homeonews - Farmacia Natural

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HOMEONEWS
Edición N° 9
Enero – Febrero - Marzo de 2008
Director: Farm. Fernando Estevez Castillo
PUBLICACION BIMESTRAL
DISTRIBUCION GRATUITA
PARA PROFESIONALES DE LA SALUD
Homeonews
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Edición N° 9 – Enero – Febrero - Marzo de 2008
Edición n° 9
Enero – Febrero - Marzo de 2008
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:
Actividad antiinflamatoria del Taraxacum officinale, pág. 6.
3- Alopatía:
La inmunosupresión inducida por radiación UV es mayor en hombres y
puede ser prevenida por nicotinamida, pág. 20.
4- Homeopatía:
Tratamiento de los sofocones de calor con Homeopatía: resultados de un
estudio observacional, pág. 39.
5- Nutrición:
Importancia medicinal del jugo de pomelo y su interacción con ciertas
drogas, pág. 52.
6- Notas de interés:
-Primer Encuentro Chileno de Preparados Homeopáticos elaborados en
Farmacias; pág. 70.
-XVIII Congreso Farmacéutico Argentino; pág 73.
-Homeopatía: Primeras Jornadas del Comahue; pág. 74.
-Jornadas sobre Ejercicio Profesional Farmacéutico en la Universidad
Nacional de La Plata; pág. 76.
7- Novedades:
-Nuevos Productos: Dermomega®; pág. 77.
-“Amigos de lo Natural”, la hora de la Naturaleza llegó a la Radio; pág. 78.
8- Cursos y Congresos:
-Cursos a distancia: “Fitomedicina (2008)” y “Fitodermatología y Fitoestética
(2008); pág. 80.
-Curso Superior de Medicina Naturista para Profesionales; pág. 87.
-VIII Curso y I Simposio Internacional sobre Inmunonutrición; pág. 89.
-63º Congreso de la Liga Médica Homeopática Internacional; pág. 89.
9- Formulario de suscripción, pág. 90.
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Foto de tapa: Taraxacum officinale (Asteraceae).
Las opiniones vertidas en los artículos firmados son responsabilidad de sus autores.
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EDITORIAL
Estimados colegas del equipo de salud:
Un nuevo año ha comenzado y Homeonews, a través del presente número,
vuelve a comunicarse con Uds., retrasado, pero con mucho más material para
suplir esta ausencia temporaria.
En este número podrá encontrar mucha información y varios trabajos
recientemente publicados, en cada uno de los Capítulos ofrecidos:
FITOTERAPIA: “actividad antiinflamatoria del Taraxacum officinale”;
ALOPATIA: “la inmunosupresión inducida por radiación UV es mayor en
hombres y puede ser prevenida por nicotinamida”, HOMEOPATIA: “resultados
de un estudio observacional para el tratamiento de los sofocones de calor con
Homeopatía” y NUTRICION: “la importancia medicinal del jugo de pomelo y su
interacción con ciertas drogas”. En NOTAS DE INTERES, los pormenores de
varias actividades tales como el Primer Encuentro Chileno de Preparados
Homeopáticos elaborados en Farmacias; el XVIII Congreso Farmacéutico
Argentino; las Primeras Jornadas de Homeopatía del Comahue y las Jornadas
sobre Ejercicio Profesional Farmacéutico realizadas en la Universidad Nacional
de La Plata. Con respecto a NOVEDADES, Laboratorios Dr. Madaus, a través
de su División Cosmética “OMS”, presentó más productos de la línea
DERMOMEGA® y “AMIGOS DE LO NATURAL”, programa radial de FM
Palermo, comenzó su segundo año en el aire, con más invitados y entrevistas
exclusivas. En CURSOS Y CONGRESOS, toda la información referida a: dos
Cursos ofrecidos en la modalidad a distancia por la Asociación Argentina de
Fitomedicina: “Fitomedicina” y “Fitodermatología – Fitoestética”, el Curso
Superior de Medicina Naturista de la Asociación Argentina de Médicos
Naturistas; el VIII Curso y I Simposio Internacional sobre Inmunonutrición y el
63º Congreso de la Liga Médica Homeopática Internacional.
Por último, vuelvo a agradecer a todos los lectores, que a través de diversos
medios me hicieron llegar sus inquietudes y me incentivan día a día para
continuar con esta publicación.
Hasta el próximo número de Homeonews!!!
Farm. Fernando Estévez Castillo
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FITOTERAPIA
ACTIVIDAD ANTIINFLAMATORIA DEL TARAXACUM OFFICINALE
Hye-Jin Jeona, Hyun-Jung Kangb, Hyun-Joo Junga, Young-Sook Kanga, ChangJin Limb, Young-Myeong Kimc, d and Eun-Hee Parka.
a
College of Pharmacy, Sookmyung Women's University, Cheongpa-dong,
Yongsan-ku, Seoul 140-742, Republic of Korea.
b
Division of Life Sciences and Research Institute of Life Sciences, Kangwon
National University, Chuncheon 200-701, Republic of Korea.
c
Department of Molecular and Cellular Biochemistry, School of Medicine,
Kangwon National University, Chuncheon 200-701, Republic of Korea.
d
Vascular System Research Center, Kangwon National University, Chuncheon
200-701, Republic of Korea.
[Journal of Ethnopharmacology 115 (2008) 82-88]
RESUMEN
El Taraxacum officinale ha sido ampliamente utilizado en la medicina folklórica
para el tratamiento de diversas patologías. La planta seca fue extraida con
alcohol 70% para obtener el extracto etanólico (TEE). Para los experimentos,
se utilizaron distintas fracciones obtenidas a partir del TEE en forma sucesiva,
acetato de etilo (EA), n-butanol (BuOH) y agua (Aq). TEE mostró actividad de
captura de radicales libres en el ensayo con DPPH (1,1-diphenyl-2picrylhydrazyl), un efecto reductor de los niveles de las especies reactivas de
oxígeno intracelulares (ROS), y una actividad antiangiogénica en el estudio de
la membrana corioalantoidea del embrión de pollo (CAM). En el modelo de la
bolsa de aire inducida por carragenina, TEE inhibió la producción de exudado,
y redujo significativamente los niveles de óxido nítrico (NO) y leucocitos.
También mostró un efecto inhibitorio sobre la permeabilidad vascular inducida
por el ácido acético, así como también una inhibición dosis-dependiente en el
ensayo de contorsión abdominal en ratones inducido por ácido acético. Fueron
evaluados los efectos supresores del TEE en la producción de NO y la
expresión de la óxido nítrico sintetasa inducible (iNOS) y la ciclooxigenasa-2
(COX-2) en macrófagos estimulados por lipopolisacáridos (LPS). Entre todas
las fracciones, la de n-butanol (BuOH) resultó ser la más efectiva en el ensayo
CAM. En síntesis el Taraxacum officinale posee actividades antiangiogénica,
antiinflamatoria y antinoceptiva a través de la inhibición de la producción de NO
y de la expresión de la COX-2 y/o su actividad antioxidante.
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Palabras clave:
Taraxacum officinale; antinociceptivo; antiinflamatorio;
antioxidante; ciclooxigenasa-2; óxido nítrico sintetasa inducible; óxido nítrico;
especies reactivas del oxígeno.
ARTICULO ORIGINAL
1-Introduction
Some plants of the genus Taraxacum, known as dandelion, have long been
used in folk medicine to treat hepatic disorders and some women's diseases,
such as breast and uterus cancers, and as lactating, choleretic, diuretic, and
anti-inflammatory remedies ([Ahmad et al., 2000] and [Kisiel and Barszcz,
2000]). Pharmacological activities of Taraxacum plants, especially Taraxacum
officinale F. Weber ex Wiggers (Asteraceae), have been in part evaluated so far
(Schutz et al., 2006). Taraxacum officinale was assessed to contain acute antiinflammatory activity by showing its protective effect against cholecystokinininduced acute pancreatitis in rats (Seo et al., 2005). Two flavonoid compounds,
luteolin and luteolin-7-O-glucoside, rich in the ethyl acetate fraction of
Taraxacum officinale suppress production of nitric oxide (NO) and prostaglandin
E2 in LPS-activated RAW264.7 macrophage cells, which is attributed to the
suppression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2
(COX-2) (Hu and Kitts, 2004). On the contrary, the aqueous extract of
Taraxacum officinale is able to enhance production of NO in interferon-γ (IFNγ)-activated mouse peritoneal macrophages through the induction of iNOS (Kim
et al., 1999). Taraxacum officinale-induced apoptosis of human hepatoma
HepG2 cells through tumor necrosis factor (TNF)-α and interleukin (IL)-1α
secretion (Koo et al., 2004), and also showed cytotoxic activity in a human
colon colorectal adenocarcinoma cell line Caco-2 (Hu and Kitts, 2003).
However, in primary cultures of rat astrocytes stimulated with LPS and TNF-αinducing substance P, Taraxacum officinale significantly inhibits production of
TNF-α by inhibiting IL-1 production, indicating an anti-inflammatory activity of
Taraxacum officinale in the central nervous system (Kim et al., 2000).
Additionally, other species of the genus Taraxacum were elucidated to contain
various other pharmacological activities. The aqueous extract of Taraxacum
mongolicum was elucidated to interact with a fluoroquinoline-type antibiotic,
ciprofloxacin, which modifies its bioavailability and disposition (Zhu et al., 1999).
Taraxacum japonicum exhibited strong anti-tumor-promoting activities on the
two-stage carcinogenesis of mouse skin tumor induced by an initiator and a
promoter, suggesting its chemopreventive activity (Takasaki et al., 1999). In the
recent analysis, two new guaianolide glucosides, deacetylmatricarin 8-O-βglucopyranoside and 11β-hydroxyleukodin 11-O-β-glucopyranoside, were
isolated from Taraxacum obovatum (Michalska and Kisiel, 2003), and
taraxafolide and (+)-taraxafolin-B were newly identified from Taraxacum
formosanum (Leu et al., 2005). Differences in constituents and pharmacological
activities of various species in the genus Taraxacum remain obscure. The
current work demonstrates that the ethanol extract of Taraxacum officinale
possesses anti-angiogenic, anti-inflammatory and anti-nociceptive activities. It is
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also able to down-regulate production of NO and COX-2 and reduce level of
reactive oxygen species (ROS) in the activated macrophage cells.
2-Materials and methods
2.1. Chemicals
Indomethacin, dexamethasone, Evans blue, λ-carrageenan, 2,2-diphenyl-1picrylhydrazyl (DPPH), l-ascorbic acid, sodium dodecyl sulfate (SDS), leupeptin,
pepstatin, phenylmethanosulfonyl fluoride (PMSF), Escherichia coli
lipopolysaccharide (LPS), HEPES and Griess reagent were purchased from
Sigma Chemical Co. (St. Louis, MI, USA). Dulbecco's-modified Eagle's medium
(DMEM), fetal bovine serum (FBS), penicillin–streptomycin and trypsin–EDTA
were from Gibco-BRL (Gaithersburg, MD, USA). All other chemicals used were
of reagent grade or better.
2.2. Experimental animals
The in vivo experiments were done using male ICR mice ( 25 g) or male
Sprague–Dawley rats ( 140 g), which were purchased from Samtaco Animal
Farm, Osan, Korea. The animal room was maintained at 23 ± 2 °C with a 12 h
light/dark cycle. Food and tap water were supplied ad libitum. The ethical
guidelines, described in the NIH Guide for Care and Use of Laboratory Animals,
were followed throughout the experiments.
2.3. Plant material
The dried aerial parts of Taraxacum officinale were purchased at Kyungdong
Folk Medicine Market, Seoul, Korea in March 2004, and authenticated by Prof.
Ki-Oug Yoo, Division of Life Sciences, Kangwon National University,
Chuncheon, Korea. The voucher specimen of the plant material was deposited
in the herbarium of the Division of Life Sciences, College of Natural Sciences,
Kangwon National University under the acquisition no. KWNU56517.
2.4. Preparation of ethanol extract (TEE) and its fractions
The dried plants were ground under liquid nitrogen and extracted for 1 month
with 70% ethanol at room temperature. The ethanol extract (TEE) was
evaporated in vacuo as previously described (Park et al., 2003). The yield was
18.4%. For fractionation, TEE was extracted successively with equal volumes of
ethyl acetate (EA) and n-butanol (BuOH), leaving residual aqueous fraction
(Aq). Each fraction was evaporated in vacuo to yield the residues of EA
(10.2%), BuOH (21.7%) and Aq (68.1%) fractions, respectively.
2.5. Cell culture
RAW264.7 cell line, a murine macrophage cell line, was from American Type
Culture Collection (Manassas, VA, USA). The mammalian cells were cultured in
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Dulbecco's-modified Eagle's medium with 10% heat-inactivated fetal bovine
serum (FBS), 25 mM HEPES (pH 7.5), 100 U/ml penicillin and 100 µg/ml
streptomycin. The cells were plated at a density of 1 × 106 and preincubated for
24 h at 37 °C, and maintained in a humidified atmosphere containing 5% CO2.
For all experiments, the cells were grown to 80–90% confluence, and subjected
to no more than 20 cell passages.
2.6. Chorioallantoic membrane (CAM) assay
Anti-angiogenic activity was determined using CAM assay as previously
described (Song et al., 2004). The fertilized chicken eggs were kept in a
humidified egg incubator at 37 °C. After 3.5-day incubation, about 2 ml of
albumin was aspirated from the eggs through the small hole drilled at the
narrow end of the eggs, allowing the small chorioallantoic membrane and yolk
sac to drop away from the shell membrane. The shell covering the air sac was
punched out and removed by forceps, and the shell membrane on the floor of
the air sac was peeled away. In the 4.5-day-old chick embryo, a sample-loaded
Thermanox coverslip was applied to the CAM surface. Two days after returning
the chick embryo to the incubator, an appropriate volume of 10% fat emulsion
(Intralipose, 10%) was injected into a 6.5-day-old embryo chorioallantois. The
eggs were then observed under a microscope. The vascular response of each
egg was graded as 0, 1+ or 2+. Convergence of a few vessels toward the CAM
surface was denoted as 1+, while 2+ reflected an increased density and length
of vessels toward the CAM face.
2.7. Assay for DPPH radical scavenging activity
DPPH scavenging activity of TEE and its BuOH fraction was determined as
previously described (Song et al., 2004). In brief, the reaction mixtures
containing various concentrations of TEE or its BuOH fraction and 300 µM
DPPH solution in a 96-well microtiter plate were incubated at 37 °C for 30 min,
and absorbance was measured at 490 nm.
2.8. Acetic acid-induced vascular permeability
According to a modification of the method of Whittle (1964), acetic acid-induced
vascular permeability test was performed. Mice were divided into groups of
eight. One hour after oral administration of vehicle (saline), TEE (50, 100 or
200 mg/kg) or aminopyrine (100 mg/kg), 1% Evans blue solution (0.1 ml/10 g
body weight) was injected intravenously in each mouse. Thirty minutes later,
0.7% acetic acid (0.1 ml/10 g body weight) in saline was intraperitoneally
injected. Thirty minutes after administration of acetic acid, the mice were
sacrificed by cervical dislocation. Ten millilitres of saline was injected into the
peritoneal cavity, and the washing solution was collected in a test tube. The
concentration of Evans blue in the peritoneal cavity was determined by the
absorbance at 630 nm in a spectrophotometer. The vascular permeability was
represented in terms of the absorbance (A630) which leaked into the cavity.
Experiments were performed in triplicate.
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2.9. Carrageenan-induced air pouch formation
According to a modification of the procedure of Ghosh et al. (2000), λcarrageenan-induced air pouch formation was performed. Six days prior to drug
treatment, the air pouch was formed in the intrascapular region of rats by initial
subcutaneous injection of 20 ml sterile air and successive injections of 10 ml
sterile air every 3 days to sustain its patency (Sedgwick and Lees, 1986). On
day 0, vehicle (saline), TEE (1.0 mg per pouch), BuOH fraction (1.0 mg per
pouch) or dexamethasone (0.01 mg per pouch) was injected into the pouch 1 h
prior to the λ-carrageenan injection (0.1 ml of 1.0% solution) into the pouch.
After 15 min, the pouch cavity was opened and the exudates were collected.
The exudate volumes were measured using a graduate tube. Aliquots were
diluted with Turk solution, and the polymorphonuclear leukocytes were counted
in a standard hemocytometer chamber. Experiments were performed in
triplicate.
2.10. Acetic acid-induced writhing response
As described by Olajide et al. (2000), the response to an intraperitoneal
injection of acetic acid solution, which manifests contraction of the abdominal
muscles and stretching of hind limbs, was measured. Nociception was induced
by intraperitoneal injection of 1.0% acetic acid solution at the dose of
0.1 ml/10 g body weight. Each experimental group of mice (n = 8) was orally
treated with vehicle (saline), TEE (50, 100 or 200 mg/kg) or aminopyrine
(100 mg/kg) as a positive control. From 10 min later, the number of writhes was
counted during the 10 min period. Independent experiments were repeated
three times.
2.11. Nitrite analysis
Accumulated nitrite (NO2−) in the culture media and the exudates obtained from
the air pouches was spectrophotometrically determined based on the Griess
reaction (Sherman et al., 1993). The samples (100 µl) were incubated with
100 µl Griess reagent (6 mg/ml) at room temperature for 10 min, and then
NO2− concentration was determined by the absorbance at 540 nm. The
standard curve was constructed using the known concentrations of sodium
nitrite.
2.12. Determination of intracellular ROS
For analysis of intracellular ROS, the redox-sensitive fluorescent probe DCFHDA was used, as previously described (Royall and Ischiropoulos, 1993). Cells
were incubated with 5 µM DCFH-DA for 30 min at 37 °C. The harvested cells
were immediately analyzed by a flow cytometry.
