects, its medicinal use remained very restricted.
Besides its use as a fatal poison, the plant’s seeds have been used as a
sedative, antispasmodic, and analgesic. External application was directed at
treating herpes, certain types of skin infection, and breast tumors.44 Conium
maculatum remains, however, a classic homeopathic remedy prescribed for
enlarged and indurated immovable growths in glandular tissues occurring in
aging patients. Thus, Conium maculatum is mostly used for breast cysts and
tumors as well as prostate cancer. Within this symptomatic picture, homeopaths
have reported successful breast and prostate cancer treatment.45 Unfortunately,
no basic science research has been conducted beyond the plant’s powerful
neurotoxic and teratogenic effects, and studies remain limited to the field of
phytochemistry.46 Our findings with regard to Conium maculatum in cellular and
animal cancer models constitute the first report of its kind. In the abovedescribed experimental setting, Conium maculatum did not show any toxicity. It
did not affect the proliferation and viability of cells in vitro, and no toxicity was
observed in mice. As a component of our chosen regimen, Conium maculatum
did not significantly decrease tumor growth when compared to Sabal serrulata
monotherapy.
Carcinosin is a nosode (a nosode is obtained from a diseased tissue or body
secretions rather than animals, plants, or minerals) occupying a special place in
homeopathy. Carcinosin could be viewed as a new therapeutic tool developed
in the first part of the twentieth century by W. Boericke, J. H. Compton Burnett,
and J. H. Clarke, and subsequently revived by Dr D. M. Foubister in the
1950s.47 It is traditionally prescribed for cancer patients presenting with an array
of emotional problems, such as fear and low selfesteem.
Depending on the preparation procedure, carcinosin could be obtained from a
single tumor, as is the case for the Boiron and Dolisos brands in the United
States, 15 tumors (Dolisos brand in Holland, Belgium, and Switzerland), or 58
tumors (Stauffen brand in Germany).48 Carcinosin is therefore a new remedy
awaiting not only full provings but also a standardized preparation procedure.
Carcinosin 200 CH, a confirmed nosode of liver carcinoma used as
monotherapy in p-dimethylaminoazo-benzene-induced hepatocarcinogenesis in
mice treated daily until sacrifice, showed anticytotoxic, anticlastogenic, and
some degree of antitumor effects.26 In our experimental setting, carcinosin used
once a week as part of a multitreatment regimen did not result in decreased
tumor growth. The effect of the multitreatment regimen on tumor growth was in
fact of the same magnitude as the succussed water effect. By week 10, which
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47
marked the end of the experiment, the most pronounced tumor growth reduction
was observed with the monotreatment SS 200 CH, followed by succussed
water (DiUF 200 CH) and the multitreatment regimen (MT). It would be of
interest in future studies to observe the results of continuing treatment until the
end of the experiment in order to mimic the clinically recommended
homeopathic treatment approach. The observed treatment effect was sustained
for 5 weeks after gavage cessation. This could indicate that homeopathy has a
long-term effect and might act at the genomic level, targeting the underlying
molecular mechanisms and pathways involved in the disease.
Deciphering the mechanistic aspects of the homeopathic effect is one of the
most challenging endeavors in modern science. We observed that Sabal
serrulata exerted its proliferative inhibitory effect specifically on human prostate
cancer and that this effect was not obtained by using other remedies. This may
suggest that the treatment’s specificity is indicative of a cellular mechanism that
remains yet to be elucidated.
A potential cellular mechanism is suggested by the work of Gaddipati and
colleagues, who observed growth inhibition of DU-145, PC-3, and LNCaP
human prostate cancer cells following treatment with a pure compound derived
from Arnebia nobilis root—Shikonin analog 93/637—at nonhomeopathic
concentrations. Insulin-like growth factors (IGFs), known for their involvement in
cell proliferation and their mitogenic effects, were impacted by that treatment.
Thus, mRNA of IGF-I and IGF-IR was decreased in LNCaP, IGF-II in DU-145,
and IGF-II and VEGF (vascular endothelial growth factor) in PC-3.49
Finding the best control for experimental and clinical research in homeopathy is
an ongoing discussion.
Most studies have been unable to assert the beneficial effect of homeopathy
over control,50,51 resulting in a number of explanatory theories. The potentization
process, for example, the most enigmatic procedure in homeopathy, has been
associated with the facilitation of a charged mineral-leak from the glass
containers into the homeopathic solution, which in turn might exert an effect
independent of the purported remedy.52
Therefore, studies carried out with potentized controls will be more instructive.
Investigating the influence of container materials and storage duration in glass
and polyethylene containers on double distilled water and Argentum nitricum
dissolved in double distilled water after potentization, as assessed by
inductively coupled
plasma-mass spectroscopy, Witt and colleagues
demonstrated that element concentrations (Li, Na, Mg, Al, Si, Mn, Cu) were
present to a higher degree in glass and already elevated during the first
potentization step at the initial storage time.53 Thus, the authors recommend the
use of succussed controls, stored for the same time period and in the same
type of container as their remedy counterparts. Using either nuclear magnetic
resonance54 or a biologic effect in mice,55 a few reports documenting
differences to this effect have been released. However, further attempts to
demonstrate or replicate these differences56 remained unsuccessful.
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48
In our study, we used succussed controls both in vitro and in vivo. There was a
clear-cut difference in cell proliferation when Sabal serrulata was used as
compared to a series of succussed and unsuccussed control solutions. In the in
vivo study, by week 5, only 50% of animals receiving SS 200 CH developed
tumors compared to 72% of the succussed water group, and 67% in the
untreated group. These findings correspond to our experimental setting, that is,
treatment for 5 weeks with 5 additional weeks of follow-up. The argument that
compounds leaching from glass containers as a result of the potentization
process might exert a therapeutic effect has created an intense debate in the
scientific community. In future studies, alternate nonglass containers should be
considered as an additional control. Our study demonstrates a biologic
response to homeopathic treatment as manifested by cell proliferation and
tumor growth in cellular and animal models. This biologic effect was (i)
significantly stronger to Sabal serrulata than to controls and (ii) specific to
human prostate cancer. These data suggest Sabal serrulata as a homeopathic
remedy of choice for prostate pathology. Repeating the in vivo pilot study will
ensure experimental reproducibility of our findings and permit the application of
modified protocols more accurately reflecting the homeopathic therapeutic
approach. In addition, new technologies capable of gene, protein, and pathway
assessments in living organisms, such as functional genomics and proteomics,
may elucidate the mechanisms underlying our observed antiproliferative and
antitumorigenic effects. Controlled clinical studies would be needed to confirm
this finding and assess Sabal serrulata as a remedy of choice.
Acknowledgments
This work was supported by a grant (SIIB-0000011) from the Samueli Institute
for Information Biology. Hakima Amri is supported by a KO7 grant (AT001193)
from the National Center for Complementary and Alternative Medicine at the
National Institutes of Health.
The authors would like to thank Dr V. Papadopoulos for his support of the
initially generated data, and Dr Abu-Asab for critically reviewing the manuscript.
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NUTRICION
ESTUDIO PILOTO ABIERTO PARA MEDIR LOS EFECTOS DE ALTAS
DOSIS DE CONCENTRADOS DE EPA/DHA EN LOS FOSFOLIPIDOS DE
PLASMA Y EL COMPORTAMIENTO DE NIÑOS CON DEFICIT DE
ATENCION E HIPERACTIVIDAD
Paul J. Sorgi1, Edward M. Hallowell1, Heather L. Hutchins2, Barry Sears2.
1
Hallowell Center, 142 North Road, Suite F 105, Sudbury, MA 01776, USA.
Inflammation Research Foundation, 222 Rosewood Drive, Suite 500, Danvers,
MA 01923, USA
2
[Nutrition Journal 2007, 6:16]
RESUMEN
Antecedentes: El deficit de atención con hiperactividad (ADHD) es la
enfermedad neurológica más común en niños. Este estudio piloto evaluó los
efectos de la suplementación de altas dosis ácido eicosapentanoico (EPA) y
ácido docosahexanoico (DHA) sobre los fosfolípidos aislados de plasma y el
comportamiento en niños con ADHD (subtipo principalmente desatento y
subtipo combinado).
Métodos: nueve niños fueron suplementados inicialmente con 16.2g EPA/DHA
por día. La dosificación se fue ajustando de acuerdo a la relación de ácido
araquidónico (AA) a EPA en los fosfolípidos aislados de plasma, a las cuatro
semanas, para llegar al nivel normalmente encontrado en la población
japonesa
.
Resultados: Al final de las ocho semanas de estudio, la suplementación llevó a
un incremento significativo en EPA y DHA, así como una reducción significativa
en la relación AA:EPA (20.78±5.26 a 5.95±7.35, p<0.01). Un psiquiatra (que no
conocía la composición del suplemento ni las modificaciones en las
dosificaciones) registró mejorías significativas en el comportamiento
(desatención, hiperactividad, comportamiento desafiante y desórdenes
conductuales). También hubo una correlación significativa entre la reducción en
la relación AA:EPA y los puntajes de severidad global de la enfermedad.
Conclusiones: Los resultados encontrados en este pequeño estudio piloto
sugieren que la suplementación con altas dosis de EPA/DHA puede mejorar el
comportamiento en niños con ADHD.