2.13. Immunoblot analysis
The RAW264.7 cells were incubated with LPS (1 µg/ml) in the presence or
absence of TEE for 24 h and then washed twice with ice-cold phosphateDirector: Fernando Estevez Castillo
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buffered saline (PBS). The cells were lysed in a buffer containing 20 mM
HEPES (pH 7.9), 0.1 M KCl, 0.3 M NaCl, 10 mM EDTA, 1% SDS, 1 mM PMSF,
1 µg/ml leupeptin and 1 µg/ml pepstatin. Western blotting was performed as
previously described (Kim et al., 2002). For immunoblotting, anti-inducible nitric
oxide synthase (anti-iNOS; Transduction Laboratories, Lexington, KY, USA)
and anti-cyclooxygenase-2 (anti-COX-2; Transduction Laboratories, Lexington,
KY, USA) and anti-β-actin (Sigma–Aldrich, St. Louis, MO, USA) antibodies were
used.
2.14. Statistical analysis
The data were analyzed for statistical significance using Student's t-test. PValues less than 0.05 were considered to be significant.
3-Results and discussion
Angiogenesis consists of degradation of the basement membrane of existing
blood vessels, migration, proliferation and rearrangement of endothelial cells,
and formation of new blood vessels (Risau, 1995). Down-regulation of
angiogenesis has been considered to be advantageous for the prevention of
neoplastic growth and inflammation. In reality, some anti-angiogenic substances
are effective in animal models of arthritis, and several antirheumatic drugs, such
as indomethacin, methotrexate and corticosteroids, contain anti-angiogenic
activity (Tong et al., 2004). Current anti-angiogenic strategies are based on
inhibition of endothelial cell proliferation, interference with endothelial cell
adhesion and migration, and interference with metalloproteinases (Griffioen and
Molema, 2000).
The chick chorioallantoic membrane (CAM) assay was used for assessing the
inhibitory activity of TEE and its fractions on vascular development. Retinoic
acid was used as a positive control for the assay, since it inhibits angiogenesis
by down-regulating the expression and release of pro-angiogenic factors
(Iurlaro et al., 1998). The disk weight was unable to give any changes in
vascular density, indicating that it was unable to affect the growth of blood
vessels in the CAM assay (data not shown). After the 2-day treatment, retinoic
acid at 1 µg per egg gave 82–90% in the branching patterns of blood vessels
(Fig. 1 and Fig. 2). When 0.1, 0.3, 1.0 and 3.0 µg per egg of TEE was applied in
the CAM assay, the inhibition percentages in CAM angiogenesis were
measured to be 30.8, 44.4, 52.4 and 70.0%, respectively (Fig. 1). This indicates
that TEE contains potent anti-angiogenic activity in a dose-dependent manner.
TEE was successively fractionated using ethyl acetate and n-butanol to
basically figure out the chemical characters of active anti-angiogenic principle(s)
present in TEE. Among the fractions used, the BuOH fraction showed highest
inhibitory activity in the CAM angiogenesis (Fig. 2A). When the BuOH fraction at
0.1, 0.3, 1.0 and 3.0 µg was applied in the assay, the inhibitory percentages
were 34.2, 44.1, 60.0 and 69.2%, respectively (Fig. 2B). When luteolin, a
flavonoid compound from Taraxacum officinale (Williams et al., 1996), at 0.3,
1.0 and 3.0 µg per egg was applied in the CAM assay, it gave rise to an
inhibition of 52.4, 59.1 and 67.6% in the CAM angiogenesis, respectively. This
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result indicates that luteolin is one of anti-angiogenic principles in Taraxacum
officinale, although it may not be a major anti-angiogenic component in
Taraxacum officinale. Taken together, TEE possesses a strong antiangiogencic activity, and the BuOH fraction is most effective among the
fractions. Luteolin might be partly responsible for anti-angiogenic activity of
TEE. Anti-angiogenic activity of Taraxacum officinale might provide a
pharmacological basis on its folkloric use for the treatment of inflammatory
diseases and cancer.
Fig. 1. Inhibitory effect of the 70% ethanol extract (TEE) prepared from Taraxacum officinale on the chick embryo
chorioallantoic membrane (CAM) angiogenesis. Retinoic acid (RA, 1 µg per egg) was used as a positive control. Each
column represents mean ± S.E. *P < 0.05; **P < 0.01; ***P < 0.001.
Fig. 2. Inhibitory effects of TEE fractions (A) and dose-dependent anti-angiogenic activity of n-butanol fraction (BuOH)
(B) on the chick embryo chorioallantoic membrane (CAM) angiogenesis. Retinoic acid (RA, 1 µg per egg) was used as a
positive control. One microgram of each fraction was applied per egg. EA: ethyl acetate fraction; BuOH: n-butanol
fraction; Aq: aqueous fraction. Each column represents mean ± S.E. *P < 0.05; **P < 0.01; ***P < 0.001.
In order to assess an anti-inflammatory activity of TEE, the two inflammatory
models, such as acetic acid-induced vascular permeability and carrageenaninduced air pouch models, were used. In vascular permeability assay,
mediators of inflammation, released following stimulation, leads to dilation of
arterioles and venules and increased vascular permeability (Vogel and Vogel,
1997). TEE at the oral doses of 50, 100 and 200 mg/kg showed an inhibition in
vascular permeability, respectively (Table 1). From this finding, it is assumed
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that an anti-inflammatory activity of TEE arises from its protection on the
release of inflammatory mediators at the first stage. The carrageenan-induced
air pouch model is known to be an excellent acute inflammatory model in which
fluid extravasation, leukocyte migration and various biochemical parameters in
the exudate involved in the inflammatory response can be easily detected. The
injection of carrageenan into a subcutaneous air pouch on the dorsal surface of
rats initiates an inflammatory process. In the carrageenan-induced air pouch
model, dexamethasone (0.01 mg per pouch), a nonselective cyclooxygenase
inhibitor, reduced the volumes of the exudates by 53.7% (Table 2). Treatment
with TEE (1.0 mg per pouch) and the BuOH fraction (1.0 mg per pouch) gave
rise to an inhibition in the exudates volume, with respect to the control (Table 2).
Total numbers of the polymorphonuclear leukocytes in the air pouches were
also diminished by the treatment with TEE and the BuOH fraction (Table 2).
Luteolin at 0.1 mg/kg also diminished the volume of exudate and total number
of the polymorphonuclear leukocytes in the air pouch by 14.1 and 35.3%,
respectively. Collectively, TEE is confirmed to possess an acute antiinflammatory activity.
Table 1.
Effect of TEE on acetic acid-induced vascular permeability in mice
Group
Dose (mg/kg, p.o.) A630
Inhibition (%)
Control –
2.24 ± 0.08
–
TEE
50
1.73 ± 0.18
23.1
TEE
100
1.18 ± 0.08**
47.5
TEE
200
0.57 ± 0.11*** 74.8
AP
100
0.30 ± 0.04*** 86.6
The results are expressed as mean ± S.E. of n = 8. Inhibition percentages were calculated with respect to the control
treated with saline only. Aminopyrine (AP) was chosen as a positive control. **P < 0.01; ***P < 0.001, compared with the
control group.
Table 2.
Effects of TEE and its BuOH fraction on carrageenan-induced air pouch model
in rats
Exudate (ml)
Total leukocytes
(×105 cells)
NO (µM)
Control –
8.04 ± 0.07
1427.1 ± 74.2
25.2 ± 2.4
TEE
5.64 ± 0.27*
710.1 ± 64.5** (50.2)
14.0 ± 1.2*
Group
Dose (mg
per pouch)
1.0
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Group
Dose (mg
per pouch)
Exudate (ml)
Total leukocytes
(×105 cells)
(29.9)
NO (µM)
(44.4)
BuOH
1.0
5.41 ± 0.20*
(32.7)
564.7 ± 22.5** (60.4)
10.9 ± 0.6*
(56.7)
DEXA
0.01
3.72 ± 0.29**
(53.7)
343.1 ± 25.0***
(76.0)
3.7 ± 0.5*
(85.3)
The results are expressed as mean ± S.E. of n = 8. Figures in parentheses indicate inhibitory percentages with respect
to the corresponding control. Dexamethasone (DEXA) was used as a positive control. *P < 0.05; **P < 0.01;
***P < 0.001, compared with the control group.
Since TEE was identified to have anti-inflammatory activity in acetic acidinduced vascular permeability (Table 1) and carrageenan-induced air pouch
(Table 2) models, its anti-nociceptive activity was examined using acetic acidinduced writhing response. As shown in Fig. 3, TEE at 50, 100 and 200 mg/kg,
p.o., caused an inhibition by 35.1, 54.8 and 78.0%, respectively, in the writhing
response induced by acetic acid. Its inhibitory activity appeared to be dosedependent. The degree of inhibition at 200 mg/kg was comparable to the value
obtained with 100 mg/ml aminopyrine used as a positive control (Fig. 3). This
finding indicates that TEE also contains potent anti-nociceptive activity in
addition to anti-inflammatory activity, subsequently suggesting that
prostaglandin biosynthesis might be commonly involved in the anti-inflammatory
and anti-nociceptive activities of TEE.
Fig. 3. Effect of TEE on the acetic acid-induced writhing response in mice. TEE (50, 100 or 200 mg/kg) was orally
administered. Aminopyrine (AP, 100 mg/kg body weight) was used as a positive control. Experiments were performed in
triplicate. Each column represents mean ± S.E. *P < 0.05; **P < 0.01; ***P < 0.001.
Nitric oxide (NO) is one of well-known pro-inflammatory mediators in the
pathogenesis of inflammation. For the expression of inducible nitric oxide
synthase (iNOS), the mammalian cells should be triggered by specific
stimulants such as pro-inflammatory cytokines and bacterial lipopolysaccharide
(LPS; Chesrown et al., 1994). Since iNOS-derived NO is involved in
inflammation (Singh et al., 2000), suppression of iNOS is closely linked with
anti-inflammatory action. Inhibitory effect of TEE was examined on LPS-induced
NO production in the RAW264.7 macrophages (Fig. 4). The accumulated nitrite,
determined by the Griess method, in the medium was used as an index for NO
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15
level. After the treatment with LPS, the nitrite content markedly increased (Fig.
4). When the macrophage cells were treated with 0.25, 0.5 and 1.0 mg/ml TEE,
NO production induced by LPS was significantly suppressed in a dosedependent manner (Fig. 4). No significant cytotoxic effects on the macrophages
were observed at the used concentrations of TEE, which was determined by
MTT assay (data not shown). With the assumption that the inhibition of NO
production by TEE would be caused by a down-regulation in the iNOS protein
level, the effect of TEE on the iNOS expression was examined in the
macrophages cells treated with LPS. As shown in Fig. 5, TEE dose-dependently
suppressed iNOS induction without changes in the levels of β-actin, an internal
control, indicating the specific inhibition of iNOS expression by TEE.
Suppressive effect of TEE on the production of NO was confirmed in in vivo
experiments. As shown in Table 2, TEE gave rise to a marked decrease on the
content of nitrite in the exudates obtained from the carrageenan-induced air
pouch model, which corresponds with the in vitro results obtained with using the
macrophages (Fig. 4). Luteolin was also able to decrease the nitrite level in the
carrageenan-induced air pouch (data not shown), supporting that luteolin is one
of anti-inflammatory principles in Taraxacum officinale. This corresponds with
the in vitro finding that luteolin could suppress iNOS induction in the LPSactivated RAW264.7 macrophages (Hu and Kitts, 2004). In contrast to
constitutive cyclooxygenase-1 (COX-1), inducible cyclooxygenase-2 (COX-2) is
activated by tissue damage during inflammatory process. Various natural
products of plant and marine origin have been shown to contain their antiinflammatory activities through suppression of COX-2 (Jachak, 2006). In a
dose-dependent manner, TEE was also able to suppress COX-2 expression in
LPS-stimulated RAW264.7 macrophage cells (Fig. 5). Based on this finding,
TEE is assumed to show its anti-inflammatory activity via the suppression of
COX-2 expression. Taken together, it is likely that TEE shows its antiinflammatory and anti-nociceptive activities through the reduction of NO
production and COX-2 expression.
Fig. 4. Inhibitory effect of TEE on LPS-induced NO production in RAW264.7 macrophage cells. The values are
mean ± S.E. of the three independent experiments. ***P < 0.001.
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16
Fig. 5. Inhibitory effect of TEE on LPS-induced production of inducible nitric oxide synthase (iNOS) and
cyclooxygenase-2 (COX-2) in RAW264.7 macrophage cells. β-Actin was used as an internal control. This blot is a
representative of the three independent experiments.
Many anti-inflammatory agents of medicinal herbal origin have also been known
to possess antioxidant activities. TEE was able to directly scavenge the stable
DPPH radical in a concentration-dependent manner (Fig. 6). The BuOH fraction
showed a little higher scavenging activity (Fig. 6). Although ROS at low
concentrations play the role of an intracellular messenger of various
physiological events, including cell proliferation and apoptosis, the production of
large amounts of ROS is considered cytotoxic and related with various
disorders. As shown in Fig. 7, TEE was able to reduce ROS level, which was
elevated by LPS in the macrophages. This is consistent with the previous
finding that dandelion flower extract was capable of suppressing superoxide
and hydroxyl radical (Hu and Kitts, 2005). Taken together, it is likely that TEE
shows its anti-angiogenic, anti-inflammatory and anti-nociceptive activities
through reduction of NO production, down-regulation of COX-2 expression and
reduction of ROS level.
Fig. 6. The DPPH scavenging activity of TEE. Vitamin C (○) was used as a positive control. DPPH concentration used
was 100 µM. A representative of three independent experiments is shown.
Fig. 7. Effect of TEE on reactive oxygen species (ROS) level in RAW264.7 macrophage cells activated with LPS. ROS
level was represented as DCF fluorescence. *P < 0.05.
4. Conclusions
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17
In conclusion, the ethanol extract of Taraxacum officinale F. Weber ex Wiggers
(TEE) contains anti-angiogenic, acute anti-inflammatory and anti-nociceptive
activities. The BuOH fraction is most effective in the CAM assay among the
fractions of TEE. TEE also possesses an inhibitory activity on in vitro NO
production in the stimulated mammalian cells and in vivo NO production in the
air pouch. It is capable of diminishing expression of iNOS and COX-2 in LPSstimulated RAW264.7 cells. TEE also possesses a scavenging activity on
DPPH and a reducing activity on ROS level in LPS-activated macrophages.
These findings provide additional pharmacological information on the
therapeutic efficacy of Taraxacum officinale. It would be regarded as another
starting point for the development of an anti-inflammatory therapy with fewer
side effects.
Acknowledgement
This work was supported by the SRC program of MOST/KOSEF (R11-2005017).
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ALOPATIA
LA INMUNOSUPRESION INDUCIDA POR RADIACION UV ES MAYOR EN
HOMBRES Y PUEDE SER PREVENIDA POR NICOTINAMIDA TOPICA
Diona L Damian1, Clare R S Patterson1, Michael Stapelberg1, Joohong Park1,
Ross St C Barnetson1 and Gary M Halliday1
1
Department of Dermatology, Melanoma and Skin Cancer Research Institute,
Sydney Cancer Centre, University of Sydney, Royal Prince Alfred Hospital,
Camperdown, New South Wales, Australia
[Journal of Investigative Dermatology (2008) 128, 447-454]
RESUMEN
La inmunosupresión inducida por radiación UV aumenta la carcinogénesis
cutánea. La incidencia de de cancer de piel continúa aumentando a pesar del
incremento del uso de los filtros solares, los cuales son menos efectivos en
prevenir la inmunosupresión que las quemaduras solares. Utilizando la
reacción de Mantoux como un modelo de la inmunidad de la piel, se investigó
los efectos de las radiaciones UV solares simuladas (ss) y sus componentes
UVA y UVB, además de ensayar la capacidad de la nicotinamida de uso tópico
para proteger de la inmunosupresión inducida por radiación UV. En un ensayo
a doble ciego, voluntarios sanos que dieron positiva la reacción de Mantoux,
fueron irradiados sobre sus espaldas, a las cuales le aplicaron previamente, en
diferentes sitios, nicotinamida 5% o el vehículo. Posteriormente la evaluación
de los sitios irradiados y los adyacentes no irradiados, permitieron medir la
inmunosupresión inducida por UV con y sin nicotinamida. Las dosis de
suberitema ssUV produjeron inmunosupresión significativa, a diferencia de sus
componentes UVB y UVA aplicados independientemente. Los hombres fueron
inmunosuprimidos por dosis ssUV tres veces menores a aquellas requeridas
para inmunosuprimir a las mujeres. Esta puede ser una causa importante de la
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21
mayor incidencia y mortalidad de cáncer de piel, observada en hombres. La
nicotinamida resultó ser un agente preventivo de la inmunosupresión, cuyo
mecanismo de protección puede ser dilucidado a través de estudios genéticos,
sugiriendo alteraciones en las proteinas del complemento, el metabolismo
energético y los caminos de la apoptosis. La nicotinamida es una droga segura
y barata que podría incorporarse a los protectores solares o a los productos
post-solares, para mejorar la protección contra la inmunosupresión.
ARTICULO ORIGINAL
Introduction
Skin cancer is the most common form of malignancy in Caucasian populations
(Diepgen and Mahler, 2002). Immunosuppression enhances the development of
skin cancers, as seen most dramatically in transplant recipients whose skin
cancer risk is severalfold higher than that of the immunocompetent population
(Bordea et al., 2004). UV radiation in sunlight has profound immunosuppressive
effects on the skin (Damian et al., 2001), which play a central role in cutaneous
carcinogenesis (Noonan et al., 2003; Ullrich, 2005). The exact mechanisms of
UV-induced immunosuppression, and the relative contribution of UVB (290–
320 nm) and UVA (320–400 nm), are as yet unclear.
Various animal and human models of skin immunity have been used to
demonstrate UV-induced immunosuppression in vivo. UV irradiation can impair
both induction (primary sensitization) and elicitation of immune responses to
cutaneous allergens (Damian et al., 2001; Wolf et al., 2003). Systemic UVinduced immunosuppression can be measured following sensitization at a site
distant from the irradiated field, whereas local immunosuppression is observed
when antigen is applied at the site of UV exposure. Mantoux testing with
tuberculin purified protein derivative (PPD) is used in clinical practice to assess
tuberculosis immunity and exposure status. Mantoux-positive subjects, who
have been either exposed to tuberculosis or vaccinated with Bacille CalmetteGuerin, develop localized induration and erythema 48–72 hours after
intradermal injection of PPD. The diameter of induration can be measured
clinically using the "pen method" whereby a ballpoint pen is used to mark the
outer aspects of the Mantoux response (Bouros et al., 1991). Erythema at
reaction sites, assessed via reflectance spectrometry, provides a more sensitive
measure of Mantoux intensity, which correlates well with the diameter of
induration (Damian and Halliday, 2002).
Men have both a higher incidence of and mortality from skin cancer (Foote et
al., 2001; Molife et al., 2001) but the effect of gender on susceptibility to UVinduced immunosuppression in humans is unknown. Immunosuppression
occurs with UV doses well below the sunburn threshold, and sunscreens may
be less effective at preventing immunosuppression than sunburn (Damian et al.,
1999; Poon et al., 2003); improved protection from the immune effects of UV is
thus likely to reduce the incidence of malignant and premalignant skin lesions.
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Nicotinamide, the active form of vitamin B3, is used clinically in the treatment of
a variety of inflammatory skin disorders including bullous pemphigoid, acne, and
rosacea (Niren, 2006). Although the exact mechanism of action in these
settings is unknown, nicotinamide is a known endogenous inhibitor of the
nuclear enzyme poly-ADP-ribose polymerase (PARP), which regulates the
expression of immunomodulatory proteins such as inducible nitric oxide
synthase, intercellular adhesion molecule 1, major histocompatibility complex
class II, and NF- B (Virag and Szabo, 2002).
Nicotinamide has also been shown to prevent UV-induced immunosuppression
and carcinogenesis in mice (Gensler, 1997, 1999) but its effects on UV
immunosuppression in humans have not yet been investigated. We have
previously shown that UV exposure attenuates Mantoux reactions in Bacille
Calmette-Guerin-vaccinated volunteers (Damian et al., 1998; Friedmann et al.,
2004), and now report the effects of gender and nicotinamide on UV-induced
suppression of the Mantoux reaction in humans.
Results
Subjects:
Of 75 people who started the protocol, 5 did not complete due to unrelated
reasons. None of the subjects who completed the study were excluded from the
results and none suffered significant adverse effects from the study. Table 1
shows the similar characteristics of volunteers who completed the various
studies
Mantoux-induced erythema increases in proportion to PPD dose
Although all subjects had initial Mantoux tests performed the week before UV
irradiation, only 12 volunteers from various study groups were initially tested
with the PPD dose combination of 1, 2, and 5 U (Figure S1). The erythema
index (EI) of subsequent Mantoux reactions was significantly correlated with
PPD dose, as shown by a repeated measures linear regression (r=0.705, n=36,
P<0.001).
UV irradiation did not cause systemic immunosuppression
The initial, pre-irradiation Mantoux tests (lateral lower back) were compared
with those of unirradiated nicotinamide- and vehicle-treated controls adjacent to
the irradiated areas (medial lower back). Subjects were excluded from this
analysis if initial PPD doses were different from those subsequently used. The
mean EI of the initial Mantoux tests did not significantly differ from subsequent
control tests in any of the groups. Therefore, solar-simulated (ss) UV, UVB, or
UVA exposure did not cause systemic suppression of Mantoux reactions.
Nicotinamide in the absence of UV had no immune effects in any study, as the
EI of unirradiated control sites treated with nicotinamide did not differ from the
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EI of unirradiated initial or vehicle-treated sites. Similarly, there was no
significant difference in the unirradiated control EI of men and women.
Topical 5% nicotinamide prevents ssUV-induced immunosuppression but
not sunburn
The effect of 5% nicotinamide applied before ssUV exposure in 20 volunteers
(10 men, 10 women) is shown in Figure 1a. Exposure of vehicle-treated skin to
1.48 or 2.22 J/cm2 ssUV for 3 consecutive days significantly suppressed
Mantoux reactions by 19.4% (mean EI=13.8, SEM=3.7; P<0.01) and 27.7%
(mean
EI=19.8, SEM=2.8; P<0.001), respectively. When irradiated
nicotinamide-treated sites were compared with unirradiated nicotinamidetreated control sites, significant immunosuppression no longer occurred. Hence,
5% nicotinamide applied before exposure prevented ssUV-induced
immunosuppression. This protective effect of nicotinamide treatment was
confirmed by repeated measures analysis of variance (P<0.0001).
The effect of nicotinamide applied immediately after irradiation in the second
group of 20 volunteers (10 men, 10 women) is shown in Figure 1b. There were
no significant differences in baseline characteristics between the two groups.
Three consecutive daily exposures to 0.74 J/cm2 suppressed Mantoux
reactions by 24.8% (mean EI=16.3, SEM=6.2; P<0.05) and exposures to 1.48
and 2.22 J/cm2 caused suppression of 29.1% (mean EI=19.2, SEM=6.2;
P<0.05) and 43.8% (mean EI=28.8, SEM=5.7; P<0.001), respectively. At each
of the three fixed doses, significant immunosuppression was prevented by
application of 5% nicotinamide after irradiation. The protective effect of
nicotinamide treatment was again confirmed by repeated measures analysis of
variance (P<0.0001).
The minimal erythema dose (MED) was unchanged by nicotinamide applied
before or after ssUV exposure (Table 2; paired two-tailed Student's t-test).
Mean erythema (EI) at vehicle-treated MED sites was not significantly different
to the EI at the nicotinamide-treated site exposed to the same UV dose whether
nicotinamide was applied before or after ssUV exposure. Hence, nicotinamide
did not prevent sunburn. Spectrophotometry (Ultrospec 2100 pro UV/Visible
Spectrophotometer, Biochrom Ltd, Cambridge, UK) of 5% nicotinamide in
vehicle confirmed negligible absorption between 290 and 400 nm.
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Figure 1
Topical 5% nicotinamide protects from immunosuppression when applied
before (a) or after (b) ssUV exposure. Results are presented as mean+SEM; *
P<0.05, ** P<0.01, and *** P<0.001 (compared with unirradiated site, paired twotailed Student's t-test; Bonferroni correction applied; each n=20).
25
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Table 1. Baseline characteristics of volunteers
Nicotinamide and
ssUV
Nicotinamide
before and after
combined1
Characteristic
Before
(n=20)
After
(n=20)
Females
(n=18)
Males
(n=18)
UVA
only
(n=15;
7
men)
Age (years)
(range)
35 (22–
63)
38 (23–
62)
41 (2563)
32 (2356)
30
(20–
54)
31 (20–50)
33 (21–50)
MED J/cm2
ssUV (range)
2.15
(1.11–
3.01)
2.06
(0.74–
3.72)
2.15
(1.113.75)
2.05
(0.74–
3.7)
2.64
(0.79–
7.95)
not
determined
4.22 (2.69–
7.68)
Skin color
Melanin index
in relative
units (range)
-76 (129 to 5)
-59 (117 to 20)
-79 (123 to 36)
-60 (129 to 5)
-35 (130 to
148)
-40 (-130
to 25)
-58 (-105
to 14)
5:9:6:0
5:10:5:0
4:11:3:0
6:6:6:0
6:4:4:1
3:5:7:0
2:2:0:1
Number of
subjects
2
2
2
2
3
2
2
Previous
NMSC3
0
2
1
1
1
0
0
UVB only
(n=15; 8
men)
Microarray
(n=5; 4
men)
Skin type
I/II/III/IV2
Current smokers
MED, minimal erythema dose; NMSC, non-melanoma skin cancer; ssUV, solarsimulated UV.
1
Two women and two men participated in both studies therefore one set of each of
their results was excluded from analysis.
2
Fitzpatrick's skin types (Fitzpatrick, 1998): I, constitutive skin color pale, does not
tan; II, pale, tans with difficulty; III, pale, tans readily; IV, light brown, tans
profusely.
3
No patients had previous melanoma.
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Table 2
Nicotinamide
application
Before ssUV
After ssUV
Vehicle
(Jcm2)
Nicotinamide
(J/cm2)
Pvalue
MED
2.15 0.11
2.12 0.12
0.61
EI at
MED
85 6.82
79 5.38
0.214
MED
2.06 0.19
2.12 0.21
0.46
EI at
MED
89 6.85
85 6.68
0.148
EI, erythema index; MED, minimal erythema dose; ssUV, solar-simulated UV.
In 20 volunteers, nicotinamide was applied 15 minutes before MED testing on one
side of the back whereas at the same time base lotion was applied on the other side
of the back. There was no significant difference between the mean MED (shown
SEM), nor in the mean EI at skin irradiated with one vehicle-treated MED (EI at
MED) between base lotion-treated sites and nicotinamide-treated sites. In 20
volunteers, nicotinamide was applied immediately after MED testing on one side of
the back and base lotion was applied on the other side of the back. Again, there
was no significant difference between the mean MED between base lotion-treated
sites and nicotinamide-treated sites.
Figure 2
Men are more immunosuppressed by ssUV than women. Results are
presented as mean SEM; * P<0.01 and ** P<0.001 (compared with unirradiated
site, paired two-tailed Student's t-test; Bonferroni correction applied; n=36).
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Men are more susceptible to ssUV-induced immunosuppression than
women
To analyze the effects of gender, subjects from both ssUV studies, in which the
irradiation protocols were identical, were combined. When the studies were
analyzed separately, the results were similar and therefore we present the
results of the combined studies only. Four subjects participated in both studies.
One set of their results was therefore excluded, based on matching MEDs as
evenly as possible for male and female volunteers. Four of the female
volunteers were taking oral contraceptives, 5 were postmenopausal, and 9 were
premenopausal. Because of the small numbers of women in each group, it was
not possible to correlate hormonal status with susceptibility to
immunosuppression.
When ssUV-induced immunosuppression at vehicle-treated sites was compared
between men and women, men were significantly more immunosuppressed
than women (repeated measures analysis of variance P=0.0224) and the
threshold dose for immunosuppression was at least three times lower in men
than women (Figure 2). Among male volunteers, significant immunosuppression
was observed at all doses of ssUV, whereas female volunteers were only
significantly immunosuppressed by the highest dose. Although both men and
women were significantly immunosuppressed by the highest ssUV dose,
immunosuppression was 40% greater in men. Nicotinamide prevented
suppression of Mantoux responses in both men and women (results not
shown). In this combined group of volunteers, immunosuppression following
exposure to the two highest ssUV doses correlated to MED (r=-0.587, P<0.001
and r=-0.353, P<0.05, respectively, using linear regression analysis); subjects
who were more easily sunburned were also more susceptible to UV
immunosuppression.
Component UVB and
immunosuppressive
UVA
doses
were
not
independently
The effect of irradiation with UVA or UVB alone on the Mantoux response was
investigated in separate groups of 15 volunteers. Subjects were exposed to
UVA or UVB on 3 consecutive days at doses equivalent to the UVA and UVB
components of the previously used ssUV doses (0.75, 1.50, and 2.24 J/cm2 of
UVA and 0.075, 0.150, and 0.225 J/cm2 of UVB). Comparison of Mantouxinduced erythema at irradiated and unirradiated sites showed no significant
immunosuppression at any dose of UVB or UVA. Nicotinamide had no immune
effects in this experiment (Figure S2).
Genes involved in complement, energy metabolism and apoptosis
pathways are differentially regulated in vehicle- and nicotinamide-treated
irradiated skin
Six healthy volunteers (five men and one woman) were recruited for ssUV
irradiation, biopsy, and microarray analysis. In each volunteer, two microarrays
were compared and analyzed (vehicle-treated unirradiated vs vehicle-treated
Homeonews
28
irradiated sites; and nicotinamide-treated unirradiated vs nicotinamide-treated
irradiated sites). Results from one (male) volunteer were excluded because of
technical inability to extract the microarray data due to inadequate hybridization.
Gene set enrichment analysis (GSEA) (false discovery rate 0.25, P<0.05) was
applied to identify differentially regulated functional gene sets. In vehicle-treated
skin, no significantly enriched pathways were upregulated by ssUV irradiation.
Instead, a number of pathways were downregulated, including those relating to
apoptosis (10 pathways), energy metabolism (5 pathways), and immune
function including complement (4 pathways) (Tables S1 and S2). Highly
overlapping genes in apoptosis-related pathways were protein kinase C
(PRKCA), cytochrome c (CYCS), insulin-like growth factor 1 receptor (IGF1R),
BAD, BCL2, AKT1, caspase 3 (CASP3), HRAS, and TP53. In energy-related
pathways, the leading edge subset of genes in the electron transport chain
pathway (i.e., the genes most responsible for the enrichment signal) were
mitochondrial ATP synthase (ATP5A1), succinate dehydrogenase complex
subunits a and b (SDHA, SDHB), and cytochrome c (CYCS), which are key
genes in energy production. In the citrate pathway, the nicotinamide adenine
dinucleotide (NAD+)-dependent enzymes isocitrate dehydrogenase (IDH1,
IDH3B) and succinate-CoA ligase (SUCLG1, SUCLA2) were also
downregulated. The leading edge subset of genes in complement pathways
were C1Q, C1R, C1S, C4b, and C3. In nicotinamide-treated skin, significant
downregulation of these pathways was no longer observed. Hence,
nicotinamide inhibited ssUV-induced dysregulation of these genes.
In nicotinamide-treated irradiated skin, there was upregulation of the cadmium
induces DNA synthesis and proliferation in macrophages (cdmac) pathway with
leading edge subset genes comprising PLCB1, PRKCA, PRKCB1, HRAS,
CUZD1, MAP2K1 (MEK1 or MKK1), MAPK3 (ERK1), TNF, and RELA. The
histone deacetylase (hdac) pathway (involved in calcium regulation; McKinsey
et al., 2000) was downregulated by ssUV in the presence of both vehicle and
nicotinamide (leading edge genes in nicotinamide skin AKT1, CALM2, CAMK1,
HDAC5, MEF2A, MEF2C, and NFATC2). Pathways for arginine and proline
metabolism were also downregulated in nicotinamide-treated irradiated skin.
The genes in these pathways, involved in energy metabolism such as providing
precursors to the citrate cycle (Davis, 1986) were NOS3, GOT1, CKM, ASS,
SMS, AMD1, CPS1, AOC3, OAT, and CKMT2.
Discussion
Topical application of nicotinamide prevented UV-induced immunosuppression
when applied either before or after UV exposure. The ssUV used in this study
closely approximated the spectrum of natural sunlight, and was delivered at
doses equivalent to those readily encountered on a daily basis. ssUV equivalent
to 8 minutes of sun exposure (COLIPA, 1994) on 3 consecutive days caused
more than 40% immunosuppression, and immunosuppression of 25% was
caused by UV doses well below the average MED. Hence, significant
immunosuppression occurred in the absence of sunburn.
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29
Immunosuppression was prevented at all doses tested, with no adverse effects,
when nicotinamide was applied before or after UV exposure. The protective
effects of nicotinamide therefore do not result from sunscreening activity. This
was confirmed by the lack of effect on MED and negligible UV absorbance by
spectrophotometry. Although the baseline characteristics of the two ssUV
groups were similar, the second group showed higher levels of
immunosuppression. This is likely to reflect normal interindividual variation in
susceptibility to UV-induced immunosuppression (Damian et al., 1998; Kelly et
al., 2000). Individuals who are more susceptible to UV-induced
immunosuppression are at a greater risk of both melanoma and non-melanoma
skin cancer (Yoshikawa et al., 1990); however, identifying these individuals is
difficult as there are no clinically recognizable signs of cutaneous
immunosuppression. As previously reported by Kelly et al. (2000), we found that
immunosuppression was significantly correlated to sunburn threshold; palerskinned individuals were more susceptible to not only sunburn, but also UV
immunosuppression.
We analyzed our microarray data using the innovative, supervised
computational method GSEA (Subramanian et al., 2005). Compared with
unsupervised methods of analysis such as gene clustering and grouping based
solely on gene expression, the pathway-oriented approach of GSEA is better
able to detect relatively subtle differences between sample classes and
examines entire pathways rather than single genes. For example, differential
activity can be identified with a mean difference in gene expression of only 20%
(Mootha et al., 2003). Leading edge analysis, showing the gene sets most
responsible for the enrichment signal, provided additional clues to identify the
most critical subpathways.
Analysis of ssUV-regulated gene expression in vehicle-treated human skin
revealed several downregulated enriched biological pathways mainly related to
complement, apoptosis, and energy metabolism. Complement has been shown
to be involved early in the elicitation phase of DTH reactions in mice (Tsuji et
al., 1997), and is also known to be modulated by UV irradiation (Hammerberg et
al., 1998). In humans exposed to 3 MED of UVB, C3 activation was observed
3–12 hours after irradiation but not at later time points (Terui et al., 2001). In our
study, there was downregulation of complement pathways in vehicle-treated
skin, prevented by topical nicotinamide. It is possible that ssUV may have
upregulated complement in vehicle-treated skin if biopsies were performed at
an earlier time point, or in response to higher UV doses.