ARTICULO ORIGINAL
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Background
Attention deficit hyperactivity disorder (ADHD) is a neurological condition
characterized by the inability to concentrate in a sustained manner, to pay
attention to tasks, and to control impulsive actions [1]. It is estimated that 3 to 7
percent of children have this disorder, and boys are affected to a much greater
extent than girls [2]. As many as 60 to 80 percent of children with ADHD
continue to have problems with this condition as they become adults [1]. The
etiology appears to be multi-factorial with both genetic and environmental
influences. Among these influences is an observed decrease in long-chain (LC)
polyunsaturated fatty acids (PUFAs) in children with ADHD. Some proposed
mechanisms for the low levels of PUFAs include insufficient dietary intake,
inefficient conversion of shorter chain PUFAs to LC PUFAs or rapid metabolism
of LC PUFAs [3]. Stevens et al. [4, 5] found that young boys with ADHD and
symptoms of essential fatty acid (EFA) deficiency (excessive thirst, dry skin and
hair, brittle nails, frequent urination and/or hyperfollicular keratoses) are
characterized by low levels of LC PUFAs, including AA, EPA and DHA in the
plasma phospholipids compared to control. This group of children with ADHD
also had a high ratio of AA to EPA compared to control (68.87 vs. 45.83
respectively) suggesting the depression of EPA was greater than that of AA [4,
5]. Other studies from the same group have also reported greater AA:EPA
ratios in children [3] and young adults [6] with ADHD compared to control.
The findings that children with ADHD have altered PUFA levels led to
interventional studies that supplemented with these fatty acids. Hirayama et al.
[7] found that supplementation of 0.61g of LC omega-3 fatty acids per day for
two months (primarily DHA in foods) had no effect when analyzing parent and
teacher assessments separately in children with ADHD; however, when
analyzing assessments together, physical aggression significantly improved
compared to the placebo group [8]. Voigt et al. [9] supplemented children with
ADHD for four months with 0.35 g of DHA per day and found no improvements
in any ADHD symptoms.
Richardson and Puri [10] supplemented children with ADHD related symptoms,
primarily dyslexia, for three months with 1.67g per day of omega-3 and omega6 fatty acids or olive oil placebo in a double-blind randomized fashion. Half of
the scales tested (seven of 14) improved compared to placebo, including
cognition, anxiety/shyness, psychosomatic subscales, restlessness/impulsivity
and three global scales; however, the participants were children with ADHDrelated symptoms not diagnosed with ADHD in accordance to DSM IV criteria.
The only study that measured the AA:EPA ratio was that of Stevens et al. [11]
who supplemented children with ADHD and symptoms of EFA deficiency with
0.66g per day of both omega-3 and omega-6 PUFAs for four months. Although
the AA:EPA ratio decreased from 33.04 to 15.19, only two of 16 behavioral
outcome measures significantly improved compared to the placebo group
suggesting the decreased AA:EPA ratio may not have been lowered enough to
observe a greater impact on behavior.
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Depression is often a co-morbidity of ADHD and an increased AA:EPA ratio has
been shown to positively correlate with severity of depression [12]. High-dose
dietary supplementation with EPA and DHA (9.6g) has been shown as an
effective adjunctive treatment for bipolar depression [13]. Epidemiological data
has shown that the Japanese population has low rates of depression [14],
compared to the US population and they have a high intake of fish and low
AA:EPA ratio [15]. The ratio of AA:EPA in the isolated plasma phospholipids of
the Japanese population is approximately 1.3 to 3 [15, 16]; young boys with
ADHD in the United States had AA:EPA ratios greater than 30 [4, 5, 11]. A
recent study found negative correlations between omega-3 status and behavior
in young adults with ADHD suggesting lower omega-3 status may be
associated with severity of behavioral symptoms [6].
The interventional studies in children with ADHD demonstrate that some
behavior may improve with PUFA supplementation [5, 8, 10]; however, the
findings have not been consistent and few have monitored fatty acid levels in
the plasma phospholipids. A possible association between ADHD behaviors
and omega-3 status, particularly the AA:EPA ratio and the lack of consistent
results led us to hypothesize that insufficient levels of omega-3 fatty acids, or
lack of sufficient reduction of the AA:EPA ratio, are two possible explanations
for the inconsistent findings of previous studies. To address this hypothesis, we
undertook an open-label pilot study to first determine if children with ADHD
would adhere to a protocol of high-dose EPA/DHA concentrates (initial dosage
of 16.2g EPA and DHA per day) to reach the goal AA:EPA ratio between 1.5
and 3 as found in the Japanese population. Second, behavior was assessed by
a psychiatrist specialized in this childhood disorder to measure what effect such
a reduced AA:EPA ratio would have on behavior.
Methods
Study design and participants: This was an eight-week, open-label, proof-ofefficacy pilot study. Nine children aged 8-16 were recruited from the patient
population under treatment for ADHD-primarily inattentive subtype or ADHDcombined subtype at the Hallowell Center, Sudbury, MA. There were more boys
(n=6) than girls (n=3). Two-thirds (n=6) presented with ADHD-combined
subtype, and one-third (n=3) with ADHD-primarily inattentive subtype according
to criteria of the Diagnostic Statistical Manual (DSM) IV [17]. Two of the three
participants who presented with ADHD-primarily inattentive subtype were girls.
Participant characteristics are outlined in Table 1. All participants had an
established relationship with the psychiatrist involved in the study. Three
participants voluntarily discontinued stimulant medication prior to study initiation
with the psychiatrist’s approval. The remainder continued with their treatment
regime for the duration of the study. There were no medication dosage changes
during the course of the eight-week study. Children and parents/guardians
provided informed and written assent and consent respectively. Integreview,
Houston, TX, approved the study for the use of human subjects in research.
Table 1. Baseline Characteristics of Study Participants*
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Age (y)
Gender (% male)
Race (% white)
School grade
ADD %
ADHD %
Years since diagnosis
11.44±1.51
67
100
6.00±1.77
33
67
2.63±1.41
Height (in)
Weight (lbs)
Taking stimulant
medication (%)
61.67±5.13
113.67±34.04
* Reported
67
values are means±SD (n=9) or percentages.
Study Intervention: At the start of the study, all participants were instructed to
consume two tablespoons (30mL) of a liquid EPA/DHA concentrate (supplied by
the Inflammation Research Foundation) providing 16.2g of LC omega-3 fatty
acids (10.8g EPA and 5.4g DHA) per day. The EPA/DHA concentrate dosage
was adjusted at week four based on the AA:EPA ratio in the isolated plasma
phospholipids as follows: if the AA:EPA ratio was below 1.0, the dosage was
decreased to 15 ml (5.4g EPA, 2.7g DHA per day), if the AA:EPA ratio was
between 1.0 and 1.5 the dosage was decreased to 20ml (8.1g EPA, 4g DHA
per day). Isolated plasma phospholipids are not subject to daily fluctuations in
dietary intake and are a reliable marker of fatty acid levels [18] and correlate to
dietary intake of fatty fish [19-21] and fish oil supplementation [22, 23]. EPA
levels were used to monitor adherence to the supplementation protocol and the
participant’s parent/guardian was phoned once per week to monitor adherence
and adverse effects of the EPA/DHA concentrates. The children and at least
one parent/guardian met with the psychiatrist at three time points: baseline
(week 0), midpoint (week four) and conclusion (week eight). At the initial
(baseline) visit participants were advised to follow a “healthy diet” that
encouraged fruits, vegetables and balanced intake of macronutrients at meals
and snacks. At each of the three meetings, the psychiatrist conducted
behavioral assessments, and a phlebotomist drew blood for fatty acid analysis.
Fatty acid analysis of the isolated plasma phospholipids was completed by
Nutrasource Diagnostics, Guelph, ON, Canada, as described by Laidlaw and
Holub [23].
Behavioral Assessment: The ADHD Symptom Checklist-4 (ADHD SC-4) was
used to monitor behavioral changes by the psychiatrist at each meeting.
Retrospectively the psychiatrist asked the parent/guardian and child each of the
checklist questions and also observed symptoms during the process. This
questionnaire
categorizes
behavior
as
inattention,
hyperactivity,
oppositional/defiant, and conduct disorder. There was also a section to monitor
medication side effects. Inattention and hyperactivity scores can range from 0 to
27 each. Oppositional/defiant scores range from 0 to 24 and conduct disorder
from 0 to 3 [24, 25].
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The Clinical Global Impression Scale was used by the psychiatrist to rate
participants’ severity of illness [26]. The scores are derived from a 7-point Likert
scale [26]. Severity of illness ranged from 1 as normal (not at all symptomatic),
to 7 as among the most symptomatic patients. Although the psychiatrist knew
the children were part of a study, he was blind to dosage adjustments and
protocol adherence. The parents also completed the short form Conner’s
Parent’s Rating Scale (CPRS) [27-29] at baseline, week four and week eight.
Responses were scored and categorized into 4 groups: oppositional behavior,
cognitive problems/inattention, hyperactivity and an ADHD index.