UV radiation-induced apoptosis is a protective response to cellular injury that
removes potentially genetically damaged cells from the skin through the
formation of sunburn cells (Melnikova and Ananthaswamy, 2005), although
imunohistochemistry of human skin irradiated with very low doses of ssUV (0.5–
1 MED; within the range used in these studies) may not show any increase in
apoptotic cell counts (Murphy et al., 2002). Our gene array analysis of vehicletreated skin showed ssUV-induced downregulation of the IGF-1R signaling
pathway including the antiapoptotic genes IGF1R and AKT1. Also
downregulated in vehicle-treated skin was the programmed cell death pathway,
Homeonews
30
including the antiapoptotic gene BCL-2. Hence, ssUV exposure had
proapoptotic effects in our transcriptional study. This is consistent with the
results of Enk et al. (2006), who used unsupervised gene clustering and
functional grouping to report microarray findings in human skin irradiated in vivo
with supraerythemal UVB doses (4 MED) . In contrast with our findings, Enk et
al. (2006) found that UVB differentially regulated several pathways including
those relating to S100 protein, serine protease inhibitors, and extracellular
matrix factors such as metalloproteinases as well as apoptosis. This may reflect
the much higher UV dose used. Nicotinamide prevented all of these effects. The
apoptotic genes BCL2, TP53, IGF1R, PRKCA, and AKT1, comprising the
leading edge subset of genes in the Tel pathway, are involved in regulation of
telomerase activity, which enables the addition of telomeric repeats to
telomeres and is thought to be involved in the early stages of cutaneous
carcinogenesis (Ueda, 2000). UV irradiation increases the rate of telomere
shortening in skin cells (Kosmadaki and Gilchrest, 2004), consistent with our
findings that ssUV downregulated the telomerase pathway, and suggesting a
protective effect of nicotinamide on this pathway.
Our observed downregulation of genes for energy production in several
pathways in vehicle-treated, irradiated skin is consistent with ssUV-induced
cellular energy depletion (Jacobsen et al., 2001). This pathway was no longer
downregulated in nicotinamide-treated skin, suggesting that nicotinamide
induces changes in energy metabolism as well as apoptosis. Intracellular
nicotinamide is metabolized to NAD+, the essential coenzyme in ATP
production and the sole substrate of the nuclear enzyme PARP (Hageman and
Stierum, 2001). PARP is involved in multiple cellular functions, including
regulation of p53 expression (Wieler et al., 2003), and is rapidly activated in
response to DNA damage. Although modest PARP activation enhances DNA
repair, overactivation can cause cell death. Nicotinamide is an endogenous
PARP inhibitor (Hageman and Stierum, 2001); hence PARP inhibition by
nicotinamide may have reduced cellular damage. Like Enk et al. (2006), we
found that ssUV downregulated p53, whereas in the presence of nicotinamide,
p53 downregulation was prevented. Nicotinamide has also been shown to alter
p53 regulation directly, independent of PARP (McLure et al., 2004).
The gene expression profile of nicotinamide-treated, irradiated skin showed
upregulation of the enriched pathway cdmac, which includes genes that overlap
with UVA-induced ERK activation (protein kinase C; PRKCA, PRKCB1,
phospholipase C, RAS and the extracellular signal-regulated kinases 1 and 2,
ERK, or MAPK3) (He et al., 2004). Direct NADH insertion is known to increase
intracellular calcium (Kaplin et al., 1996). Phospholipase activation and calcium
increase are required for ERK activation, which plays an important role in cell
proliferation and differentiation. It is possible that a nicotinamide-induced
increase in intracellular calcium might be an essential upstream signal regulator
for the ERK activation (He et al., 2004).
For the first time, we have shown that ssUV-induced immunosuppression is
greater in men. Only the highest ssUV dose caused significant
immunosuppression in female volunteers. In contrast, men were significantly
Homeonews
31
immunosuppressed by ssUV doses three times less than the sunburn threshold,
and were more immunosuppressed than women at all doses tested. Male and
female volunteers were well matched for MED and skin color and were of
similar ages. The incidence of smoking, which not only suppresses systemic
immunity but is also associated with cutaneous squamous-cell carcinoma
(Freiman et al., 2004), was the same in men and women as was previous
history of skin cancer. Hence, these factors were not a cause of greater
immunosuppression in men.
Similar findings have been reported in mice, where UVB-induced
immunosuppression was significantly greater in male than in female mice and
this was reversed by injecting males with 17- -estradiol before irradiation
(Hiramoto et al., 2004). In female mice, ssUV-induced immunosuppression was
exacerbated by topical application of an estrogen receptor antagonist and
attenuated by topical 17- -estradiol (Widyarini et al., 2006). Immune cells such
as lymphocytes and macrophages are known to bear sex steroid receptors,
which implies that estrogen may influence cytokine production by these cells
(Kovacs and Messingham, 2002). Male gender is an independent risk factor for
immunosuppression following surgical procedures (Wichmann et al., 2003), and
murine studies suggest that testosterone is responsible (Wichmann et al.,
1996). Our findings may explain the higher female incidence of cutaneous
disorders such as polymorphous light eruption (Mastalier et al., 1998), as well
as the greater skin cancer incidence and mortality observed in men (Foote et
al., 2001; Molife et al., 2001).
In our study, low doses of ssUV (UVA+UVB) were immunosuppressive but
when the UVA and UVB components of various ssUV doses were studied
individually, we found that neither UVA alone nor UVB alone was
immunosuppressive. This suggests that at the very low UV doses used here, an
interaction between the effects of UVA and UVB leads to immunosuppression,
as has been described in studies of ssUV-induced suppression of contact
hypersensitivity to nickel in nickel-allergic volunteers (Poon et al., 2005).
Immunosuppressive effects may have been detected with higher individual
component doses of UVA and UVB.
In conclusion, we have shown that a likely interactive effect of UVB and UVA
produces ssUV-induced immunosuppression at doses well below the sunburn
threshold, and that men are far more susceptible to this immunosuppression
than women. Nicotinamide appeared to mediate its immuno protective effects
by preventing ssUV-induced changes in complement, apoptosis, and cellular
energy pathways, consistent with its known roles as a PARP inhibitor, ATP
precursor, and anti-inflammatory agent. Nicotinamide also influenced ssUVinduced transcriptional regulation of genes in the cdmac and arginine catabolic
pathways. Whether this novel finding is related to the protective effects of
nicotinamide on the skin requires further investigation with functional studies.
Skin cancer incidence is rising and sunscreens can be improved by ensuring
protection from immunosuppression as well as sunburn.
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32
Materials and Methods
Participants
Healthy Mantoux-positive volunteers who had previously been vaccinated with
BCG were recruited and were required to cease any vitamin supplementation
and avoid sun exposure on their back at least 4 weeks before and during the
study. The study was conducted according to the Declaration of Helsinki
Principles, and approval was obtained from the Sydney University and Central
Sydney Area Health Service Ethics Committees. All volunteers provided written
informed consent before inclusion.
Study techniques
The UV source, described in detail previously (Damian and Halliday, 2002), was
a 1,000 W xenon arc solar simulator (Oriel, Stratford, CT), filtered to attenuate
visible and infrared wavelengths, remove UVC (<290 nm), and modify the
spectral output so that it simulated sunlight (ssUV), or comprised predominantly
UVB or UVA only (Damian and Halliday, 2002). Spectra were measured at 1 nm
intervals with an OL754 spectroradiometer (Optronics, Orlando, FL), which had
been calibrated with standard lamps. An IL-1350 broadband radiometer with
interchangeable UVA (SED 038) and UVB (SED 240) detectors (International
Light, Newburyport, MA) was calibrated against the source using the
spectroradiometer and this was used to enable rapid measurement of irradiance
before each irradiation.
One week before irradiation, volunteers were tested with three different
concentrations of tuberculin PPD (CSL Limited, Parkville, Victoria, Australia),
diluted in 0.9% normal saline to a volume of 0.05 ml and injected intradermally
on the lower back to confirm positivity and allow selection of the most
appropriate PPD dose for further testing in each volunteer. Different PPD dose
ranges were used depending on the subjects' previous reactivity. The intensity
of subsequent Mantoux reactions was assessed 72 hours after injection using
the "pen method" for measuring Mantoux diameter (Bouros et al., 1991). Only
participants with a Mantoux diameter 4 mm were eligible for the study.
Mantoux reactions were also measured with a reflectance erythema meter
(Diastron, Hampshire, UK), which we have previously found to provide a more
sensitive and reliable measure of changes in skin immunity than diameter
(Damian et al., 1998; Friedmann et al., 2004). Erythema induced by PPD was
calculated as the difference between the EI of the Mantoux response and the EI
of adjacent skin. Erythema meter readings were taken in triplicate and an
average EI for each site was recorded.
Nicotinamide (Fluka Chemie AG, Buchs, Switzerland) was prepared in 1:2:1
propylene glycol, ethanol, and distilled water vehicle at a concentration of 5%.
The clear, colorless solutions, prepared fortnightly in our laboratory, were
applied (2 l/ cm2) topically to test sites on the mid- to lower back in a
randomized, double-blinded manner. Subjects were asked to avoid washing the
test sites for at least 8 hours after each application.
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33
Study design
The week after initial Mantoux testing, separate 2.0 2.5 cm areas on each side
of the lower back were irradiated with one of three fixed doses of ssUV (0.74,
1.48, and 2.22 J/cm2) daily for 3 consecutive days. Adjacent, unirradiated sites
on each side served as immunologically intact controls. Nicotinamide lotion was
applied to test sites on one side of the back, and vehicle to the opposite side,
15 minutes before or immediately after each ssUV exposure in separate
studies. Mantoux tests were performed at irradiated and unirradiated sites
immediately after the final irradiation and measured 72 hours later.
Each volunteer's MED or sunburn susceptibility was determined by exposing
ten 1 cm squares on the upper back to graded ssUV doses and noting the dose
that caused threshold erythema 24 hours later. The effects of nicotinamide and
vehicle on MED were assessed in all subjects both visually and with the
erythema meter. A separate melanin index function in the erythema meter was
used to measure the skin color of the mid-back.
Additional groups of Mantoux-positive volunteers were recruited to assess the
immune effects of UVB and UVA doses approximating those contained within
the ssUV doses, with nicotinamide applied to one side of the back and vehicle
to the other immediately after irradiation as described above.
Microarray study
To investigate possible mechanisms of the immune effects of ssUV and
nicotinamide, six volunteers were irradiated with a single, fixed dose of ssUV
(2.22 J/cm2; 0.5 average MED of this group) onto two areas of their lower
backs. These sites were treated with nicotinamide or vehicle immediately after
irradiation, as were two adjacent, unirradiated sites. Nicotinamide was applied
after irradiation to exclude completely any theoretical possibility of a
sunscreening effect of nicotinamide. Twenty-four hours later, a 3 mm punch
biopsy was taken from each of the four sites. Total RNA was extracted using
TRIzol reagent (Gibco Invitrogen Life Technologies, Carlsbad, CA), purified and
DNase-treated using the RNeasy Fibrous Tissue Mini Kit (Qiagen Sciences,
Valencia, CA), and amplified using the MessageAmp II aRNA Kit (Ambion Inc.,
Austin, TX). Total RNA (60–70 g) was then reverse-transcribed into cDNA with
direct incorporation of cyanine 3-dCTP and cyanine 5-dCTP fluorescent dyes
(Perkin Elmer Life Sciences, Boston, MA). Following hybridization onto
Compugen 19,000 human oligonucleotide microarray slides (Adelaide
Microarray Facility, The University of Adelaide, Australia), microarrays were
scanned using an Axon scanner (Axon Instruments, Sunnyvale, CA) with
GenePix Pro 5.0 software.
Preprocessing and normalization were applied to all microarray expression data
before the assessment of differential gene expression, using GSEA
methodology (Subramanian et al., 2005). To input microarray data into GSEA,
the accession numbers from the microarrays of normalized treated groups were
mapped to corresponding gene symbols using the EASE software in the
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34
Database for Annotation, Visualization, and Integration Discovery (DAVID)
(Dennis et al., 2003; Hosack et al., 2003). GSEA was performed as previously
described using a C2 human-specific gene set library containing 522 gene sets
whose products are involved in specific metabolic and signaling pathways
(Subramanian et al., 2005). We used the default setting signal-to-noise ranking
metric in GSEA to rank genes. The statistical significance (P-value) of each
pathway was estimated by using phenotype-based permutation estimation
using 1,000 random permutations. We chose pathways with a significant
enrichment score (P<0.05) that had been adjusted for multiple comparisons
using the false discovery rate (q<0.25) for further interpretation. The false
discovery rate is a quantity that describes for a set of tests that are deemed
significant at or below a given level what proportion of them are likely to be
false-positive findings (Storey and Tibshirani, 2003).
Statistical analysis
Immunosuppression at each site ( EI) was calculated as the difference between
the EI of unirradiated control sites and the EI of irradiated test sites. Statistical
comparisons were made using paired two-tailed Student's t-tests, with EI
considered significant if P<0.05 following Bonferroni correction. All data sets in
the immunosuppression and MED experiments showed normal distribution
(Kolmogorov–Smirnov test).
Results are presented as
immunosuppression using
Correlations were performed
measures linear regression (a
STATA v 9.2) as stated.
mean SEM. We analyzed intervention and
repeated measures analysis of variance.
using linear regression analysis or repeated
random intercept linear mixed model fitted using
Conflict of interest
The authors state no conflict of interest.
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Acknowledgments
We are grateful to our participating volunteers, and to Drs Lesley Francis and
Patrick FitzGerald for statistical advice and analysis. This study was funded by
the Cancer Institute New South Wales, the University of Sydney Cancer
Research Fund, and the Dermatology Research Foundation. Associate
Professor Damian is supported by a Cancer Institute New South Wales
Fellowship.
Supplementary material
Table S1. Summary of GSEA results with FDR<0.25.
Table S2. Genes regulated by ssUV and nicotinamide: rank in gene list.
Homeonews
39
Figure S1. Mantoux-induced erythema index (EI) increases with the dose of
tuberculin purified protein derivative (PPD).
Figure S2. Low-dose UVB (A) or UVA (B) did not suppress Mantoux-induced
erythema.
HOMEOPATIA
TRATAMIENTO DE LOS SOFOCONES DE CALOR CON HOMEOPATIA.
RESULTADOS DE UN ESTUDIO OBSERVACIONAL
MF Bordet1, A Colas1, P Marijnen2, JL Masson3 and M Trichard4
1
Boiron, Sainte-Foy-lès-Lyon, France ; 2Reims, France ; 3Ecully, France ; 4Lyon,
France.
[Homeopathy, Volume 97, Issue 1, January 2008, pages 10-15]
RESUMEN
Objetivo
Existe una gran controversia con respecto al tratamiento de los síntomas de la
menopausia. Se evaluó el tratamiento homeopático para los sofocones de calor
y sus efectos sobre la calidad de vida de las mujeres menopáusicas.
Métodos
Estudio observacional, abierto, multinacional, prospectivo, pragmático y no
comparativo, de tratamientos homeopáticos prescriptos y su efectividad,
observando el impacto sobre la calidad de vida.
Resultados
Noventa y nueve médicos, en ocho países, tomaron parte en este estudio e
incluyeron cuatrocientos treinta y ocho pacientes con un promedio de edad de
55 años.
Los medicamentos homeopáticos fueron prescriptos a todos los pacientes; 98%
de los productos prescriptos fueron homeopáticos. Los más prescriptos fueron:
Lachesis mutus, Belladonna, Sepia officinalis, Sulphur y Sanguinaria
canadensis. Tratamientos no homeopáticos y suplementos dietarios fueron
utilizados en el 5% de los pacientes.
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40
Este estudio observacional reveló una reducción significativa (p<0.001) en la
frecuencia de los sofocones de calor por día y noche y en las molestias diarias
que ellos causan (caída promedio de 3.6 y 3.8 puntos respectivamente, en una
escala visual analógica de 10 cm; p<0.001).
99% de las mujeres informaron la desaparición o disminución de sus síntomas,
ocurriendo esto comúnmente dentro de los 15 días de comienzo del tratamiento
homeopático.
Conclusiones
Los resultados de este estudio observacional, sugieren que el tratamiento
homeopático para los sofocones de calor en las mujeres menopáusicas, es
efectivo. Se deberán realizar otros estudios, incluyendo estudios controlados y
randomizados.
Palabras clave: homeopatía; sofocones de calor; tratamiento homeopático;
estudio observacional; menopausia.
ARTICULO ORIGINAL
Introduction
The menopause is defined by at least 12 months of amenorrhea in women aged
at least 50 (with or without a measured increase in serum level of FSH),
negative testing for progesterone in women aged at least 451 or bilateral
oophorectomy in women of child-bearing age.
Hot flushes (or flashes) are sudden sensations of intense heat, mainly affecting
the upper part of the body and lasting for 1–5 min on average. They may be
accompanied by facial redness, perspiration that is sometimes heavy,
palpitations, anxiety, irritability and nocturnal sweating. The physiological
mechanism governing hot flushes is not precisely known. During the
menopause has started, 8 women in 10 report hot flushes of varying intensity,
which may affect their sleep and quality of life.[1] and [2] These hot flushes are
the main reason for instigating hormone replacement treatment (HRT).
According to the survey undertaken in April 2004 by the “Société Française
d’études par Sondage” (Sofres—French Society for Studies via Surveys), on
behalf of the “Agence Nationale d’accréditation et d’évaluation en Santé”
(Anaes—National Agency for Health Accreditation and Evaluation), 25.5% of
menopausal women aged 45–70 in December 2003 were taking hormone
replacement treatment. The iatrogenic consequences of these treatments is a
major public health issue.3
Although they may have an effect on hot flushes, soya derivatives, specifically
phyto-oestrogens’ are products for which the risks have not been evaluated and
are not monitored, and which do not meet health and safety requirements for
medicinal substances. The “Agence Française de Sécurité Sanitaire des
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41
Produits de Santé” (Afssaps—French Health Products Safety Agency) does not
recommend soya derivatives alone to treat hot flushes.3
Hot flushes and their consequences in menopausal women can be treated with
homeopathic treatment. Lachesis mutus, Sulphur, Sepia officinalis, Belladonna,
Glonoinum, Sanguinaria canadensis and Amylium nitrosum are the medicines
most commonly indicated for the treatment of hot flushes in menopausal
women.4
Several studies have been published evaluating homeopathy (individualized or
not) in menopausal symptoms, particularly in women who have suffered from
breast cancer.[1], [5], [6] and [7] Jacobs et al's study was a randomized, doubleblind study versus placebo performed over 1 year with 83 women suffering from
breast cancer; patients received either individualized homeopathic treatment or
a homeopathic complex or a placebo. This study did not show any significant
difference between the three patient groups relative to the severity and
frequency of hot flushes although there was a positive trend in the
“individualized homeopathic treatment” group during the first 3 months of the
study. But there was a significant improvement in quality of life in the 2 groups
of patients taking homeopathic treatment compared with the group who
received the placebo.5
Thompson et al conducted a prospective observational study with 45 women
suffering from breast cancer. The homeopathic approach (individualized
treatment) was evaluated in this study. The authors concluded that there was a
significant reduction in symptoms linked to oestrogen deficiency between the
start and end of the study.6
A second study by Thompson et al was a randomized, double-blind study
versus placebo which was performed over 4 months with 57 women suffering
from breast cancer; individualized homeopathic treatment was compared with a
placebo: this study did not show any significant difference between the 2 patient
groups for the criteria evaluated.7
Literature reviews and observational studies have also been published on
alternative and complementary treatments for menopausal symptoms[8], [9] and
[10] and hot flushes.[2], [11] and [12] These studies show that some
complementary treatments can be beneficial to patients and recommend that
further randomized clinical studies be performed to confirm these results.
The homeopathic strategy is therefore a valid part of the therapeutic arsenal,
particularly in the current context where hormone replacement therapy is being
questioned and vigilance required on the use of food supplements based on
soya isoflavones alone.[13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23]
and [24]
In this context, we decided to perform an observational study with physicians
prescribing homeopathic medicines. The study objective was to evaluate
homeopathic treatment for hot flushes in menopausal women in terms of
prescribed medical treatment, effectiveness and impact on quality of life.
Homeonews
42
Method
Study design
An open, multi-national pragmatic, prospective, non-comparative observational
study of the practice of physicians prescribing homeopathic drugs was
organized in 2005 with physicians from 8 different countries.
Recruitment of investigating physicians
This observational study was proposed to 157 physicians who prescribe
homeopathic medicines. The physicians, GPs or gynaecologists, were recruited
on a voluntary basis if they were interested.
This study was observational and each physician remained totally free
regarding to his prescriptions and his treatment choices so it was not necessary
to ask the advice of an ethics committee.
Patient selection
Inclusion criteria:
• women aged over 45;
• established menopause;
• suffering from hot flushes;
• not taking either homeopathic treatment or hormone treatment to reduce their
hot flushes;
• not taking Raloxifene.
Patients using topical hormone treatment for vulvo-vaginal trophic disorders
linked to the menopause were included in the study.
We defined established menopause as follows:
• at least 12 months of amenorrhea in women aged at least 50;
• or testing negative for progesterone (ie the absence of withdrawal bleeding
after administration of a progestational drug for 10 days per month over at least
3 consecutive months) in women aged at least 45;
• or when a bilateral oophorectomy had been performed on a previously
menstruating woman.
Exclusion criteria:
• patients not meeting the inclusion criteria;
• patients suffering from hormone-dependent cancer.
Evaluation criteria
The patients were assessed twice during the study: at the inclusion visit and at
the final visit.
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43
Clinical effectiveness
The evolution of clinical symptoms and the diurnal and nocturnal frequency of
hot flushes was evaluated as follows:
(1) The evolution of the patients’ clinical condition was measured at final visit by
a question with four responses: disappearance (no symptom), improvement
(lessening of symptoms), no change (same symptoms) or aggravation
(deterioration of symptoms).
(2) Diurnal frequency of hot flushes, compared at the inclusion visit and the final
visit. We measured the percentage of patients who reported 0 to 5, 6 to 10 or
more than 10 hot flushes per day, at each visit.
(3) Nocturnal frequency of hot flushes, compared at the inclusion visit and at the
final visit. We measured the percentage of patients who reported 0 to 5, 6 to 10
or more than 10 hot flushes at night, at each visit.
(4) The percentage of patients who suffered from daily hot flushes was
compared at the inclusion visit and at the final visit of the study.
(5) These measures were recorded by physicians who questioned patients for
retrospective recall.
Quality of life
The evolution of the impact of hot flushes on quality of life was measured by two
different visual analogue scales, graded from 0 to 10.
One scale measured the discomfort caused during daytime with the question:
“When you have a hot flushes during the day, how would you describe the
discomfort in your life ” A score of 10 indicates the most disturbed day life.
The other scale measured the effect on sleep by using the question: “When you
have hot flushes at night, how would you describe the consequences on your
sleep ” A score of 10 indicates the most disturbed sleep.
These scales were recorded by patients at the inclusion visit and at the final
visit of the study. These scales were specifically developed for the study but
were not validated.
Duration of the study
The period of inclusion in the study was from 17 January to 30 June 2005.
Follow-up was provided between 2 and 6 months following the inclusion visit,
depending on the physician's practice.
Statistical analysis
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44
The results analysis was per protocol because it concerns all patients who
adhered strictly to the protocol, particularly relative to respecting the inclusion
criteria. The statistical analysis was performed using tests appropriate for the
variables, ie:
• for qualitative variables: Chi-squared test (χ2);
• for quantitative variables: Student's test.
Alpha risk was set at 5%.
No subgroup analysis was performed.
Results
The physicians
Ninety-nine physicians in 8 countries took part in this observational study: 53
French, 23 Tunisian, 9 Brazilian, 5 Polish, 3 Bulgarian, 3 Portuguese, 2
Moroccans and 1 Italian.
The patients
A total of 489 patients were included in this study. We analysed the data for 438
case files. The 51 case files excluded are explained by:
• 33 lost to follow-up;
• 18 cases did not meeting the inclusion criteria;
The geographical distribution of the patients was as follows: 241 France (55%),
102 Tunisia (23%), 32 Brazil (7%), 32 Poland (7%), 14 Bulgaria (3%), 7
Morocco (2%), 5 Portugal (1%) and 5 Italy (1%). The average age of the
patients was 55 (45–76).
The patients were followed at the inclusion visit and at the final visit depending
on the physician's practice. The average duration of follow-up was 98 days.
11% of patients were followed-up in 60 days, 66% of patients were followed-up
from 60 to 120 days, 17% of patients were followed-up from 120 to 180 days
and 6% of patients were followed-up later than 180 days.
Medical treatments
Since this was an observational study, each physician remained totally free
regarding to his prescriptions and treatment choices. Participating physicians
prescribed a total of 1506 prescription lines for 438 patients, ie 3.4 medications
per patient, on average. One prescription line corresponds to one medication
prescribed to one patient at the inclusion visit. Medications were given
simultaneously or sequentially depending on the physician's practice.
Homeopathic treatment was prescribed for all the patients. Homeopathic
treatments covered 98% of the prescribed medication (1475 prescription lines).
Five percent of patients (22 patients) also received non-homeopathic
medication (notably minerals) and/or food supplements (notably soya-based).
These treatments covered 2% of the total prescriptions (31 prescription lines).
Table 1 shows the 12 homeopathic medications most prescribed during this
study; the main ones are: Lachesis mutus, Belladonna, Sepia officinalis,
45
Homeonews
Sulphur, Sanguinaria canadensis and Glonoinum. Lachesis mutus, Sepia
officinalis and Sulphur were most often prescribed at a dilution of 9 cH, whereas
Belladonna, Sanguinaria canadensis and Glonoinum were more frequently
prescribed at a dilution of 15 cH. Sixty-five percent of the 438 patients received
Lachesis mutus and 43% received Belladonna. Sepia officinalis, Sulphur,
Sanguinaria canadensis and Glonoinum were prescribed for 26%, 25%, 21%
and 15% of the patients, respectively.
Table 1. The 12 most prescribed homeopathic medications
Names of
homeopathic
medications
Number of
lines
Total
medications
Total homeopathic
medications
%
Total
(%)
%
Total (%)
Lachesis mutus
298
19.79
19.79
20.20
20.20
Belladonna
190
12.62
32.40
12.88
33.08
Sepia officinalis
130
8.63
41.04
8.81
41.90
Sulphur
110
7.30
48.34
7.46%
49.36
Sanguinaria
canadensis
92
6.11
54.45
6.24
55.59
Glonoinum
67
4.45
58.90
4.54
60.14
FSH
66
4.38
63.28
4.47
64.61
Folliculinum
63
4.18
67.46
4.27
68.88
Ignatia amara
53
3.52
70.98
3.59
72.47
LH-RH
46
3.05
74.04
3.12
75.59
Thuja occidentalis
45
2.99
77.03
3.05
78.64
Amylium nitrosum
40
2.66
79.68
2.71
81.36
Others
275
18.26
97.94
18.64
100.00
Total homeopathic
medications
1475
97.94
–
100.00
–
Total medications
1506
100.00 –
–
–
Table 2 shows the 16 homeopathic medications most prescribed for the 83
patients who noted a disappearance of their symptoms. Lachesis mutus,
46
Homeonews
Belladonna, Sepia officinalis, Folliculinum, Sanguinaria canadensis, Sulphur
and FSH were the main homeopathic treatments prescribed for these patients.
Table 3 shows the 16 homeopathic medications most prescribed for the 301
patients who noted an improvement in their symptoms. Lachesis mutus,
Belladonna, Sulphur, Sepia officinalis, Sanguinaria canadensis, Glonoinum and
FSH were the main homeopathic treatments prescribed for these patients.
Table 2. The 16 most prescribed homeopathic medications for the 83 patients
who noted a disappearance of their symptoms
Names of homeopathic medications
prescribed for the patients who noted a
disappearance of their symptoms
Number
of lines
%
Total
(%)
Lachesis mutus
51
18.35
18.35
Belladonna
41
14.75
33.09
Sepia officinalis
35
12.59
45.68
Folliculinum
15
5.40
51.08
Sanguinaria canadensis
15
5.40
56.47
Sulphur
14
5.04
61.51
FSH
13
4.68
66.19
Glonoinum
12
4.32
70.50
Thuja occidentalis
11
3.96
74.46
Ignatia amara
8
2.88
77.34
LH-RH
8
2.88
80.22
Natrum muriaticum
5
1.80
82.01
Luteinum
5
1.80
83.81
Progesteronum
4
1.44
85.25
Amylium nitrosum
4
1.44
86.69
Lycopodium clavatum
3
1.08
87.77
Others
34
12.23
100.00
Total homeopathic medications
278
100.00 –
47
Homeonews
Table 3. The 16 most prescribed homeopathic medications for the 301 patients
who noted an improvement in their symptoms
Homeopathic medications prescribed for
patients with improved symptoms
Number of
lines
%
Total
(%)
Lachesis mutus
217
21.34
21.34
Belladonna
121
11.90
33.24
Sulphur
81
7.96
41.20
Sepia officinalis
78
7.67
48.87
Sanguinaria canadensis
70
6.88
55.75
Glonoinum
45
4.42
60.18
FSH
42
4.13
64.31
Folliculinum
40
3.93
68.24
Ignatia amara
38
3.74
71.98
LH-RH
30
2.95
74.93
Thuja occidentalis
30
2.95
77.88
Amylium nitrosum
28
2.75
80.63
Nux vomica
16
1.57
82.20
Pulsatilla
11
1.08
83.28
Natrum muriaticum
10
0.98
84.27
Actaea racemosa
10
0.98
85.25
Others
150
14.75
100.00
Total homeopathic medications
1017
100.00 –
Clinical effectiveness
At the inclusion visit, 89% of patients suffered from daily hot flushes. This
percentage was reduced to 39% at the final visit (p<0.001). Thus more than
50% of the patients suffering from daily hot flushes at the beginning of the
study, no longer suffered daily from them at the final visit. At the inclusion visit,
46%, 38% and 16% of the patients experienced 0 to 5, 6 to 10 and more than
10 hot flushes per day respectively, compared to 90%, 8% and 2% of patients,
respectively at the final visit (see Figure 1). The number of diurnal hot flushes
fell significantly between the inclusion and follow-up visits (p<0.001). At the
inclusion visit, 69%, 23% and 8% of the patients, experienced 0–5, 6–10 and
48
Homeonews
more than 10 hot flushes per night respectively, compared to 93%, 5% and 1%
of patients, respectively, at the final visit (see Figure 2). The number of
nocturnal hot flushes fell significantly between the inclusion and follow-up visits
(p<0.001). Ninety percent of the women (384 patients) noted either the
disappearance or lessening of their symptoms (Table 4). Favourable evolution
was determined by disappearance or improvement of patients’ symptoms (selfassessment). This favourable evolution occurred most frequently within 15 days
of starting the treatment (Table 5).
Figure 1. Diurnal frequency of hot flushes
Figure 2. Nocturnal frequency of hot flushes
Table 4. Evolution of the patients' clinical condition
Evolution of clinical condition Patients
%
Disappearance
83
19.39
Improvement
301
70.33
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Homeonews
Evolution of clinical condition Patients
%
No change
34
7.94
Deterioration
10
2.34
Total
428
100.00
Missing values
10
Table 5. Time taken for favourable evolution of clinical condition
Time taken for favourable evolution of clinical condition Patients
%
Within 15 days
152
40.64
15 days to 1 month
134
35.83
More than 1 month
88
23.53
Total
374
100.00
Missing values
10
Quality of life
Concerning the discomfort caused during daytime, the mean score was 6.1
(SD=2.3) at the inclusion visit and 2.5 (SD=2.0) at the final visit (p<0.001).
Concerning the disturbance to sleep, the mean score was 6.2 (SD=2.6) at the
inclusion visit and 2.4 (SD=2.3) at the final visit (p<0.001). Quality of life
therefore significantly improved during the study period, with a fall of 3.6 and 3.8
points, respectively, in the 2 items measured on a visual analogue scale.
Discussion and conclusión
We performed an observational study with physicians who prescribe
homeopathic treatments; this was not a comparative study of two groups of
patients receiving different treatment, which is its main limitation.
During the study, patients were allowed to take other medication and products
in addition to those prescribed by the participating physicians. Of the 83 patients
who noted a disappearance of their symptoms, 32 (39%) had taken other
products, mainly soya/yam-based phytotherapies (10 patients). Of the 301
patients who noted a lessening of their symptoms, 137 (46%) had taken other
products, mainly soya/yam-based phytotherapies (48 patients). Of the 44
patients who noted no change or an aggravation of their symptoms, 18 (41%)
had taken other products again, mainly soya/yam-based phytotherapies (11
patients).
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50
These last data lead us to suppose that the consumption of products other than
the homeopathic medication did not affect the results because the proportion of
patients who took other products was comparable in each group of results.
It would be interesting to perform a randomized, double-blind comparative study
using an appropriate method to evaluate the homeopathic medication
effectiveness (with a validated tool like Greene Climateric Scale for example) in
the treatment of hot flushes in menopausal women.
In conclusion, the results of this observational study suggest that homeopathic
treatment is effective for hot flushes. Further investigation is justified.
Acknowledgements
We would like thank all the physicians who took part in this study as well as
Boiron laboratories local representatives who enabled this observational study
to be followed outside France. We would also like to thank Gilles Chaufferin for
his support and assistance in performing this study. This study was financed by
Boiron laboratories. The authors have no conflicts of interests directly
concerning the content of this study.
Referentes
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2 H.A. Philp, Hot flashes–a review of the literature on alternative and
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3 Afssaps/Anaes. Rapport d’orientation. Traitements hormonaux substitutifs de
la ménopause. 11 mai 2004, p. 78.
4 Jouanny J, Crapanne JB, Dancer H, Masson JL. La ménopause.
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11 D.G. Carroll, Nonhormonal therapies for hot flashes in menopause, Am Fam
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12 A. Clover and D. Ratsey, Homeopathic treatment of hot flushes: a pilot
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13 J.E. Rossouw, G.L. Anderson and R.L. Prentice et al., Writing group for the
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14 J.A. Cauley, J. Robbins and Z. Chen et al., Women's Health Initiative
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15 R.T. Chlebowski, S.L. Hendrix and R.D. Langer et al., WHI Investigators.
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Study, JAMA 289 (24) (2003), pp. 3243–3253.
16 G.L. Anderson, H.L. Judd and A.M. Kaunitz et al., Women's Health Initiative
Investigators. Effects of estrogen plus progestin on gynecologic cancers and
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17 J.E. Manson, J. Hsia and K.C. Johnson et al., Women's Health Initiative
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19 J. Hays, J.K. Ockene and R.L. Brunner et al., Women's Health Initiative
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1 Testing for progesterone is said to be negative in the absence of withdrawal
bleeding after the administration of a progestational treatment for 10 days per
month for at least 3 consecutive months.
NUTRICION
IMPORTANCIA MEDICINAL DEL JUGO DE POMELO Y SU INTERACCION
CON CIERTAS DROGAS
Jawad Kiani* Sardar Z Imam*
*Medical College, Aga Khan University, Stadium Road, Karachi, Pakistan
[Nutrition Journal 2007, 6:33]
RESUMEN
El jugo de pomelo se consume ampliamente en todo el mundo como preventivo
de de las enfermedades cardiovasculares y del cáncer. Sin embargo, se
encontró que es un inhibidor del sistema citocromo P-450 3A4 (intestino),
responsable del metabolismo de primer paso de muchas drogas. La bomba Pglicoproteína, encontrada en las microvellosidades de la pared intestinal,
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53
encargada del transporte de muchos de los sustratos del sistema citocromo P450 3A4, también ha sido inhibida por el jugo de pomelo. Por inhibición de
estos sistemas enzimáticos, el jugo de pomelo altera la farmacocinética de una
variedad importante de medicamentos, dando lugar a la elevación de sus
concentraciones séricas. Sus efectos más notorios se pueden ver en el grupo
de drogas antagonistas de los canales de calico y las estatinas. En el caso de
muchas drogas, el aumento de la concentración sérica está asociado con
aumento de la frecuencia de efectos adversos dependientes de las dosis. En
esta revisión, hemos discutido sobre la fitoquímica del jugo de pomelo, sus
principales componentes e interacciones con otras drogas (mecanismos de
acción) y sus implicancias clínicas.