Statistical Analysis: Summary statistics are reported as mean±SD and
medians. Statistical analyses were performed using Stata for Mac (version 9,
StataCorp LP, College Station, Texas). Fatty acids, ADHD SC-4, CPRS, and
severity of illness were reported for baseline (week 0), midpoint (week four) and
at the conclusion of the study (week eight). The nonparametric Friedman test
was used to assess changes over time. If the Friedman test was statistically
significant at the 0.05 level, then the Wilcoxon signed rank test was used as a
posthoc test to compare changes from baseline to four and eight weeks.
Spearman correlations were used to identify a relationship between changes in
the primary fatty acid outcome variable, the AA:EPA ratio, and the primary
behavioral outcome variable, severity of illness.
Results
Effect of EPA/DHA Concentrates on Isolated Plasma Phospholipid Fatty Acid
Levels: Blood was monitored throughout the study to ensure that the AA:EPA
ratio was greater than 1.0 because of the potential concern with high-dose
EPA/DHA supplementation on prolonged bleeding times; although, a recent
study of the Japanese indicated no adverse effects related to EPA intake in
patients whose AA:EPA ration was lowered to 0.8 [15]. To maintain the goal
AA:EPA ratio between 1.5 and 3 dosage adjustments were made at week four
based on fatty acid results. At week four, three participants had an AA:EPA ratio
below 1.0 and adjusted their EPA/DHA concentrate dosage to 15ml per day;
two participants had AA:EPA ratios between 1.0 and 1.5 and adjusted their
dosage to 20ml EPA/DHA concentrate; the remaining four participants had an
AA:EPA ratio of 1.5 or above, and were instructed to continue with the initial
daily dosage. Four of the five participants whose dosage was adjusted at week
four increased their AA:EPA ratio by week eight, however the AA:EPA ratio
remained less than 3 (Figure 1).
Two participants had an AA:EPA ratio less than one at week eight and upon
exiting the study were advised to decrease the supplement dosage if they were
to continue with the protocol post study.
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Figure 1. AA:EPA ratio changes from week 4 to 8 in the participants with EPA/DHA concentrate
dosage changes.*
* Each line represents a participant’s AA:EPA ratio from week 4 to week 8 in the five who were
instructed to decrease their intake of the EPA/DHA concentrate.
Overall, at the conclusion of the eight weeks of supplementation, the average
EPA and DHA levels in the isolated plasma phospholipids significantly
increased by a factor of 9.5 and 2.4 respectively (Table 2).
The AA tended to decrease at eight weeks, although the reduction was not
significant (p=0.07). As a consequence of AA and EPA changes, there was a
71% reduction in the mean AA:EPA ratio (20.78±5.26 to 5.95±7.35, p<0.01)
from baseline to week eight. The EPA/DHA concentrate dosage adjustment at
week four resulted in the average EPA and DHA levels to increase from week
four to eight with a corresponding 42% relative increase (4.19±.5.45 to
5.95±7.35, p=0.07) in the AA:EPA ratio; in contrast, the relative increase in
median AA:EPA ratio over the same period was only 16% and better reflects
the actual changes among compliant study participants. Nonetheless, these
increases demonstrate sensitivity to EPA and DHA supplementation dosage.
Table 2. Fatty acids from the isolated plasma phospholipids described as means SD
and median.*
Plasma FA
Baseline
Week 4
Week 8
n-6
18:2 (LA)
median
20:3 (DGLA)
median
20:4 (AA)
median
22.61±1.39
21.95
3.12±0.44
3.09
9.52±0.70
9.34
17.81±2.85
17.49
1.86±0.82
2.25
8.92±0.83
8.92
21.88±4.89
21.08
2.15±0.64
2.05
8.69±1.30
8.37
0.13±0.07
0.13
0.49±0.12
0.46
0.13±0.07
0.1
5.89±4.27a
6.13
0.13±0.06
0.12
4.64±3.65a
4.72
n-3
18:3 (LNA)
median
20:5 (EPA)
median
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22:6 (DHA)
median
Totals and ratios
Saturated
median
Monounsaturated
median
Polyunsaturated
median
total n-6
median
total n-3
median
n-6: n-3 ratio
median
AA:EPA ratio
median
AA:EPA ratio (n=7)#
median
2.30±0.88
2.07
5.68±1.28a
6.11
5.61±2.14a
6.19
44.29±0.99
44.2
15.43±1.38
15.7
40.27±1.03
40.21
36.37±0.99
36.57
3.90±0.87
3.66
9.74±2.14
9.61
20.78±5.26
20.14
20.73±5.26
19.58
43.94±1.26
44.04
13.64±1.18
13.51
42.41±1.43
42.02
29.07±4.31a
29.54
13.35±5.27a
12.74
2.79±1.88a
2.39
4.19±5.45a
1.46
2.53±3.49a
1.34
42.19±1.05
42.53
12.31±2.12
11.93
45.51±1.26
45.38
33.42±5.67
31.59
12.09±6.17a
13.38
3.93±2.73a
2.36
5.95±7.35a
1.69
2.52±2.91
1.39
* Values are mean±SD and medians (n=9). a p<0.01 using Wilcoxon signed rank test to
compare to baseline. LA, linoleic acid; DGLA, dihomogammalinolenic acid; AA, arachidonic
acid; LNA, linolenic acid; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid.
Protocol Adherence:
The largest AA:EPA reduction for most participants occurred in the first four
weeks (Figure 2). Figure 2 shows that one participant’s AA:EPA ratio returned
to baseline levels at week eight following a reduction at week four. Furthermore,
this participant’s EPA and DHA levels also returned to near baseline levels,
indicating poor compliance from week four to eight. This participant’s parent
reported poor protocol adherence for the second half of the study, which mimics
the fatty acid data. A second participant who refused to consume the liquid was
switched to a capsule supplementation and was instructed to consume 24 onegram capsules (9.6g EPA and 4.8g DHA) per day from week two to week eight.
The lack of change in the AA:EPA ratio in this participant indicated noncompliance. We chose less than 100% increase in the isolated plasma
phospholipids for EPA and DHA as an indicator of poor compliance.
The two non-compliant children were not of the same ADHD subtype or gender.
All other participants had greater than a 100% increase in both EPA and DHA
levels at the conclusion of the study and were considered compliant with study
supplementation protocol.
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Figure 2. AA: EPA ratio changes at week 0, week 4 and week 8.*
*Each line represents a participant’s AA:EPA ratio from baseline to week 4 and week 8, dashed
lines represent the participants whose EPA/DHA concentrate dosage was not changed at week
4.
Adverse Effects: One participant reported loose stools while taking 30ml of the
liquid EPA/DHA concentrate per day. At week four, the dosage was decreased
to 15ml per day with no subsequent adverse events. No observational effects
on bleeding were reported by the parents. One child had adverse effects (tics)
related to stimulant medication prior to study initiation that continued throughout
the study. Sleep disturbance is another know adverse effect of medication for
the treatment for ADHD [30]; four of the nine children had improvements in
sleep noted by the parents.
Behavioral analysis:
All categories of the ADHD SC-4 significantly improved by week eight.
Specifically, inattention, hyperactivity, oppositional/defiant behavior and conduct
disorder all significantly improved over the course of the study (Table 3). The
CPRS showed significant improvements (p<0.05) in all four categories
(oppositional behavior, cognitive problems/inattention, hyperactivity, and the
ADHD index) over the eight week study as well (Table 3). The severity of illness
score, assessed by the psychiatrist, tended to improve (p=0.08) over time. On
average, the severity of illness score decreased by 1 point from 4.4 (moderately
symptomatic) to 3.3 (mildly symptomatic).
The two subjects who were identified as non-compliant from parental reports
and fatty acid levels were the only participants who were scored a 5 (markedly
symptomatic) at baseline and week eight.
Table 3. Behavioral assessment*
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Assessment
Baseline
Week 4
Week 8
18.11±5.37
17
10.56±5.46a
9
9.78±6.91a
10
Baseline
Week 4
Week 8
11.33±4.53
10
7.67±5.96
6
5.22±3.99a
4
ADHD SC-4
Oppositional/defiant
Median
ADHD SC-4
Conduct disorder
Median
CPRS-Oppositional
behavior
median
10.11±6.79
11
5.44±3.88b
7
5.22±3.56b
5
5.22±6.26
4
0.89±0.93b
1
1.11±2.26b
0
8.67±4.58
5.38±3.11
4.89±2.93a
7
5.5
6
CPRS- Cognitive
problems/
inattention
median
11.56±5.13
7.00±3.89b
8.44±6.48
12
8.5
8
CPRS- Hyperactivity
Median
5.89±3.79
6
2.63±2.39
3
3.22±4.49
2
CPRS- ADHD index
Median
22.67±9.03
22
13.63±6.37a
13
15.44±9.49b
14
Clinical Severity of
Illness
Median
4.38±0.74
3.56±0.73
3.33±1.12c
4.5
3
3
ADHD SC-4
Inattention
Median
Assessment
ADHD SC-4
Hyperactivity
Median
* Values are mean±SD and medians (n=9). ADHD SC-4, Attention Deficit Hyperactivity
Disorder Symptom Checklist 4. CPRS, Conners’ Parents Rating Scale a p<0.01, b
p<0.05 using Wilcoxon signed rank test to compare to baseline; c p=0.08 using
Friedman test to compare to baseline.