ARTICULO ORIGINAL
Introduction
The grapefruit, thought to be a cross between an orange and a shaddock, was
developed in the West Indies in the early 1700s and first introduced to Florida in
the 1820s. Since the early part of the 20th century, mutant strains of white
grapefruit have appeared with pink to slightly reddish colour, and have been
propagated by citriculturists into several strains of grapefruit. The three major
types of grapefruit that exist today are white, pink/red and ruby/rio red varieties.
Grapefruit juice combines the sweet and tangy flavour of the orange and
shaddock and also provides up to 69% of the RDA for vitamin C along with as
many as 250 mg of Potassium [1].
However, the wide consumption of grapefruit juice cannot entirely be attributed
to its taste, and nutritive value. In fact, much of the enthusiasm in its use stems
from medical research that has suggested that grapefruit juice reduces
atherosclerotic plaque formation [2] and inhibits breast cancer cell proliferation
and mammary cell tumorigenesis [3,4]. Traditionally grapefruit juice has been
found to contain antioxidant, antinitrosaminic, antiseptic, aperitif, cardiotonic,
detoxicant, hypocholesterolemic, sedative and stomachic activities. In the light
of its above activities, it has been traditionally indicated throughout time for
anorexia, bacteria, benign prostatic hypertrophy, cancers (breast, colon,
prostate, lung, skin and throat), candida, cold, diabetes, dysuria, high
cholesterol, infection, insomnia, mycobacterium, mycosis, nervousness,
pseudomonas, rheumatism, staphylococcus and yeast.
However, as many as fifteen years ago, investigators found that grapefruit juice
can markedly augment oral drug bioavailability. This was an unexpected
observation from an interaction study between the dihydropyridine calcium
channel antagonist, felodipine, and ethanol in which grapefruit juice was used
as a flavour supplement to mask the taste of the ethanol [5]. Studies that
followed, confirmed that grapefruit juice significantly increased the oral
bioavailability of felodipine [6,7]. Subsequent studies probed the constituents of
grapefruit juice, its interaction with various other drugs and the mechanisms of
action of those interactions. Several grapefruit juice-drug interactions were
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54
discovered and these remain a potential concern especially since the juice and
drugs are often consumed together at breakfast. An increasing number of
adverse drug reactions might be avoided on the basis of knowledge about the
interaction of grapefruit juice and relevant drugs. Therefore, patients need to be
educated about the hazards (and advantages) of grapefruit interaction with
medication. In recent years, more drugs have been investigated for their
interaction with grapefruit juice and new models have been proposed for the
mechanism of such interaction. This article presents a simplistic summary of
most examples of such interactions and also explores the phytochemistry and
possible mechanisms of action involved in drug-grapefruit juice interactions in
light of recent studies on this subject.
Mechanism of action
The mechanism of action of this interaction involves inhibition of the CYP 3A4, a
member of the cytochrome P 450 (CYP) enzyme system. CYP is a large
multigene family of heme-containing enzymes located in the endoplasmic
reticulum of cells throughout the body. It is especially concentrated in the liver
and intestinal wall where it is involved in oxidative biotransformation of various
endogenous and exogenous substances. CYP 3A isoforms constitute 70% of
CYP enzymes in enterocytes [8,9]. P-glycoprotein (Pgp), a member of the ABC
(adenosine triphosphate-binding cassette), is another membrane transporter
located in the apical brush border of enterocytes. Once taken up by the
enterocytes, a lipophilic drug may be metabolized by CYP 3A4 or be pumped
back into the lumen by the Pgp. Hence the oral delivery of many drugs is limited
by the actions of CYP 3 A4 or Pgp. Metabolism by the CYP 3A4 will also occur
in the liver before the drug finally enters the systemic circulation. Grapefruit
juice causes inhibition of CYP 3A4 and thus serves to increase the bioavalability
of the drug by decreasing its pre-systemic metabolism [10]. This action is in
essence, similar to that caused by CYP-inhibiting drugs like itraconazole,
ketoconazole and erythromycin [11-13].
Grapefruit juice causes quick and irreversible sustained inhibition of the CYP
system, possibly by greatly accelerating the degradation of these enzymes
while also reducing translation from its mRNA. However, the process of
transcription of mRNA from the cell DNA is not affected. Overall, grapefruit juice
reduces the levels of CYP 3A4 in the cells by as much as 47% within four hours
of ingestion of grapefruit juice with the resultant increased bioavailability being
maintained for as long as 24 hours, by which time 30% of its effect is still
detectable [14-17]. It has been observed that decreased content of CYP3A4
was not associated with increased CYP3A4 mRNA, probably indicating the
absence of a feedback mechanism for CYP3A4 expression. Restoration of
CYP3A4 activity would therefore require denovo synthesis or enterocyte
replacement, accounting for the prolonged duration of the actions of grapefruit
juice [18].
Grapefruit juice shows a high variability of the magnitude of effect among
individuals. This variability is dependent upon inherent differences in enteric
CYP3A4 protein expression such that individuals with highest baseline CYP3A4
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have the highest proportional increase [19,20]. However, the effects of
grapefruit juice are predominantly on the intestinal CYP rather than hepatic
CYP. This is shown by the fact that most of the drugs that are involved in
interaction with grapefruit juice undergo their primary metabolism at the
intestinal level and in usual quantity, grapefruit juice does not affect the
pharmacokinetics of these drugs when they are administered intravenously.
Furthermore, while it increases the area under the plasma concentration-time
curve (AUC), it has no significant effect on the half life of the drugs [10,21-23].
In contrast to the clear inhibitory effects of grapefruit juice on CYP 3A4, the
effects of grapefruit juice on Pgp are controversial, ranging from activation to
inhibition. Earlier results have shown grapefruit juice to cause activation of Pgp
in vitro [24]. Any such activation in vivo will mean a greater efflux of the drug
back into the lumen, thereby decreasing the oral bioavailability of that drug and
at least partially, if not completely offsetting the effects produced by the
inhibition of CYP system of enzymes. This is taken as an explanation for the
less-than-expected increase in the bioavailability of drugs that are established
substrates of Pgp [24]. However, grapefruit juice does not change the
absorption of digoxin, a prototypical P-glycoprotein substrate, likely because it
has high inherent oral bioavailability [17,25]. However, recent studies have
demonstrated the inhibition of Pgp by grapefruit juice both by its downregulation and inhibition of function [26,27]. For example, grapefruit juice
increases the bioavailability of cyclosporine. This effect is thought to be
primarily though Pgp inhibition (instead of CYP3A4 inhibition) since orange juice
mediated reduction in enterocyte CYP3A4 concentrations did not produce a
similar increase in bioavailability [17]. In fact, grapefruit juice has also shown
inhibition of multidrug resistant protein 2 (MRP2), an efflux protein closely
related to Pgp in terms of its expression and function [26].
Yet, in spite of all what is known, the mechanism of action of grapefruit juicedrug interaction requires further investigation. Investigators still need to
determine for certainty any in vivo effect of grapefruit juice on Pgp. One study
[28] has also reported the action of grapefruit juice independent of its actions on
Pgp and CYP 3A4. This also requires further investigation. Similarly, grapefruit
and even orange juice have also recently been shown to be potent in vitro
inhibitors of a number of organic anion-transporting polypeptides (OATPs) that
are involved in apical-to-basal transport of drugs in the small intestine
[17,18,25,29]. They were also found to decrease the absorption of the nonmetabolized OATP substrate, fexofenadine hence pointing towards inhibition of
intestinal uptake transporters by fruit juices to decrease drug bioavailability. This
newly proposed mechanism of action and its effect vis a vis various medications
also demands further investigation [25,29].
Assessment of the in vitro CYP inhibition potential for these natural products
has important implications for predicting the likelihood of natural product-drug
interactions if these products are taken concomitantly. The susceptibility of
CYP3A4 to modulation by food constituents may be related to its high level of
expression in the intestine, as well as its broad substrate specificity. Reported
ethnic differences in the activity of this enzyme may be partly due to dietary
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factors.
Food-drug
interactions
involving
CYP1A2,
CYP2E1,
glucuronosyltransferases and glutathione S-transferases have also been
documented, although most of these interactions are modest in magnitude and
clinically relevant only for drugs that have a narrow therapeutic range. Recently,
interactions involving drug transporters, including P-glycoprotein and the
organic anion transporting polypeptide, have also been identified. Hence a lot of
food varieties have the potential to require dosage adjustment to maintain drug
concentrations within their therapeutic windows, especially with drugs that have
a high first pass degradation [30]. Further research is needed to determine the
scope, magnitude and clinical importance of food effects on drug metabolism
and transport.
Relevant phytochemistry
Another area in which the search for definite answers continues, is the quest to
find the active constituents of grapefruit juice that are responsible for its actions
on CYP enzyme systems and Pgp. The components of grapefruit juice that are
responsible for clinical drug interactions have yet to be fully determined but the
compounds thought to be responsible for this action include flavonoid
glycosides (narirutin, naringin, naringinen, quercetin, kaemferol, hesperidin,
neohesperidin, didymin, and poncirin) [8,31-34], furanocoumarins (6',7'dihydroxybergamottin,
bergamottin)
and
sesquiterpen
(nootkatone)[8,22,32,35,36].
Flavanoids exist in grapefruit juice in the form of glycosides, with naringin being
the most abundant. Upon ingestion, these are converted to aglycones and
sugars by the action of intestinal flora. Being polyphenolic and electron rich,
these compounds can theoretically inhibit the CYP enzymes. However, studies
have at most shown an in vitro effect by these compounds on the these
enzymes and have failed to identify any in vivo effect by them [37,38], leading to
an implication that they are probably not the main active ingredients of
grapefruit juice [1,39]. Studies have even failed to demonstrate any sort of
activity in naringin although its metabolite naringinin was observed to be active
in vitro. Yet, because of their huge quantities in grapefruit juice, and the fact that
naringin is not present in other citrus juices, flavanoids remain a subject of
research.
The main focus at present, however, is on furanocoumarins. This group
includes Bergamottin, its derivative 6' 7' dihydroxybergamottin (DHB) and a host
of other compounds [40]. Controversy still exists on the degree of their role in
the inhibitory effects of grapefruit juice. Several studies have shown DHB
[23,35,40] and to an extent Bergamottin [23] to be important contributors to the
grapefruit juice effect. In one study, the inhibitory potency of DHB and four
recently isolated furanocoumarins, when mixed with one another, almost
approached that of grapefruit juice. Omission of any of the components resulted
in decreased potency, suggesting that all major furanocoumarins contribute to
the inhibitory effects of grapefruit juice [40]. However, others have suggested
that DHB and Bergamottin are not the primary substances responsible for
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inhibition of CYP activity clinically [41,42]. For now, this topic also remains a
subject of intense research.
Drug-grapefruit juice interactions
Anti-hypertensive drugs and amiodarone
1,4-Dihydropyridine calcium antagonists are lipid soluble drugs used in the
treatment of essential hypertension and angina pectoris and metabolized in vivo
by CYP3A4. Since the effects of grapefruit juice were first noticed with
felodipine, this class of drugs has been intensively studied with grapefruit juice.
The degree to which the intestinal CYP system metabolizes this class of drugs
and affects their oral bioavailability varies markedly. In a study done by Lundahl
J et al., it was found that the intake of grapefruit juice led to an increase in the
oral bioavailability by 112% [43]. However, this study also found out that the
intravenous pharmacokinetics of felodipine were not significantly altered with
grapefruit juice. The main acute effect of the grapefruit juice on the plasma
concentrations of felodipine was believed to be mediated by inhibition of gut
wall metabolism. Grapefruit juice-felodipine interaction increases with increasing
frequency and amount of grapefruit juice ingestion, hence it has been
determined that an interval of 2–3 days between grapefruit juice intake and
felodipine administration is necessary if the interaction is to be avoided [44].
Blood pressure responses to felodipine with grapefruit juice have also been
assessed in the elderly and the systolic and diastolic blood pressures were
found to be lower with grapefruit juice in the single-dose state, whereas they
were not different between treatments in the steady-state dose [45]. The
different blood pressure results between the studies can be explained by
felodipine concentration-blood pressure response relationships. The elderly
should be particularly cautioned about concomitant grapefruit juice and
felodipine ingestion.
In the benzothiazepine calcium channel antagonists group, diltiazem has been
found to have an increased bioavailability on co administration of a single intake
of grapefruit juice. Inhibition of intestinal metabolism and/or P-glycoprotein efflux
transport was believed to be possibly responsible for this effect [46]. However in
contrast to this, another study showed the bioavailability to be unchanged with
grapefruit juice suggesting that factors other than biotransformation may be
contributing [47].
Compared with water, grapefruit juice increased the maximum concentration of
nisoldipine and reduced the time to reach maximum nisoldipine concentration
[48]. However, the effects of grapefruit pulp intake were smaller than those
produced by grapefruit juice intake, indicating that grapefruit pulp and juice have
different effects on the pharmacokinetics [49].
A clinical study was performed to see the duration of this interaction in the body.
Eight healthy volunteers were given grapefruit juice at 14, 38, 72 and 96 hours.
Compared with the control group, the maximum plasma concentration of
nisoldipine was significantly increased after grapefruit juice intake in at 0 and 14
hours, and the plasma concentration was significantly increased at each time till
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72 hours [50]. It is therefore necessary to withhold grapefruit juice for at least 3
days before administration of the drug to prevent grapefruit juice -nisoldipine
interaction.
Regarding verapamil, there are conflicting reports about its interaction with
grapefruit juice. One study showed an increase in its bioavailability at steady
state [51] while another showed no significant change in pharmacokinetics on a
single administration.
ACE-inhibitors like enalapril, captopril, lisinopril and ramipril have not shown any
interaction with grapefruit juice although such an interaction might be possible
with angiotensin II type 1 receptor antagonists like losartan and valsartan [18].
Thiazide diuretics and alph 1 adrenergic antagonists (doxazosin, terazosin,
prazosin) have also shown no interaction with grapefruit juice [18].
Amiodarone, an antiarrythmic, is metabolized by CYP3A to Ndesethylamiodarone (N-DEA), a metabolite more potent than the parent drug
[17]. On interaction with grapefruit juice, there has been shown to be complete
inhibition of N-DEA production [52] leading to an overall decrease in the
arrythmogenic side effects of amiodarone [17]. These results are in agreement
with in vitro data pointing to the involvement of CYP3A in the metabolism of
amiodarone and other Ca antagonists, suggesting that this interaction should be
taken into account when prescribing this antiarrhythmic drug. Similarly
grapefruit juice has been found to increase oral nimodipine bioavailability [53].
The same cannot be said of amlodipine, on which grapefruit juice has no
appreciable effect [54].
One of the possible active ingredients in commercial grapefruit juice is
Bergamottin, as mentioned before. This was determined after studying the
effects of the furanocoumarin derivative on nifedipine (NFP) pharmacokinetics,
suggesting that bergamottin in grapefruit might be the substance that elevates
the NFP plasma concentrations [55].
Further studies have also been done to determine if even unprocessed
grapefruit could cause drug interactions. It has been shown that unprocessed
grapefruit can cause a drug interaction with felodipine [56]. 6', 7'Dihydroxybergamottin and naringin were implicated to be more important in this
case because they are present in higher concentrations in grapefruit extracts.
Antimicrobials
With antivirals, authors concluded that concomitant administration of grapefruit
juice increases gastric pH and delays indinavir absorption but does not
uniformly affect the systemic bioavailability of indinavir in HIV-infected subjects
[57,58]. Similarly grapefruit juice has been shown clinically to not significantly
affect amprenavir pharmacokinetics [59]. It is suggested that this may be
because the primary metabolism of these drugs is not in the small intestine.
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On the other hand regarding saquinavir, it has been shown that grapefruit juice
increases the bioavailability of saquinavir without affecting its clearance,
suggesting that inhibition of intestinal CYP3A4 may contribute [60]. And since
the antiretroviral effect of saquinavir is dose-dependent, it has been suggested
that inhibition of CYP3A4 may represent a way to enhance its effectiveness
without increasing the dose.
Amongst anti malarials, grapefruit juice significantly increases the oral
bioavailability of artemether but does not prevent the time-dependent reduction
in bioavailability or elimination half-life, suggesting a role for intestinal CYP3A4
in the presystemic metabolism of artemether [61,62]. Similar results have also
been seen after a single oral dose of praziquantel with 250 ml of grapefruit juice
[63].
Quinine appears to be unaffected in its pharmacokinetics. Since quinine is a low
clearance drug with a relatively high oral bioavailability, and is primarily
metabolised by human liver CYP3A4, the lack of effect of grapefruit juice on
quinine pharmacokinetics again supports the view that the site of CYP inhibition
by grapefruit juice is mainly in the gut [17,64]. However for quinidine, grapefruit
juice reduces its total clearance and increases the elimination half-life by 19%
[65].
In antibiotics, administration of grapefruit juice increased the time to peak
concentration of clarithromycin but did not affect other pharmacokinetic
parameters [66] while in antiparasitics, albendazole showed an increase in
bioavailability upon administration of grapefruit juice [67].
Benzodiazepines and CNS drugs
A marked interaction between oral midazolam and grapefruit juice has been
found and the data is consistent again with a reduced first-pass metabolism of
midazolam, resulting in increased bioavailability of midazolam [68,69]. The
clinical importance of this is especially for patients with other causes for
increased midazolam bioavailability such as advanced age, cirrhosis of the liver,
and administration of other inhibitors of cytochrome P450. Thus, patients with
liver cirrhosis are more dependent on the intestine for metabolism of CYP3A4
substrates than subjects with normal liver function. Another important
implication of this interaction is in dentistry. Oral midazolam is a frequently used
sedative in pediatric dentistry. Although an oral form of midazolam is now
commercially available, some practitioners continue to use the IV midazolam as
an oral medication. If the injectible form of midazolam is administered orally, its
bitter taste requires the use of a flavoring agent like grapefruit juice. This results
in increased blood plasma levels of midazolam causing excessive levels of
sedation for the pediatric patient. Grapefruit juice therefore should be
contraindicated for use with oral midazolam especially in such patients [70].
Similar results have also been seen with triazolam [71].
One study however, did show that grapefruit juice did not have any particular
interaction with oral doses of 10 mg midazolam and 0.25 mg triazolam in
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healthy young subjects [72]. However, since more studies have determined
increases in midazolam and triazolam bioavailbility, grapefruit juice should be
administered with caution with these drugs. However, alprazolam remains
unaffected in pharmacokinetics or pharmacodynamics due to its high
bioavailability [73].
Among antipsychotics, clozapine remained unaffected after consumption of
regular-strength grapefruit juice, usually taken as 250 mL b.i.d., for 14 days [74].
One reason for this is that enzymes other than CYP3A4 also mediate clozapine
disposition. Haloperidol remains unaffected by grapefruit juice [75].
In anti convulsants, grapefruit juice increases the bioavailability of
carbamazepine [76] but does not affect the pharmacokinetics of phenytoin [77].
Grapefruit juice considerably increases plasma buspirone concentrations [78]
and also increases sertraline bioavailability [79]. Grapefruit juice therefore
should be contraindicated during administration of buspirone and sertraline.
Antihistamines and Serotonin Analogs
A number of studies have shown that a single glass of grapefruit juice produced
an individual-dependent, variable increase in the systemic bioavailability of
cisapride by inhibition of intestinal cytochrome P450 3A4 (CYP3A4) activity. [8082] It has therefore been recommended that concomitant use of high amounts
of grapefruit juice with cisapride should be avoided, at least in patients with risk
factors for cardiac arrhythmia.
The effect of grapefruit juice on racemic nitrendipine was also to increase its
bioavailability and it was found that it inhibits the stereoselective metabolism of
nitrendipine in humans [83].
Regarding terfenidine, the ingestion of grapefruit juice leads to its enhanced
systemic bioavailability [84,85]. This is especially important because the raised
levels of terfenidine can prolong the QT interval in the electrocardiogram
sufficiently to precipitate the ventricular arrhythmia of Torsade-des-pointes [86].
Incidentally, both terfenidine and cisapride have been globally withdrawn from
the market due to serious cardiac arrythmias precipitated by their interaction
with other drugs if simultaneously taken.
Statins and other cholesterol-lowering agents
Taking simvastatin first, the active ingredient bergamottin has been shown to
inhibit simvastatin (SV) metabolism and increase the serum concentrations of
simvastatin and its active metabolite simvastatin acid, and, to a lesser extent,
those of active and total HMG-CoA reductase inhibitors [87,88]. The probable
mechanism of this interaction was also the inhibition of CYP3A4-mediated firstpass metabolism of simvastatin by grapefruit juice in the small intestine.
Bergamottin (BG) and naringenin (NRG) could therefore be applied as markers
in food-drug interaction studies in order to adjust posology and the dose of
simvastatin should be accordingly reduced.
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Another study further found out that, when simvastatin is taken 24 hours after
ingestion of "high-dose" grapefruit juice, the effect on the concentration of
simvastatin is only about 10% of the effect observed during concomitant intake
of grapefruit juice and simvastatin. It was also shown that the interaction
potential of even high amounts of grapefruit juice with CYP3A4 substrates
dissipates within 3 to 7 days after ingestion of the last dose of grapefruit juice
[89].
The grapefruit juice effect has also been studied on lovastatin. Lovastatin and
its active metabolite, lovastatin acid had greatly increased serum concentrations
after grapefruit juice administration [90]. However, one other study has shown a
minimal effect of a glass of regular-strength grapefruit juice on plasma
concentration after a 40 mg evening dose of lovastatin [91].
Although grapefruit juice also increases the AUC of atorvastatin, the actual
increase in activity is fairly modest, possibly due to a simultaneous effect of
decreasing the AUC of active metabolites of atorvastatin [17]. Regardless,
grapefruit juice should not be concomitantly ingested with atorvastatin,
lovastatin or simvastatin. On the other hand, pravastatin, fluvastatin and
rosuvastatin are three statin drugs that have been shown not to interact with
grapefruit juice [18]. These may be useful alternatives in settings where there is
a concern regarding potential interaction with grapefruit juice.
Other cholesterol-lowering agents like nicotinic acid and common fibric acid
derivatives and bile acid sequestrants have shown no interaction, and therefore
may be safely used, with grapefruit juice [18].
Chemotherapeutics
In patients with autoimmune diseases, the effect of chronic grapefruit juice
administration on steady state blood concentrations of cyclosporine and
metabolites is an increase in both parent and metabolite profiles [92]. This
interaction was studied in renal transplant recipients. Administration of
cyclosporine with grapefruit juice compared with water induced a moderate,
butsignificant increase in the systemic exposure of cyclosporine [93,94]. Most of
these studies involving cyclosporine were done on adult patients. However, one
study was also done in the paediatric population. This study showed that
alterations in cyclosporine absorption and elimination only occur with concurrent
grapefruit juice ingestion when stable pediatric renal transplant patients are
taking the oral cyclosporine solution, but not the microemulsion formulation [95].
Regarding prednisolone and etoposide, grapefruit juice has been found to have
no significant effect on the metabolism of prednisolone [96] but in the case of
etoposide, it has been shown to decrease its bioavailability [97].
Conclusion
In light of the wide ranging effects of grapefruit juice on the pharmacokinetics of
various drugs, physicians need to be aware of these interactions and should
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make an attempt to warn and educate their patients regarding potential
consequences of concomitant ingestion of these two items. Patient-to-patient
variability should be kept in mind and elderly should be particularly warned
about these interactions since they are more prone to grapefruit juice-drug
interactions [17]. Physicians should also consider using these effects to their
own advantage in order to reduce the dosage requirements of certain drugs.
However, since further research is required into the mechanism of action of
grapefruit juice, it is still premature to recommend it as an adjunctive booster
with other drugs.
Abbreviations
AUC = area under the plasma concentration-time curve
CYP = cytochrome P -450
DEA = desethylamiodarone
DHB = dihydroxybergamottin
HMG – CoA = 3 – hydroxyl – 3 – methylglutaryl coenzyme A
NFP = nifedipine
OATP = organic anion-transporting polypeptides
Pgp = P – glycoprotein
RDA = Recommended daily allowance
SV = simvastatin
Competing interests
The author(s) declare that they have no competing interests.
Authors' contributions
Both authors contributed equally.
Acknowledgements
This was an independent review done by the authors.
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3A function after single doses of grapefruit juice. Clin Pharmacol Ther 2003,
74:121-9.
Soldner A, Christians U, Susuanto M, Wacher VJ, Silverman JA, Benet LZ
:Grapefruit juice activates P-glycoprotein-mediated drug transport. Pharm Res
1999, 16:478-485.
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model for drug interactions. Eur J Clin Invest 2003, 33(Suppl 2):10-6.
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Kuwano M, Ohtani H, Sawada Y :Effects of grapefruit juice and orange juice
components on P-glycoprotein- and MRP2-mediated drug efflux. Br J
Pharmacol 2004, 143:856-864.
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multidrug transporter P-glycoprotein in the human proximal tubular cell line HK2. Life Sci 2004, 76:293-302.
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Dresser GK, Bailey DG, Leake BF, Schwarz UI, Dawson PA, Freeman DJ, Kim
RB :Fruit juices inhibit organic anion transporting polypeptide-mediated drug
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2002, 71:11-20.
Fuhr U :Drug interactions with grapefruit juice. Extent, probable mechanism and
clinical relevance. Drug Saf 1998, 18:251-72.
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Lohezic-Le Devehat F, Marigny K, Doucet M, Javaudin L :Grapefruit juice and
drugs: a hazardous combination? Therapie 2000, 57:432-45.
Miniscalco A, Lundahl J, Regardh CG, Edgar B, Eriksson UG :Inhibition of
dihydropyridine metabolism in rat and human liver microsomes by flavanoids
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Ha Hr, Chen J, Leuenberger PM, Freiburghaus AU, Follath F :In vitro inhibition
of midazolam and quinidine metabolism by flavanoids. Eur J Clin Pharmacol
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Kakar SM, Paine MF, Stewart PW, Watkins PB :6'7'-Dihydroxybergamottin
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Fukuda K, Ohta T, Oshima Y, Ohashi N, Yoshikawa M, Yamazoe Y :Specific
CYP 3 A4 inhibitors in grapefruit juice: furocoumarin dimmers as components of
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humans. Clin Pharmacol Ther 1998, 64:248-256.
Bailey DG, Dresser GK, Bend JR :Bergamottin, lime juice, and red wine as
inhibitors of cytochrome P450 3A4 activity: comparison with grapefruit juice.
Clin Pharmacol Ther 2003, 73:529-37.
Lundahl J, Regardh CG, Edgar B, Johnsson G :Effects of grapefruit juice
ingestion – pharmacokinetics and haemodynamics of intravenously and orally
administered felodipine in healthy men. Eur J Clin Pharmacol 1997, 52:139-45.
Takanaga H, Ohnishi A, Matsuo H, Murakami H, Sata H, Kuroda K, Urae A,
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Dresser GK, Bailey DG, Carruthers SG :Grapefruit juice – felodipine interaction
in the elderly. Clin Pharmacol Ther 2000, 68:28-34.
Christensen H, Asberg A, Holmboe AB, Berg KJ :Coadministration of grapefruit
juice increases systemic exposure of diltiazem in healthy volunteers. Eur J Clin
Pharmacol 2002, 58:515-20.
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Bailey DG, Arnold JM, Strong HA, Munoz C, Spence JD :Effect of grapefruit
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Ohtani M, Kawabata S, Kariya S, Uchino K, Itou K, Kotaki H, Kasuyama K,
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Zasshi 2002, 122:323-9.
Takanaga H, Ohnishi A, Murakami H, Matsuo H, Higuchi S, Urae A, Irie S,
Furuie H, Matsukuma K, Kimura M, Kawano K, Orii Y, Tanaka T, Sawada Y
:Relationship between time after intake of grapefruit juice and the effect on
pharmacokinetics and pharmacodynamics of nisoldipine in healthy subjects.
Fuhr U, Muller-Peltzer H, Kern R, Lopez-Rojas P, Junemann M, Harder S, Staib
AH :Effects of grapefruit juice and smoking on verapamil concentrations in
steady state. Eur J Clin Pharmacol 2002, 58:45-53.
Libersa CC, Brique SA, Motte KB, Caron JF, Guedon-Moreau LM, Humbert L,
Vincent A, Devos P, Lhermitte MA :Dramatic inhibition of amiodarone
metabolism induced by grapefruit juice. Br J Clin Pharmacol 2000, 49:373-8.
Fuhr U, Maier-Bruggemann A, Blume H, Muck W, Unger S, Kuhlmann J,
Huschka C, Zaigler M, Rietbrock S, Staib AH :Grapefruit juice increases oral
nimodipine bioavailability. Int J Clin Pharmacol Ther 1998, 36:126-32.
Vincent J, Harris SI, Foulds G, Dogolo LC, Willavize S, Friedman HL :Lack of
effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of
amlodipine. Br J Clin Pharmacol 2000, 50:455-63.
Mohri K, Uesawa Y :Effects of furanocoumarin derivatives in grapefruit juice on
nifedipine pharmacokinetics in rats. Pharm Res 2001, 18:177-82.
Bailey DG, Dresser GK, Kreeft JH, Munoz C, Freeman DJ, Bend JR :Grapefruitfelodipine interaction: effect of unprocessed fruit and probable active
ingredients. Clin Pharmacol Ther 2000, 68:468-77.
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Shelton MJ, Wynn HE, Hewitt RG, DiFrancesco R :Effects of grapefruit juice on
pharmacokinetic exposure to indinavir in HIV-positive subjects. J Clin
Pharmacol 2001, 41:435-42.
Penzak SR, Acosta EP, Turner M, Edwards DJ, Hon YY, Desai HD, Jann MW
Effect of Seville orange juice and grapefruit juice on indinavir pharmacokinetics.
J Clin Pharmacol 2002, 42:1165-70.
Demarles D, Gillotin C, Bonaventure-Paci S, Vincent I, Fosse S, Taburet AM
:Single-dose pharmacokinetics of amprenavir coadministered with grapefruit
juice. Antimicrob Agents Chemother 2002, 46:1589-90.
Kupferschmidt HH, Fattinger KE, Ha HR, Follath F, Krahenbuhl S :Grapefruit
juice enhances the bioavailability of the HIV protease inhibitor saquinavir in
man. Br J Clin Pharmacol 1998, 45:355-9.
Van Agtmael MA, Gupta V, van der Graaf CA, van Boxtel CJ :The effect of
grapefruit juice on the time-dependent decline of artemether plasma levels in
healthy subjects. Clin Pharmacol Ther 1999, 66:408-14.
Van Agtmael MA, Gupta V, van der Wosten TH, Rutten JP, van Boxtel CJ
:Grapefruit juice increases the bioavailability of artemether. Eur J Clin
Pharmacol 1999, 55:405-10.
Castro N, Jung H, Medina R, Gonzalez-Esquivel D, Lopez M, Sotelo J
:Interaction between grapefruit juice and praziquantel in humans.
Antimicrob Agents Chemother 2002, 46:1614-6.
Ho PC, Chalcroft SC, Coville PF, Wanwimolruk S :Grapefruit juice has no effect
on quinine pharmacokinetics. Eur J Clin Pharmacol 1999, 55:393-8.
Damkier P, Hansen LL, Brosen K :Effect of diclofenac, disulfiram, itraconazole,
grapefruit juice and erythromycin on the pharmacokinetics of quinidine. Br J Clin
Pharmacol 1999, 48:829-38.
Cheng KL, Nafziger AN, Peloquin CA, Amsden GW :Effect of grapefruit juice on
clarithromycin pharmacokinetics. Antimicrob Agents Chemother 1998, 42:927-9.
Nagy J, Schipper HG, Koopmans RP, Butter JJ, Van Boxtel CJ, Kager PA
:Effect of grapefruit juice or cimetidine coadministration on albendazole
bioavailability. Am J Trop Med Hyg 2002, 66:260-3.
Andersen V, Pedersen N, Larsen NE, Sonne J, Larsen S :Intestinal first pass
metabolism of midazolam in liver cirrhosis – effect of grapefruit juice. Br J Clin
Pharmacol 2002, 54:120-4.
Kupferschmidt HH, Ha HR, Ziegler WH, Meier PJ, Krahenbuhl S :Interaction
between grapefruit juice and midazolam in humans. Clin Pharmacol Ther 1995,
58:20-8.
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Goho C :Oral midazolam-grapefruit juice drug interaction. Pediatr Dent 2001,
23:365-6.
Hukkinen SK, Varhe A, Olkkola KT, Neuvonen PJ :Plasma concentrations of
triazolam are increased by concomitant ingestion of grapefruit juice.
Vanakoski J, Mattila MJ, Seppala T :Grapefruit juice does not enhance the
effects of midazolam and triazolam in man. Eur J Clin Pharmacol 1996, 50:5018.
Yasui N, Kondo T, Furukori H, Kaneko S, Ohkubo T, Uno T, Osanai T,
Sugawara K, Otani K :Effects of repeated ingestion of grapefruit juice on the
single and multiple oral-dose pharmacokinetics and pharmacodynamics of
alprazolam. Psychopharmacology (Berl) 2000, 150:185-90.
Lane HY, Jann MW, Chang YC, Chiu CC, Huang MC, Lee SH, Chang WH
:Repeated ingestion of grapefruit juice does not alter clozapine's steady-state
plasma levels, effectiveness, and tolerability. J Clin Psychiatry 2001, 62:812-7.
Yasui N, Kondo T, Suzuki A, Otani K, Mihara K, Furukori H, Kaneko S, Inoue Y
:Lack of significant pharmacokinetic interaction between haloperidol and
grapefruit juice. Int Clin Psychopharmacol 1999, 14:113-8.
Garg SK, Kumar N, Bhargava VK, Prabhakar SK :Effect of grapefruit juice on
carbamazepine bioavailability in patients with epilepsy. Clin Pharmacol Ther
1998, 64:286-8.
Kumar N, Garg SK, Prabhakar S :Lack of pharmacokinetic interaction between
grapefruit juice and phenytoin in healthy male volunteers and epileptic patients.
Methods Find Exp Clin Pharmacol 1999, 21:629-32.
Lilja JJ, Kivisto KT, Backman JT, Lamberg TS, Neuvonen PJ :Grapefruit juice
substantially increases plasma concentrations of buspirone. Clin Pharmacol
Ther 1998, 64:655-60.
Lee AJ, Chan WK, Harralson AF, Buffum J, Bui BC :The effects of grapefruit
juice on sertraline metabolism: an in vitro and in vivo study. Clin Ther 1999,
21(11):1890-9.
Desta Z, Kivisto KT, Lilja JJ, Backman JT, Soukhova N, Neuvonen PJ,
Flockhart DA :Stereoselective pharmacokinetics of cisapride in healthy
volunteers and the effect of repeated administration of grapefruit juice. Br J Clin
Pharmacol 2001, 52:399-407.
Offman EM, Freeman DJ, Dresser GK, Munoz C, Bend JR, Bailey DG :Red
wine-cisapride interaction: comparison with grapefruit juice. Clin Pharmacol
Ther 2001, 70:17-23.
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Kivisto KT, Lilja JJ, Backman JT, Neuvonen PJ :Repeated consumption of
grapefruit juice considerably increases plasma concentrations of cisapride. Clin
Pharmacol Ther 1999, 66:448-53.
Soons PA, Vogels BA, Roosemalen MC, Schoemaker HC, Uchida E, Edgar B,
Lundahl J, Cohen AF, Breimer DD :Grapefruit juice and cimetidine inhibit
stereoselective metabolism of nitrendipine in humans. Clin Pharmacol Ther
1991, 50:394-403.
Van den Anker JN, de Wildt SN :Excessive terfenadine level due to drinking
grapefruit juice. Ned Tijdschr Geneeskd 1997, 141:1976-8.