Correlations: There was a significant positive correlation of the percent change
in AA:EPA ratio with the percent change in severity of illness (Rho= 0.7638,
p=0.027). However, the AA:EPA ratio did not significantly correlate with the
ADHD SC-4 or CPRS categories.
Discussion
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Supplementation with high-dose EPA/DHA concentrate resulted in significant
modifications of fatty acids, particularly a significant improvement in the AA:EPA
ratio in the isolated plasma phospholipids and improvements in behavior
assessed by a psychiatrist (blinded to protocol adherence and supplement
dosage adjustments) in this small pilot sample of children with ADHD.
At baseline fatty acid analysis of the isolated plasma phospholipids from the
children in this study were similar to that of previous studies of children with
ADHD and thirst/skin symptoms of EFA deficiency [3, 5, 11]; however, we did
not assess EFA deficiency symptoms.
Children with ADHD and thirst/skin symptoms of EFA deficiency had lower AA
and DHA levels in the plasma phospholipids compared to control groups. Both
the AA and DHA mean levels from previous studies [3, 5, 11] were within the
95% CI (8.98-10.05; 1.63-2.97, respectively) of this study’s mean AA and DHA
levels.
Supplementation of high-dose EPA/DHA concentrates resulted in marked
changes in fatty acid levels of the isolated plasma phospholipids. EPA and DHA
levels in the isolated plasma phospholipids were used to monitor compliance.
We chose the AA:EPA ratio as an important marker because of it’s relationship
with depression [12], as depression is often associated with ADHD [31]. In this
study, there was indeed a significant positive correlation between the AA:EPA
ratio and severity of illness.
Although the EPA and DHA supplementation dosages used in this study were
high compared to previous studies with children, there was no serious adverse
effect except one case of loose stools that was corrected with a lower dose.
Young et al. [32] supplemented adults with ADHD with high-dose EPA/DHA
concentrates (approximately 36g EPA and DHA per day) with no reported
serious adverse effects other than loose stools and fishy burps. The average
AA:EPA ratio after 12 weeks of the high-dose EPA/DHA supplementation in
adults with ADHD was 1.4±0.6 [32]; however, behavior was not assessed in this
study.
Stevens et al. [11] supplemented children with ADHD and thirst/skin symptoms
with 480mg DHA, 80mg EPA, 40mg AA and 60mg GLA per day. At these
levels, the AA:EPA ratio was reduced to15.19 after four months [11], which
remains 2.5 times greater than the mean AA:EPA ratio obtained in this study.
Stevens et al. [11] did monitor behavior and found improvements in conduct
assessed by the parents and attention assessed by the teachers in the PUFA
group compared to olive oil placebo. When assessed clinically, the parental
rating scales were also evaluated based on diagnostic criteria, and a significant
PUFA treatment effect was reported for oppositional/defiant disorder. The
findings by Stevens et al. [11] supports our data in that we also found
improvements in oppositional behaviors rated by the parents and improvements
in both oppositional/defiant behaviors and conduct assessed clinically by the
psychiatrist, however, a psychiatrist did not assess behavior in Stevens et al.’s
study.
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This study found a statistically significant improvement in the psychiatrist’s
report of inattention, hyperactivity, oppositional/defiant behavior and conduct
disorder based on the ADHD SC-4 questionnaire. Scores for inattention,
hyperactivity and oppositional/defiant behavior continued to improve from week
four to eight, even with the EPA/DHA concentrate dosage adjustment. The
dosage adjustment, however, did not bring the AA:EPA ratio above 3
suggesting the importance of monitoring fatty acids and the AA:EPA ratio in
particular rather than EPA/DHA dosage alone. The severity of illness scale
demonstrated a positive improvement from an average of moderately
symptomatic to mildly symptomatic. This improvement was similar regardless of
medication use or lack there of. The percent change in severity of illness also
correlated with percent decrease in the AA:EPA ratio, suggesting a connection
between the clinical improvement observed by the psychiatrist and the
improvements in the AA:EPA ratio.
Data from Stevens et al. [11] in children and Young et al. [32] in adults with
ADHD suggest that greater amounts of both EPA and DHA may be required to
decrease the AA:EPA ratio to between 1.5 and 3. The mean AA:EPA ratio at
the end of this study was 5.95±7.35 for all participants. When the two
participants who were non-compliant were removed, the AA:EPA ratio was
2.52±2.91, suggesting a daily dose between 8.1g and 16.2g of EPA/DHA
concentrate may be appropriate to decrease the AA:EPA ratio to between 1.5
and 3 and to observe improvements in behavior in children with ADHD.
There are a number of limitations to this pilot study and therefore interpretation
of results requires caution. The study is limited in that there was no placebo
group for reference comparisons as this was a pilot study to determine
appropriate dosage for protocol adherence and to maintain AA:EPA levels
between 1.5 and 3. Dietary intake was not recorded at baseline or monitored
throughout the study; therefore, we are unable to decipher intake of fatty acids
from the diet. Also related to diet, we advised the children to eat more fruits and
vegetables and consume meals and snacks that are balanced with protein,
carbohydrates (preferably fruit and vegetables) and “healthy” monounsaturated
fats. Advice for following both a “healthy diet” and high-dose fish oil
supplementation may have been confounding factors. However, the
doseresponse relationship between percent change in AA:EPA ratio and the
reduction in the severity of ADHD suggest the behavioral changes were due to,
at least in part, the intake of high-dose EPA/DHA concentrates. The lack of
behavioral change or regression to pre-study status in those subjects who were
least compliant to supplementation also suggest that behavioral changes were
associated with intake of the LC omega-3 fatty acids.
EPA/DHA concentrate dosage adjustments themselves can be viewed as a
limitation since some, but not all participants’ daily intake dosage was modified
at week four. The supplement intervention adjustment was based on the
AA:EPA ratio, therefore those whose AA:EPA ratio dropped below the goal
range was adjusted upward and by using this ratio as our goal, we also avoided
most adverse events. The lack of a proper means to monitor supplement intake,
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such as weight of returned bottles, was also a limitation of this study. However,
this was compensated for by use of isolated plasma phospholipids levels as a
means to monitor protocol adherence.
Conclusions
Although this was a small one-arm study, the results are encouraging as they
suggest that high-dose EPA and DHA (up to 16.2g per day) can be given to
children with good adherence. Also, our results concur with trends and
significant findings of some, but not all studies of PUFA supplementation in
children with ADHD or related symptoms [8, 10, 11]. The inconsistent findings
from previous studies and our results suggest that greater dosages of EPA are
needed to decrease the AA:EPA ratio to levels similar to the Japanese
population and to observe significant behavioral improvements. The findings of
this study suggest that children with ADHD and a high AA:EPA ratio might be
responsive to treatment with EPA and DHA supplementation to bring the
AA:EPA ratio to below 3.
The preliminary results found in this pilot study warrant future randomized,
placebocontrolled, double blind studies that use participant’s AA:EPA ratios to
determine EPA/DHA supplementation dosage for adjunct treatment of ADHD in
children.
Competing Interests BS is a stockholder and president of Zone Labs Inc; HLH is
a stockholder and employee of Zone Labs Inc.
Authors’ Contributions
PJS was involved with the design of the study and carried out all psychological
testing. EMH was involved with the design of the study. HLH performed the
statistical analysis and drafted the manuscript. BS conceived the study and
helped to draft the manuscript. All authors read and approved the final
manuscript.
Acknowledgements
The Inflammation Research Foundation financially supported this study. We
would like to thank Christine DeCammillis for her organizational help with the
study participants at the Hallowell Center and Garrett Fitzmaurice for his
statistical expertise.
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of the effects of supplementation with highly unsaturated fatty acids on ADHDrelated symptoms in children with specific learning difficulties. Prog
Neuropsychopharmacol Biol Psychiatry 2002, 26: 233-239.
11. Stevens L, Zhang W, Peck L, Kuczek T, Grevstad N, Mahon A, Zentall S,
Arnold L, Burgess J: EFA supplementation in children with inattention,
hyperactivity, and other disruptive behaviors. Lipids 2003, 38: 1007-1021.
12. Adams PB, Lawson S, Sanigorski A, Sinclair AJ: Arachidonic acid to
eicosapentaenoic acid ratio in blood correlates positively with clinical symptoms
of depression. Lipids 1996, 31 Suppl: S157-161.
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13. Stoll A, Severus W, Freeman M, Rueter S, Zboyan H, Diamond E, Cress K,
Marangell L: Omega 3 fatty acids in bipolar disorder: a preliminary double-blind,
placebocontrolled trial. Arch Gen Psychiatry 1999, 56: 407-412.
14. Hibbeln JR: Fish consumption and major depression. Lancet 1998, 351:
1213.
15. Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y,
Oikawa S, Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A, Nakaya N,
Sakata T, Shimada K, Shirato K: Effects of eicosapentaenoic acid on major
coronary events in hypercholesterolaemic patients (JELIS): a randomised openlabel, blinded endpoint analysis. Lancet 2007, 369: 1090-1098.
16. Nakamura T, Azuma A, Kuribayashi T, Sugihara H, Okuda S, Nakagawa M:
Serum fatty acid levels, dietary style and coronary heart disease in three
neighbouring areas in Japan: the Kumihama study. Br J Nutr 2003, 89: 267272.
17. Diagnostic and Statistical Manual of Mental Disorders- Fourth Edition (DSM
IV). edn. Washington, DC: American Psychiatric Association; 1994.
18. Zeleniuch-Jacquotte A, Chajes V, Van Kappel AL, Riboli E, Toniolo P:
Reliability of fatty acid composition in human serum phospholipids. Eur J Clin
Nutr 2000, 54: 367-372.
19. Philibert A, Vanier C, Abdelouahab N, Chan HM, Mergler D: Fish intake and
serum fatty acid profiles from freshwater fish. Am J Clin Nutr 2006, 84: 12991307.
20. Bjerve KS, Brubakk AM, Fougner KJ, Johnsen H, Midthjell K, Vik T: Omega3 fatty acids: essential fatty acids with important biological effects, and serum
phospholipid fatty acids as markers of dietary omega 3-fatty acid intake. Am J
Clin Nutr 1993, 57: 801S-805S; discussion 805S-806.
21. Kobayashi M, Sasaki S, Kawabata T, Hasegawa K, Akabane M, Tsugane S:
Single measurement of serum phospholipid fatty acid as a biomarker of specific
fatty acid intake in middle-aged Japanese men. Eur J Clin Nutr 2001, 55: 643650.
22. Stark KD, Mulvad G, Pedersen HS, Park EJ, Dewailly E, Holub BJ: Fatty
acid compositions of serum phospholipids of postmenopausal women: a
comparison between Greenland Inuit and Canadians before and after
supplementation with fish oil. Nutrition 2002, 18: 627-630.
23. Laidlaw M, Holub B: Effects of supplementation with fish oil-derived n-3 fatty
acids and gamma-linolenic acid on circulating plasma lipids and fatty acid
profiles in women. Am J Clin Nutr 2003, 77: 37-42.
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24. Gadow KD, Sprafkin J: ADHD Symptom Checklist-4- manual. edn. Stony
Brook, NY: Checkmate Plus; 1997.
25. Gadow KD, Sprafkin J: Revised norms for ADHD-SC4. edn. Stony Brook,
NY: Checkmate Plus; 1999.
26. Guy A: Clinical global Impressions rating scale. edn. Washington, DC: US
Government Printing Office; 1991.
27. Conners C: Rating scales for use in drug studies with childern.
Psychophaarmacology Bulletin, 9, 24-29 1973, 6.
28. Conners C, Sitarenios G, Parker J, Epstein J: The revised Conners' Parent
Rating Scale (CPRS-R): factor structure, reliability, and criterion validity. J
Abnorm Child Psychol 1998, 26: 257-268.
29. Conners C, Wells K, Parker J, Sitarenios G, Diamond J, Powell J: A new
self-report scale for assessment of adolescent psychopathology: factor
structure, reliability, validity, and diagnostic sensitivity. J Abnorm Child Psychol
1997, 25: 487-497.
30. Brown RT, Amler RW, Freeman WS, Perrin JM, Stein MT, Feldman HM,
Pierce K, Wolraich ML: Treatment of attention-deficit/hyperactivity disorder:
overview of the evidence. Pediatrics 2005, 115: e749-757.
31. Drabick DA, Gadow KD, Sprafkin JO: Co-occurrence of conduct disorder
and depression in a clinic-based sample of boys with ADHD. J Child Psychol
Psychiatry 2006, 47: 766-774.
32. Young GS, Conquer JA, Thomas R: Effect of randomized supplementation
with high dose olive, flax or fish oil on serum phospholipid fatty acid levels in
adults with attention deficit hyperactivity disorder. Reprod Nutr Dev 2005, 45:
549-558.
RECORDATORIO
PROF. DRA. MADELEINE BASTIDE (1935-2007)
(Farmacéutica, Inmunóloga, Investigadora, Profesora emérita de la Universidad de Montpellier)
Recuerdo la primera vez que tuve la suerte de escucharla, allá por el año 1998,
asistiendo al Curso de Inmunología y Homeopatía que dictó durante el XXIV
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Congreso Brasilero de Homeopatía, en la Ciudad de Gramado (Brasil), y por lo
cual quedé totalmente cautivado por calidad y claridad de sus
exposiciones, así como también por sus trabajos de investigación. En ese
momento pensé, que interesante sería poder compartir toda esa información
tan valiosa, aportada por tan prestigiosa investigadora, con los médicos y
farmacéuticos de Argentina, por lo cual me acerqué y tímidamente le pregunté
si existía alguna posibilidad para que pueda dictar ese mismo Curso en mí país
y de ser posible cuáles serían sus honorarios. Su respuesta fue inmediata y
afirmativa: “por supuesto que sí, y si la actividad está dirigida a mis
colegas, no tiene ningún costo”…. A partir de ese momento nos pusimos a
trabajar en la Cámara Argentina de Farmacias Homeopáticas y logramos
cristalizar el objetivo al año siguiente (1999), donde no sólo dictó un Curso en
Buenos Aires, sino también en Córdoba (Colegio de Farmacéuticos de dicha
Provincia) y en Tucumán (Colegio de Farmacéuticos de la Prov. de Tucumán y
Facultad de Bioquímica, Química y Farmacia de la Universidad Nacional de
Tucumán), actividades a las cuales me tocó asistir, como así también
acompañarla durante toda la semana que estuvo en Argentina, lo cual me
permitió conocerla aún más, no solo a la notable investigadora por sus
excelentes trabajos científicos relacionados a la homeopatía, sino
también por sus dotes de gran persona, ya que desinteresadamente nos
brindaba todo su apoyo y compartía sus conocimientos, y como si ésto
fuera poco, también mostraba ser una excelente esposa, madre y abuela,
ya que siempre buscaba una oportunidad, en los desayunos, almuerzos, cenas
y viajes compartidos, para hablar mil maravillas de su familia. Pero su contacto
conmigo, no se terminó allí, sino todo lo contrario, ya que siempre recibía
información de sus trabajos por correo postal o electrónico, así como sus
saludos para las Fiestas de Fin de Año y sus palabras de recuerdo para esa
semana tan intensa que había pasado en Argentina.
Lamentablemente, físicamente no está más con nosotros, lo cual representa
una pérdida invalorable para la Homeopatía y para todos aquellos que la
conocimos y pudimos disfrutar.
Gracias Prof. Dra. Madeleine Bastide, siempre estará en nuestros recuerdos!
FARM. ARTURO MENDEZ
(Farmacéutico Homeópata – Director Científico de Farmacias Vassallo)
Fue uno de los grandes maestros de la Farmacotecnia Homeopática
Argentina, así como también de Brasil y Uruguay. Se destacó no sólo por
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su tarea docente sino también por su constante lucha para jerarquizar el rol
del Farmacéutico en la Homeopatía, a través de la presentación de trabajos
en Congresos, participación en Mesas Redondas, Ateneos y otras actividades
que resaltaron no solamente su figura carismática sino también el valor del
profesional Farmacéutico en el equipo de Salud.
Fue un hombre de ideales, y como lo destaqué en el párrafo anterior, muy
carismático. En todas sus participaciones (Congresos, Jornadas, Seminarios,
Ateneos, etc.) siempre se imponía no sólo por sus conocimientos, sino
también por la vehemencia con la cual defendía sus conceptos, los cuales
eran matizados siempre con anécdotas de su extensa trayectoria profesional,
que mantenían a los asistentes atentos durante toda su exposición.
Mi primer contacto con él, fue en el año 1992, durante un Ateneo dictado en la
Escuela Médica Homeopática Argentina, donde se discutían las diferentes
Farmacopeas Homeopáticas, y dado mi conocimiento con respecto a la
Farmacopea Homeopática Alemana que utilizaba contínuamente en mi época
de Ayudante de Dirección Técnica de Laboratorios Dr. Madaus, me facilitó una
traducción de la misma al español (realizada por él) para que verificara si ésta
guardaba relación con la edición original, sin importarle que en esos momentos
me encontraba trabajando en la Farmacia de mayor competencia con la suya.
Luego de este primer encuentro, la historia continuó y a la vista de la
Comunidad Homeopática, podría decirse que nos consideraban dos polos
opuestos o como algunos llamaron, dos escuelas de Farmacia Homeopática
diferentes, pero desde mi punto de vista y considero que también desde el de
“Arturo”, tal como quería que lo llame, nos separaban sólo dos cosas,
trabajabamos en distintas Farmacias (dos de las más importantes) y éramos
hinchas de clubes diferentes (Arturo de River y yo de Boca), pero nos unía
algo muy importante que era el amor por nuestra profesión y también por
la Homeopatía.
El respeto personal y profesional era mútuo, a pesar que en las discusiones
muy acaloradas parecía todo lo contrario, pero si existía alguna duda, creo que
a través del libro de Sinonimias Homeopáticas, uno de los títulos escritos por
Arturo, que me obsequió y dedicó, puede dejarse de lado cualquier discusión al
respecto.
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El último trabajo que pude hacer junto a él y todos los Colegas de la Comisión
de Farmacéuticos del Colegio Oficial de Farmacéuticos y Bioquímicos de la
Ciudad de Buenos Aires, fue el Manual de Buenas Prácticas de Preparación de
Recetas Homeopáticas, a cuyas reuniones siempre asistía puntualmente y
discutía con el entusiasmo que siempre lo caracterizó, todos los puntos
tratados.
Lamentablemente, el Farm. Arturo Méndez falleció, luego de una larga lucha
con su físico que no acompañó la lucidez de su mente, pero nos ha dejado
muchas enseñanzas, tanto académicas como de la vida, por lo cual siempre lo
vamos a recordar.
Gracias Arturo por los conocimientos compartidos y las enseñanzas de
vida!!
NOVEDADES
NUEVO PRODUCTO COSMETICO:
OMS, División Cosmética de Laboratorios Dr. Madaus & Co., ha lanzado
BIOCELL FIRM®, emulsión que actúa en forma sinérgica combatiendo y
atenuando de forma efectiva los signos visibles de la celulitis a la vez que
reafirma y tonifica las áreas donde la flaccidez es crítica: vientre, glúteos,
brazos y busto. También mejora el aspecto de la “piel de naranja”
proporcionando una agradable sensación de frescura. Su fórmula renueva la
textura de la piel, mejorando la elasticidad y firmeza natural de la misma,
alisando y revirtiendo su sequedad, logrando una humectación prolongada.
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BIOCELL FIRM® está libre de fragancias sintéticas y derivados animales,
además de ser hipoalergénico, como toda la línea de productos OMS.
BIOCELL FIRM®
Tratamiento reafirmante y atenuante de la celulitis
(Centella asiática – Cafeína / L-Carnitina y Acido salicílico)
Para más información:
OMS División Cosmética de Laboratorios Dr. Madaus & Co. S.A.
Av. Luis María Campos 585 – Buenos Aires – Argentina (C1426BOD)
Tel.: (54) (11) 4771-1734 / 4772-2428
Fax: (54) (11) 4775-4380
e.mail: [email protected]
LIBROS
! “Alimentos para la Salud”, Tomo II: Micronutrientes. Dra. Elba
Albertinazzi. Editorial Menat.
En este segundo tomo, la Dra. Elba Albertinazzi se ocupa de los
Micronutrientes, sustancias esenciales que están cada vez más disminuidos
en las dietas habituales. Aquí podrá encontrar la descripción de vitaminas y
minerales, su función, necesidades y cuáles son los alimentos que las
contienen para poder mantener el organismo en perfecto estado de salud.
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! “La Dieta Inteligente”. Aprender a comer es la única manera de
adelgazar para siempre. Lic. Susana Zurschmitten. Grupal ediciones.
En este libro, la Lic. Susana Zurschmitten nos explica por qué la mayoría de
las dietas fracasan, cómo podemos combinar los alimentos para que no
resulten indigestos, qué debemos consumir para bajar los niveles de estrés de
la vida cotidiana o en etapas especiales como el embarazo y la menopausia.
Pero además nos enseña a servirnos de la naturaleza para encontrar en los
cereales, las legumbres, las semillas, las frutas secas, y las verduras, todos los
nutrientes que necesita nuestro cuerpo.
! “Plantas Medicinales Nativas del Perú”. Químico Farmacéutico Julio
Palacios Vaccaro, Magíster en Recursos Naturales Terapéuticos.
La especial ubicación geográfica del Perú hace que posea una de las floras
más ricas del mundo. A las especies existentes desde épocas remotas se
sumaron aquellas que fueron introducidas por los europeos durante la
conquista, las cuales se aclimataron rápidamente. La información contenida en
ésta obra ha sido extraída de diversas fuentes y está basada en valiosos
trabajos de investigación.
Homeonews
Para más información:
Av. Luis María Campos 575 (C1426BOD)
Buenos Aires – Argentina
Tel.: 54-11-4774-5010
Web: www.farmaciamasnatural.com.ar
NUEVO PROGRAMA RADIAL
LA NATURALEZA LLEGÓ A LA RADIO!!!!!!!!!!!!!
A partir de Junio
“AMIGOS DE LO NATURAL”
Alimentación – Salud – Ecología – Hábitos saludables
FM 94.7 (RADIO PALERMO)
TODOS LOS MIERCOLES DE 15 A 16 HS
CONDUCEN
DRA. ELBA ALBERTINAZZI
FARM. FERNANDO ESTEVEZ CASTILLO
PRODUCCION
También podés escucharlo a través de la web:
www.radiopalermo.com.ar
73
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De izq. a der.: Farm. Fernando Estevez Castillo (conductor), Lic. Susana Zurchsmitten (invitada) y Dra. Elba Albertinazzi (conductora).
ACTIVIDADES
EXPOSALUD
Durante la primera semana del mes de Julio se desarrolló, en el Predio Ferial
de la Sociedad Rural Argentina, la EXPOSALUD, organizada por la Revista
Buena Salud y que contó con el auspicio de importantes empresas dedicadas
a este rubro, entre las cuales estuvo el Laboratorio Dr. Madaus, presentando
su suplemento dietario CHIACAPS®. Esta muestra estuvo dirigida a
particulares, quienes la visitaron en gran número, los cuales podían además de
recorrer los distintos Stands y recibir asesoramiento sobre los distintos
productos ofrecidos, asistir a las diferentes conferencias brindadas. El sábado 7
y el domingo 8 de Julio fueron los días de mayor concurrencia, y donde las
Conferencias se realizaron a salón completo, teniendo además los asistentes la
posibilidad de preguntar a los disertantes sobre la temática abordada,
destacándose entre otras, la titulada “Chiacaps®: la mayor fuente natural de
Omega-3”, a cargo del Farm. Fernando Estevez Castillo de Laboratorios
Dr. Madaus.
El Farm. Fernando Estevez Castillo durante su disertación que tuvo lugar en Exposalud.
75
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II CURSO INTERNACIONAL DE FARMACIA HOMEOPATICA
(Lima – Perú)
Del 2 al 7 de Junio del corriente año se desarrolló, en la Ciudad de Lima, Perú,
el II Curso Internacional de Farmacia Homeopática correspondiente a la II
Diplomatura en Terapias Alternativas de la Universidad Nacional Mayor
San Marcos, organizado por la Asociación Peruana de Salud Integral, y para
la cual tuve el honor de ser nuevamente invitado a participar en calidad de
disertante.
Izq.: Curso Teórico Der.: Curso Práctico (explicación de fluxión continua: Homeodinamizador Hiemus
®
La parte teórica tuvo lugar en el Auditorio de la Corporación Infarmasa (Instituto
Sanitas), mientras que la práctica fue realizada en el Laboratorio de Química
Orgánica de la Facultad de Farmacia y Bioquímica (UNMSM), contando con
todos los elementos para desarrollar la actividad en forma individual y con los
equipamientos
correspondientes,
destacándo
entre
ellos
al
Homeodinamizador Hiemus®, dinamizador de fluxión contínua de
procedencia argentina, patentado por el Ing. José A. Musmarra y
comercializado por Farmacia+Natural, que se ha convertido en un suceso en
Perú, por la gran cantidad de Farmacias Homeopáticas que ya cuentan con el
mismo, debido a su fácil manejo y eficacia en la preparación de medicamentos
homeopáticos en altas potencias.
Izq.: Foto del cierre del Curso Teórico. Der.: Foto del Cierre del Curso Práctico.
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También el día 8 de Junio, por invitación de la Dra. Martha Villar López,
Directora del Programa Nacional de Medicina Complementaria de
EsSalud, dicté una Conferencia titulada: “Atención primaria: posibilidades
de aplicación del tratamiento homeopático en comunidades de Argentina”
en el Hospital Rebagliatti, dirigida a los profesionales que trabajan en el Seguro
Social de Salud (EsSalud), en el marco de la formación de recursos humanos
en la Medicina Tradicional, Alternativa y Complementaria, contribuyendo con
ello a lograr un Sistema de Salud más integrado, con mayor accesibilidad y
aceptación de los pacientes y con más eficiencia en la administración de los
recursos. Luego de la exposición, el intercambio de ideas fue muy fluído, lo
cual demostró la gran aceptación de las Terapéuticas no convencionales por
parte de los profesionales que trabajan en dicho Seguro Social. De acuerdo a
lo conversado con la Dra. Martha Villar López, tras ocho años de haber
instituido los Centros de Medicina Complementaria en el Seguro Social de
Salud, estudios realizados por la OPS/OMS y EsSalud, concluyeron que la
Medicina Complementaria era más costo/efectiva que la medicina
convencional en un 60%, para nueve patologías crónicas estudiadas. El
ahorro en el consumo de medicamentos llega a ser del 40 al 60%, lo que
trae como consecuencia un ahorro importante para las instituciones que
lo implementan y además una alta satisfacción del usuario (90%).
Por último quiero felicitar por la excelente organización y el éxito alcanzado
a la todas las personas que hicieron posible este II Curso Internacional de
Farmacia Homeopática, desde la Dra. Martha Villar López, la Dra. Q. F. Niza
Herrera, hasta las alumnas de la Mención “Gestión, Producción y Atención
Farmacéutica en Terapias Alternativas de la UNMSM” (Q.F. Lucrecia Lázaro
Valencia, Q.F. Ana Tasayco Saravia, Q.F. Liliana Tasayco Tasayco, Q.F.
Consuelo Horna Sandoval y Q.F. Patricia Chiroque Castro), además de
haber sido unos excelentes anfitriones, tal como ocurrió el año próximo pasado.
El Farm. Fernando Estevez Castillo y las Alumnas de la Mención de
Farmacia de la II Diplomatura en Terapias Alternativas UNMSM
Nos reencontraremos el próximo año para el III Curso Internacional de
Farmacia Homeopática!!!!
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ENCUENTRO DE MEDICINAS ALTERNATIVAS Y
COMPLEMENTARIAS
Aportes de las Medicinas Alternativas y Complementarias en el ámbito de
la Atención Primaria: “Enfermedades Respiratorias altas y bajas”
El 30 de Junio del corriente año se desarrolló con gran éxito el Encuentro de
Medicinas Alternativas y Complementarias organizado por la Asociación
Argentina de Medicina Integrativa y Laboratorios Dr. Madaus.
Esta actividad comenzó con un merecido Homenaje al Dr. Edgardo
Soerensen, Médico Naturista de una gran trayectoria en nuestro país y que se
caracterizó siempre por compartir sus conocimientos a través del dictado de
Cursos dirigidos a otros profesionales médicos, durante muchísimos años, en
el Auditorio del Laboratorios Dr. Madaus.
Para tal fin, la Sra. Patricia Smolinski, en su carácter de Presidenta de
Laboratorios Dr. Madaus, entregó en mano, al Dr. Edgardo Soerensen,
una Plaqueta en reconocimiento a su dilatada trayectoria profesional en la
enseñanza de la Medicina Natural en la República Argentina.
Previamente, el Dr. César Labarthe, gran amigo y colega del Dr. Soerensen,
realizó una pequeña reseña de los momentos compartidos por ambos,
destacando no solamente la calidad profesional del homenajeado sino también
su don de buena gente.
Izq.: Vista del Auditorio durante el Homenaje al Dr. Soerensen Der.: Patricia Smolinski (Presidenta de Laboratorios Dr.
Madaus y el Dr. Edgardo Soerensen mostrando la plaqueta de reconocimiento a su trayectoria.
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Izq.: Dr. Edgardo Soerensen agradeciendo el homenaje. Der.: Dr. César Labarthe, relatando anécdotas junto a su amigo y colega.
Luego de este cálido y merecido reconocimiento, se dio comienzo al Encuentro,
a través de la 1° Mesa Redonda coordinada por la Lic. Susi Reich,
Presidenta de la Asociación Argentina de Medicina Integrativa, con la
participación inicial del Dr. Norberto Arias y la Lic. Ana Herbsztein quienes
desarrollaron el tema “Comprensión de la enfermedad”, punto básico e
ineludible para todo paciente y profesional médico, previo al comienzo del
tratamiento de la misma. Luego, siguiendo con la temática del Encuentro
“Enfermedades Respiratorias”, la Dra. Mercedes Seminara planteó los
“Aportes de la Medicina Ayurveda” y a continuación la Ing. Agr. Mónica
Romero, los “Efectos e indicaciones de la Aromaterapia sobre dichas
patologías”, haciendo hincapié en la necesidad de determinar previamente la
calidad de las esencias utilizadas para lograr los resultados esperados.
Izq.: la Lic. Susi Reich (Presidenta de AAMI) al centro, junto al Dr. Norberto Arias y la Lic. Ana Hebsztein. Der.: la Ing.
Agr. Mónica Romero durante su disertación sobre Aromaterapia.
Posteriormente, luego de un breve coffee-break, tuvo lugar la 2° Mesa
Redonda coordinada por la Dra. Elba Albertinazzi (Presidenta de la
Asociación Argentina de Médicos Naturistas), siendo los oradores, el Dr. Jorge
Alonso, quien describió el tratamiento de las enfermedades respiratorias desde
la Fitomedicina, citando el trabajo realizado por la Asociación Argentina de
Fitomedicina y el Gobierno de la Provincia de Misiones, en la atención primaria
utilizando medicamentos fitoterápicos; luego la Lic. Susana Zurschmitten
presentando el tema “Cómo eliminar los lácteos y no tener carencias
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nutricionales”, y por último el Dr. Ricardo Alvarez, planteó el “Abordaje desde
la Clínica Médica Homeopática”
Izq.:Dr. Ricardo Alvarez presentando el abordaje desde la Clínica Médica Homeopática Der.: Lic. Susana Zurschmitten
exponiendo durante el desarrollo del Encuentro, a la derecha sentado el Dr. Jorge Alonso y a la izq. la Dra. Elba Albertinazzi, coordinadora de la 2° Mesa Redonda.
Antes de finalizar el Encuentro, todos los asistentes pudieron realizar preguntas
a los disertantes como así también plantear sus inquietudes, quedando el cierre
a cargo del Farm. Fernando Estevez Castillo, en representación de
Laboratorios Dr. Madaus y Farmacia+Natural, quien agradeció la presencia
de todos los asistentes y disertantes en el Auditorio del Laboratorio,
destacando como conclusión final que a través del Encuentro se pudo
mostrar distintas posibilidades de tratamiento de las enfermedades
respiratorias, que pueden ser utilizadas por los médicos, como
alternativas a los tratamientos convencionales.
MERCOFITO III.
”Entre los días 14 y 15 de junio se celebraron las Jornadas MERCOFITO III
en el aula magna de la Academia Nacional de Medicina de la República
Argentina.
Este evento fue organizado por las Comisiones de Salud de las Cámaras de
Diputados y Senadores de la Nación, junto a la Asamblea Legislativa de Rio
Grande do Sul (Brasil), Itaipú-Binacional y la Asociación Argentina de
Fitomedicina.
Estas jornadas representan una continuación de los Mercofito I y II celebrados
en años anteriores en Brasil, y marcan una tendencia creciente respecto a la
posibilidad de trabajar entre los países integrantes del Mercosur, en temas de
mutuo interés tales como Políticas Sanitarias en base a Fitomedicamentos,
generar una Farmacopea de Mercosur de tipo Herbal, posibilitar el dictado
de cursos en ámbitos académicos, armonizar aspectos legales que hacen
a las normativas de aprobación y registro de productos en la región, etc.
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El Dr. Jorge Alonso (Presidente de la Asociación Argentina de Fitomedicina) durante una de las Mesas Redondas del Mercofito III.
A las Jornadas asistieron 320 personas de diferentes ámbitos: universidades,
profesionales de la salud, legisladores, funcionarios ministeriales, empresarios,
agrónomos, etc. El crecimiento que año tras año se va observando en los
distintos Mercofito ha podido corroborarse en la presente edición, donde ya
se comprometieron a trabajar conjuntamente los países de Chile, Perú y
Bolivia, como miembros invitados. De esta manera, suman ya siete las
naciones en las que se trabajarán las diversas temáticas emprendidas (los
países fundadores son Uruguay, Brasil, Paraguay y Argentina). El día 14 de
junio, por la mañana, fue realizado el cierre del proyecto "Cultivando la Salud"
emprendido por el COE (Italia) y la Asociación Argentina de Fitomedicina. Se
procedió a evidenciar lo logrado con el proyecto en la provincia de Misiones,
donde el Ministro de Salud y sus colaboradores mostraron como se puede
fortalecer el sector productivo de una región a partir del recurso brindado por
las plantas medicinales. De esta manera fueron aprobados tres medicamentos
fitoterápicos por la ANMAT (caléndula, ambay y congorosa) y está en vísperas
de aprobarse un cuarto: la carqueja. Todos productos para ser destinados a la
Atención Primaria de la Salud, de forma gratuita.
Finalmente, cabe señalar que hubo ponencias de TODOS LOS PAISES
integrantes del Mercosur, de elevado nivel científico cada una de ellas. El
marco donde se celebró el encuentro (Academia Nacional de Medicina) exime
de comentarios en lo que a validez científica se refiere esta temática. La
presencia y auspicio de la Organización Panamericana de la Salud ha servido
de sostén y brillo a las Jornadas, cuyo corolario final tuvo la salutación de la
primera dama, la Senadora Cristina Fernández de Kirchner.
El próximo Mercofito IV, se celebrará en Asunción del Paraguay en el año 2008
(fecha a confirmar) y la Asociación Argentina de Fitomedicina ya ha adquirido el
compromiso inquebrantable de posicionar esta temática en lo más alto del
saber científico, para así poder lograr una asistencia sanitaria consustanciada
con el saber popular de nuestros pueblos originarios, respondiendo a los
cánones de seguridad, eficacia y calidad para este tipo de productos.”*
Felicitaciones Dr. Jorge Alonso por el éxito de las Jornadas y por su
incesante labor en la enseñanza y difusión de la Fitomedicina, como así
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también quiero agradecerle su invitación para participar como
Coordinador de la Mesa Redonda: “La enseñanza universitaria sobre las
plantas medicinales”.
*Texto extraido de la página web: www.plantasmedicinales.org.ar, correspondiente a la
Asociación Argentina de Fitomedicina
CURSOS, CONGRESOS Y SEMINARIOS
CURSOS
FARMACIA HOMEOPATICA
Curso Teórico Práctico
DIRECTOR: Farm. Fernando Estevez Castillo.
DICTADO POR: Prof. Tít. Dr. Alberto Gurni, Farm. Fernando Estevez Castillo.
LUGAR DONDE SE REALIZA : Departamento de Farmacología,
Farmacobotánica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires.
Cátedra
de
PERIODO DE DESARROLLO : Sábado 8 y Domingo 9 de Setiembre, Sábado 27 y Domingo
28 de Octubre de 2007.
HORARIO : Mañana: 9:00 a 12:30 hs. Tarde: 14:30 a 18:00 hs.
VACANTES : Máximo : 40 . Mínimo : 10.
REQUISITOS DE ADMISION : Farmacéuticos.
ARANCEL : $ 350 (en dos cuotas de $175 y $175 respectivamente), $5 de certificado y $ 20 de diploma
(optativo). (Incluye apuntes de clases teóricas).
CONTENIDOS MINIMOS : Teórico: Historia. Leyes de la Homeopatía. Patogenesia. Bibliografía.
Organón. Farmacopeas. Laboratorio Homeopático. Reglamentación oficial. Drogas. Vehículos. Tinturas madres.
Control de calidad de materias primas y tinturas. Soluciones. Dinamizaciones. Trituración. Escala
cincuentamilesimal. Bioterápicos. Organoterápicos. Medicamento. Formas Farmacéuticas. Buenas Prácticas de
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Preparación de medicamentos homeopáticos. Posología. Práctico: Interpretación de recetas y preparación de
dinamizaciones, trituraciones y medicamentos en las distintas formas farmacéuticas.
EVALUACION : Una evaluación final.
A los fines que establece el artículo 10° (RES. (CS) N° 1913/87) y 11º (RES. (CS) 4731/05) del
Reglamento de Doctorado, este curso acredita por cumplimiento de :
•
ASISTENCIA Y APROBACION : 2 puntos.
•
ASISTENCIA SOLAMENTE : 1 punto.
INFORMES E INSCRIPCIÓN: Facultad de Farmacia y Bioquímica (UBA), Escuela de
Graduados, Junín 956 Planta Principal.(1113), Buenos Aires. Tel/Fax : 54-11-4964-8214 / 4964-8200 int.
8315 ,e-mail : [email protected]
http ://www.ffyb.uba.ar. Horario de Atención: Lunes, Martes,
Jueves y Viernes de 13 a 19 horas.
CONTROL DE CALIDAD MICROGRÁFICO DE PLANTAS
MEDICINALES Y DE ALIMENTOS DE ORIGEN VEGETAL
Curso Teórico - Práctico
DIRECTOR: Prof. Dr. Alberto Gurni; Prof. Dr. Marcelo Wagner o.
COLABORADORES: Dr. Rafael Ricco; Dra. Graciela Bassols; Dra. Beatriz Varela; Dra. Ana
Rugna; Farm. Stella Battista; Farm y Bioq. Roxana Roldán.
LUGAR DONDE SE REALIZA : Departamento de Farmacología,
Farmacobotánica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires.
Cátedra
de
PERIODO DE DESARROLLO : 18 al 20 de octubre y 15 al 17 de noviembre de 2007.
HORARIO : Jueves a Sábados de 9 a 13 hs. y de 14 a 18 hs. Último sábado de 9 a 14 hs.
VACANTES : Máximo : 15 . Mínimo : 5.
REQUISITOS DE ADMISION : Farmacéutico, Licenciado en Industria Alimentaria,
Bioquímico.
ARANCEL : $ 300. Certificado $5. Diploma (optativo) $20.
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83
PROPOSITO: Drogas vegetales y especies alimenticias. Aplicación de técnicas micrográficas para establecer
la autenticidad, contaminación o adulteración de productos comerciales en base a plantas. Desarrollo de las
técnicas más adecuadas para observar las estructuras que permiten lograr este objetivo.
CONTENIDOS MINIMOS : Teórico: Conceptos de autenticidad, contaminación y adulteración.
Introducción a los tejidos vegetales. Distribución de cada uno en cada órgano del sistema vegetativo. Sustancias
ergásticas que aparecen en cada uno de ellos. Órganos del sistema reproductor. Constitución de la flor. Tipos de
frutos y de semillas. Estudio del material de reserva de éstas. Importancia de los tipos de tejidos y de sustancias
ergásticas en la detección de contaminantes y adulterantes. Hongos microscópicos más comunes como
contaminantes. Práctico: Se analizarán muestras del comercio de drogas vegetales, de productos farmacéuticos y
alimenticios de origen vegetal (raíces, tallos, hojas, flores, frutos, semillas) para determinar su autenticidad según la
Farmacopea. Se efectuarán disociaciones leves y fuertes, se obtendrán secciones transversales y se procederá a la
observación de la droga en polvo. Se realizarán reacciones histoquímicas. Se aplicará la micrometría. Se analizarán
granos de polen. Se observarán los hongos contaminantes más comunes.
EVALUACION : Una evaluación final.
A los fines que establece el artículo 10° (RES. (CS) N° 1913/87) y 11º (RES. (CS) 4731/05) del
Reglamento de Doctorado, este curso acredita por cumplimiento de :
•
ASISTENCIA Y APROBACION : 3 puntos.
•
ASISTENCIA SOLAMENTE : 1,5 puntos.
INFORMES E INSCRIPCIÓN: Facultad de Farmacia y Bioquímica (UBA), Escuela de
Graduados, Junín 956 Planta Principal.(1113), Buenos Aires. Tel/Fax : 54-11-4964-8214 / 4964-8200 int.
8315 ,e-mail : [email protected]
http ://www.ffyb.uba.ar. Horario de Atención: Lunes, Martes,
Jueves y Viernes de 13 a 19 horas.
CONGRESOS
XVIII CONGRESO FARMACEUTICO ARGENTINO
4, 5 y 6 de Octubre de 2007
Palmares Bureau – Mendoza - Argentina
La Profesión Farmacéutica en el Siglo XXI
Un compromiso con la Salud Comunitaria
Areas temáticas:
Economía – Educación – Ejercicio Profesional – Investigación – Medicamentos
– Política y Legislación – Regulación y Control
Informes e inscripción:
www.congresomedicamento.com.ar
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CUMBRE MUNDIAL DE ARMONIZACION EN MEDICINA
TRADICIONAL ALTERNATIVA Y COMPLEMENTARIA
7 al 11 de Noviembre de 2007
Colegio Médico del Perú - Lima – Perú
Colegio Médico del Perú
Tel: (51-1) 705-1404 /705-1400
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85
SEMINARIOS
SEMINARIO DE OBESIDAD Y DIABETES
Alimentación y Terapéuticas Naturales
ASOCIACIÓN ARGENTINA DE MEDICO NATURISTAS
Serrano 669 PB – Ciudad Autónoma de Buenos Aires
Viernes 5 de Octubre
DIRECTORA: Dra. Elba Albertinazzi
Dirigido a:
Público en general y a toda persona que quiera mejorar su metabolismo y su
calidad de vida.
Temario
14:30 hs: Inscripción.
15:00 hs: Obesidad y diabetes: cuál es su relación?. Síndrome metabólico.
Dra.Elba Albertinazzi.
16:00 hs: Indice glucémico de los alimentos con hidratos de carbono.
Ventaja de la incorporación de los cereales integrales. Lic. Ana Lía Aguado.
16:30 hs: Grasas “buenas y malas”. Función hepática e intestinal. Dra. Elba
Albertinazzi.
17.00 hs: Preguntas y discusión.
17:30 hs: Refrigerio natural, con infusiones y alimentos integrales.
18:00 hs.: Cómo pueden ayudarnos los tratamientos naturales?. Manejo del
estrés. Prof. Alejandra Rufino.
18:30 hs: Acupuntura y Homeopatía. Dra. Perla Aizemberg.
19.00 hs: Ventajas de una buena masticación: salud dental. Dr.Horacio Gallitelli
(odontólogo).
19:30 hs: Cierre de la Jornada.
Arancel
$50 (incluye refrigerio naturista, apuntes y recetas naturales bajas en calorías)
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Serrano 669 PB – Ciudad Autónoma de Buenos Aires
Tel.: (011) 4856-4443 [email protected]
www.aamenat.org.ar
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87
Si quiere que otro profesional reciba Homeonews por favor complete y envíe esta
planilla al e.mail: [email protected]
SUSCRIPCIÓN GRATUITA A HOMEONEWS
Nombre y Apellido:...........................................................................................................
Profesión:............................................................................................................................
Domicilio particular:
Calle:........................................................... Nº:.................................................................
Localidad:....................................................Prov.:............................................................
C.P.:……………..Tel.:.…..............................………….Fax:...........................................
E.Mail:……………………………………………………………………………………
Domicilio laboral:
Calle:........................................................... Nº:.................................................................
Localidad:....................................................Prov.:............................................................
C.P.:……………..Tel.:.…..............................………….Fax:...........................................
E.Mail:……………………………………………………………………………………
Temas de interés:
.............................................................................................................................................
.............................................................................................................................................
.............................................................................................................................................

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