Rau SE, Bend JR, Arnold MO, Tran LT, Spence JD, Bailey DG :Grapefruit juiceterfenadine single-dose interaction: magnitude, mechanism, and relevance.
Honig PK, Wortham DC, Lazarev A, Cantilena LR :Grapefruit juice alters the
systemic bioavailability and cardiac repolarization of terfenadine in poor
metabolizers of terfenadine. J Clin Pharmacol 1996, 36:345-51.
Le Goff-Klein N, Koffel JC, Jung L, Ubeaud G :In vitro inhibition of simvastatin
metabolism, a HMG-CoA reductase inhibitor in human and rat liver by
bergamottin, a component of grapefruit juice. Eur J Pharm Sci 2003, 18:31-5.
Lilja JJ, Kivisto KT, Neuvonen PJ :Grapefruit juice-simvastatin interaction: effect
on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA
reductase inhibitors. Clin Pharmacol Ther 1998, 64:477-83.
Lilja JJ, Kivisto KT, Neuvonen PJ :Duration of effect of grapefruit juice on the
pharmacokinetics of the CYP3A4 substrate simvastatin. Clin Pharmacol Ther
2000, 68:384-90.
Kantola T, Kivisto KT, Neuvonen PJ :Grapefruit juice greatly increases serum
concentrations of lovastatin and lovastatin acid. Clin Pharmacol Ther 1998,
63:397-402.
Rogers JD, Zhao J, Liu L, Amin RD, Gagliano KD, Porras AG, Blum RA, Wilson
MF, Stepanavage M, Vega JM :Grapefruit juice has minimal effects on plasma
concentrations of lovastatin-derived 3-hydroxy-3-methylglutaryl coenzyme A
reductase inhibitors. Clin Pharmacol Ther 1999, 66:358-66.
Ioannides-Demos LL, Christophidis N, Ryan P, Angelis P, Liolios L, McLean AJ
:Dosing implications of a clinical interaction between grapefruit juice and
cyclosporine and metabolite concentrations in patients with autoimmune
diseases. J Rheumatol 1997, 24:49-54.
Hermann M, Asberg A, Reubsaet JL, Sather S, Berg KJ, Christensen H :Intake
of grapefruit juice alters the metabolic pattern of cyclosporin A in renal
transplant recipients. Int J Clin Pharmacol Ther 2002, 40:451-6.
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Brunner LJ, Munar MY, Vallian J, Wolfson M, Stennett DJ, Meyer MM, Bennett
WM :Interaction between cyclosporine and grapefruit juice requires long-term
ingestion in stable renal transplant recipients. Pharmacotherapy 1998, 18:23-9.
Brunner LJ, Pai KS, Munar MY, Lande MB, Olyaei AJ, Mowry JA :Effect of
grapefruit juice on cyclosporin A pharmacokinetics in pediatric renal transplant
patients. Pediatr Transplant 2000, 4:313-21.
Hollander AA, van Rooij J, Lentjes GW, Arbouw F, van Bree JB, Schoemaker
RC, van Es LA, van der Woude FJ, Cohen AF :The effect of grapefruit juice on
cyclosporine and prednisone metabolism in transplant patients. Clin Pharmacol
Ther 1995, 57:318-24.
Reif S, Nicolson MC, Bisset D, Reid M, Kloft C, Jaehde U, McLeod HL :Effect of
grapefruit juice intake on etoposide bioavailability. Eur J Clin Pharmacol 2002,
58:491-4.
NOTAS DE INTERES
PRIMER ENCUENTRO CHILENO DE PREPARADOS HOMEOPATICOS
ELABORADOS EN FARMACIAS
Aspectos Técnicos y Reguladores
Santiago de Chile – República de Chile
El 8 de noviembre del año próximo pasado tuvo lugar en el Hotel Fundador de
la ciudad de Santiago, República de Chile, el Primer Encuentro Chileno de
Preparados Homeopáticos elaborados en Farmacias, organizado por el
Instituto de Salud Pública de dicho país, a través del Centro de Magistrales
y Oficinales, con la colaboración de un grupo de trabajo de especialistas.
Esta actividad fue impulsada por las directrices que señala la nueva política de
Medicamentos y a modo de complementar el nuevo Reglamento que regulará
este tipo de preparados, actualmente en revisión, contribuyendo así a la
actualización del los Químicos Farmacéuticos, disponiendo de reglas
farmacéuticas claras y precisas, conocidas por todos, que favorezcan a la
Autoridad Sanitaria a la introducción de Buenas Prácticas de Elaboración en
Farmacias y faciliten su cumplimiento.
Esta reunión se desarrolló con la presencia de un gran número de
profesionales que desarrollan su labor en los recetarios magistrales
homeopáticos, quienes tuvieron la posibilidad de realizarar preguntas e
intercambiar opiniones con los disertantes nacionales y los invitados
extranjeros, así como también con las Autoridades Sanitarias presentes.
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La Jornada comenzó con las palabras del Dr. Q. F. Eduardo Johnson Rojas,
Jefe del Departamento de Control Nacional del Instituto de Salud Pública de
Chile, quien dio la bienvenida a los asistentes e invitados, y luego siguieron las
disertaciones de acuerdo al programa establecido:
-Aplicación de Buenas Prácticas en las distintas etapas de elaboración de un
preparado homeopático, Dr. Q. F. José Paredes (Chile), Director de
Laboratorio Hoschtetter.
-La tintura madre y su preparación en el recetario de farmacia:
Recomendaciones técnicas, Dr. Q. F. Ernesto Mickman (Chile), docente de la
Universidad de Valparaíso.
-Estandarización de Normas de Preparación en Homeopatía, un paso
fundamental hacia la aplicación de Buenas Prácticas, Farm. Fernando
Estevez Castillo (Argentina), Asesor Científico de Laboratorios Dr. Madaus y
Farmacia+Natural, Director del Curso de Posgrado de Farmacia Homeopática
(Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires).
-Importancia de la calidad del agua, alcohol y envases en la elaboración de
preparados farmacéuticos homeopáticos, Q. F. Juan Riquelme (Chile), Q. F.
de Farmacia Homeopática Serey e Investigador en Esencias Florales Chilenas.
-Acción de ANVISA en la regulación de preparados homeopáticos elaborados
en Farmacias Brasileñas, Dra. Robelma De Oliveira (Brasil), Farmacéutica
especialista en regulación y vigilancia sanitaria, ANVISA, Brasil.
-Acciones del Instituto de Salud Pública de Chile frente a la nueva propuesta
reglamentaria aplicable a Recetarios de Farmacia, Dra. Q. F. Gladys Chicago
Cabrera (Chile), Jefe Sección Magistrales y Oficinales, Instituto de Salud
Pública de Chile.
De der. a izq. : Dra. Robelma De Oliveira (Brasil), Dra. Q. F. Gladys
Chicago Cabrera (Chile) y Farm. Fernando Estevez Castillo (Arg.)
Por último la Dra. Q. F. Gladys Chicago cerró el Encuentro agradeciendo la
participación de los asistentes e invitados, así como también alentó a todos los
Químicos Farmacéuticos para que participen enviando sus sugerencias y/o
recomendaciones con respecto al documento “Buenas Prácticas de
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Elaboración en Farmacias de Preparados Homeopáticos” presentado en dicha
oportunidad y publicado en la página web www.ispch.cl (entrar en la solapa
Control Nacional y luego en Productos Magistrales)
Disertantes y organizadores al terminar el Encuentro
Comentarios
En primer lugar quisiera agradecer al Instituto de Salud Pública de Chile
por la invitación recibida para participar como disertante en dicho
Encuentro, y especialmente a la Dra. Q. F. Gladys Chicago y la Q.F.
Alexandra Zuñiga, como a todo el grupo encargado de la organización,
por haber sido excelentes anfitriones, no sólo por haber estado pendientes
de hasta el más mínimo detalle relacionado a mi estadía en Chile, sino por la
calidez que demostraron hacia mi persona en cada momento que tuvieron la
posibilidad de compartir alguna actividad, sea profesional o social (Restaurant
con Show Folklórico de todas las regiones chilenas).
En segundo lugar quisiera felicitar al Instituto de Salud Pública de Chile
por la excelente organización de la actividad, la calidad de los disertantes
y lo que para mí es lo más importante, el objetivo del encuentro, ya que
desde la Autoridad Sanitaria se llama a los Químicos Farmacéuticos para
participar en la correcta implementación de las Buenas Prácticas de
Elaboración en Farmacias de Preparados Homeopáticos, a través del
conocimiento de la misma, su discusión y posterior envío de sugerencias y/o
propuestas, además de ofrecer la capacitación necesaria, lo cual los diferencia
de otras Agencias Sanitarias (especialmente de Latinoamérica) que primero
publican una regulación, aún sin tener conocimientos y sin participar a los
principales actores (en éste caso los farmacéuticos que trabajan en las
Farmacias Homeopáticas), y luego se pretende aplicar dicha legislación, lo cual
provoca verdaderos problemas en su implementación.
¡Felicitaciones por el éxito del Encuentro y por ser un ejemplo como
Autoridad Sanitaria en la implementación de Buenas Prácticas!
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XVIII CONGRESO FARMACEUTICO ARGENTINO
“La Profesión Farmacéutica en el Siglo XXI: un compromiso
con la salud comunitaria”
Ciudad de Mendoza - Argentina
Del 4 al 6 de Octubre del año pasado, se desarrolló en la Ciudad de Mendoza
el XVIII Congreso Farmacéutico Argentino organizado por la
Confederación Farmacéutica Argentina, con un temario muy amplio y la
presencia de gran cantidad de disertantes nacionales e internacionales, así
como también Autoridades Nacionales y Provinciales y legisladores tales como
el Diputado Dr. Juan Héctor Sylvestre Begnis (Presidente de la Comisión de
Acción Social y Salud Pública de la Honorable Cámara de Diputados de la
Nación) y la Diputada Farm. Fabiana Ríos, colega autora de un proyecto de
Ejercicio de la Actividad Farmacéutica y actual Gobernadora de la Provincia de
Tierra del Fuego, Antártica e Islas del Atlántico Sur.
Dentro del extenso temario, la Homeopatía tuvo su lugar, a través de una Mesa
cuyo título fue: “Formulaciones Homeopáticas: presente y futuro”,
coordinada por el Farm. Hugo Torres, y de la cual participaron la Farm.
Verónica Martínez (Comisión de Homeopatía del Colegio de Farmacéuticos de
la Provincia de Córdoba), la Farm. María Luz Font (Colegio de Farmacéuticos
de la Provincia de Buenos Aires) y el Farm. Fernando Estevez Castillo
(Director del Curso de Posgrado de “Farmacia Homeopática” de la Facultad de
Farmacia y Bioquímica de la Universidad de Buenos Aires)
El Farm. Fernando Estevez Castillo durante la presentación de su
ponencia.
La Farm. Verónica Martínez planteó la necesidad del Farmacéutico de
capacitarse en Homeopatía para poder responder a los pacientes que se
atienden por esta terapéutica, tanto desde el punto de vista técnico
(relacionado a la preparación) como en el asesoramiento necesario para
posibilitar el éxito del tratamiento (atención farmacéutica).
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La Farm. Verónica Martínez, participando como disertante
Continuando con las disertaciones, la Farm. María Luz Font, se encargó de
resaltar la gran cantidad de investigaciones que en la actualidad se están
haciendo utilizando medicamentos homeopáticos y el aumento en el uso del
mismo por parte de los pacientes, reflejado por un trabajo del Departamento de
Salud Mental del Hospital de Clínicas José de San Martín de la Facultad de
Medicina de la Universidad de Buenos Aires, donde el 55% de los pacientes
encuestados utilizó terapias alternativas, siendo las Homeopatía y las Hierbas
Medicinales las más usadas (40,8% y 37,6% respectivamente).
Por último el Farm. Fernando Estevez Castillo planteó la necesidad de que se
incorpore el medicamento homeopático a la Farmacopea Nacional Argentina y
que se legisle al respecto, ya que lamentablemente día a día se convierte en el
país más atrasado en Sudamérica en dicha materia a pesar del reconocimiento
internacional de los profesionales que la ejercen (Médicos, Farmacéuticos y
Veterinarios) que son invitados a dictar Cursos en todos los países del Mundo y
que en el caso de la Profesión Farmacéutica, se autorregulan a través de la
aplicación de Buenas Prácticas voluntarias, tomadas como referencia por otros
países para la redacción de normativas sobre el particular (por ej.: Colombia y
Chile).
(Los videos se pueden ver libremente en la página de la Confederación
Farmacéutica Argentina: www.cofa.org.ar)
HOMEOPATIA
PRIMERAS JORNADAS DEL COMAHUE
Neuquén - Argentina
El 20 y 21 de Octubre del año pasado, tuvo lugar en la Ciudad de Neuquén, las
Primeras Jornadas de Homeopatía del Comahue, organizadas por
Farmacia Farmacéuticos Asociados y auspiciado por la Escuela de
Medicina de la Universidad Nacional del Comahue (Res 427) y
Laboratorios Dr. Madaus.
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La actividad comenzó con las palabras de bienvenida del Farm. Federico
Arrigoni, Director Técnico de Farmacia Farmacéuticos Asociados,
empresa organizadora del evento y con una trayectoria destacada en dicha
ciudad,
en la preparación de medicamentos homeopáticos y
dermatocosméticos.
Luego, las Jornadas se desarrollaron en dos salones en paralelo, uno para
profesionales que se inician en Homeopatía y otro para Avanzados, para lo
cual fueron invitados como disertantes, el Dr. Ricardo Alvarez, médico
homeópata de destacada trayectoria en la enseñanza de la Medicina
Homeopática en nuestro país y el exterior, y el Farm. Fernando Estevez
Castillo, ambos docentes de la Sociedad Argentina de Investigación, Docencia
y Asistencia Homeopática (SAIDAH).
El Dr. Ricardo Alvarez explicando las características de Cicuta virosa
En el primer nivel, de Iniciación, se abordaron los siguientes temas:
introducción a la homeopatía: doctrina y práctica médica, e investigación en
homeopatía.
En el segundo nivel, de Avanzados, la temática expuesta fue: enfermedades de
la piel y de la boca; problemas relacionados a la práctica profesional
homeopática e Investigación en Homeopatía.
Por último, para ambos cursos y cerrando la última Jornada, el Dr. Alvarez se
refirió a Traumatismos.
Todas las actividades se destacaron por la activa participación de los
asistentes, quienes a través de preguntas, inquietudes o experiencias
personales, intercambiaron opiniones con los disertantes, lo cual enriqueció en
gran medida a las Primeras Jornadas de Homeopatía del Comahue.
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El Farm. Fernando Estevez Castillo durante su exposición relacionada
a la Investigación en Homeopatía.
Al finalizar, el Farm. Federico Arrigoni, agradeció la presencia de todos los
profesionales presentes, y prometió que en el futuro se organizarán más
actividades relacionadas a ésta temática.
Jornadas sobre el Ejercicio Profesional Farmacéutico
Facultad de Ciencias Exactas – Universidad Nacional de La Plata
El 27,28 y 29 de Noviembre del año pasado, la Facultad de Ciencias Exactas
de la Universidad Nacional de La Plata, organizó las Jornadas sobre el
Ejercicio Profesional Farmacéutico, teniendo en cuenta la incorporación de
las Practicas Hospitalarias Voluntarias, a partir del año 2000, las Prácticas
Farmacéuticas Obligatorias, a partir del año 2006 y las encuestas y charlas
realizadas en forma permanente con los alumnos, y cuyo objetivo principal es
promocionar diferentes variables de ejercicio profesional farmacéutico de
acuerdos con los avances en el conocimiento farmacéutico en consonancia con
los nuevos paradigmas y los avances tecnológicos existentes en nuestro país.
Los ejercicios profesionales abordados fueron: Farmacia Hospitalaria,
Farmacia Industrial y Farmacia Oficinal, para lo cual se invitaron a
profesionales de reconocida trayectoria para que expongan sobre sus
experiencias desarrolladas en nuestro país y el exterior.
Dentro de la temática de Farmacia Oficinal, se incluyó a la Homeopatía,
estando la disertación a cargo del Farm. Fernando Estevez Castillo, Director
Técnico de Farmacia+Natural y Director del Curso de Posgrado de Farmacia
Homeopática de la Facultad de Farmacia y Bioquímica de la Universidad de
Buenos Aires, quién informó a los alumnos sobre las características de
éste tipo de ejercicio profesional en Argentina y otros países, así como
también la necesidad de incorporar la enseñanza de la Farmacotecnia
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Homeopática en las Facultades de Farmacia de nuestro país, con el fin de
poder responder correctamente a una incumbencia que es propia del
profesional farmacéutico y avalada por legislación nacional (ley 17565) y
en algunas provincias por legislación local. Al finalizar los alumnos pudieron
hacer preguntas e intercambiar un diálogo fluído con el orador invitado.
¡Felicitaciones al Colega, Farm. Miguel Hermida, por organizar y coordinar
estas Jornadas, que sin lugar a dudas son muy importantes para los
alumnos de la carrera de Farmacia para poder conocer las distintas
modalidades del ejercicio profesional farmacéutico!
NOVEDADES
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línea DERMOMEGA®, especialmente formulada para pieles extra secas que
tienden a manifestar problemas dermatológicos. Todos sus activos
naturales, favorecen el restablecimiento del equilibrio lipídico de ácidos grasos
esenciales Omega-3 y Omega-6, componentes fundamentales de la barrera
cutánea, transportando los AGE (ácidos grasos esenciales) a las células de la
epidermis, aumentando la flexibilidad de las membranas celulares y
disminuyendo la pérdida transepidérmica de agua.
DERMOMEGA® es una línea dermatocósmetica a base de Salvia Chía y
Avena Sativa como componentes fundamentales, libre de parabenos,
fragancias sintéticas y derivados animales, además de ser hipoalergénico,
como toda la línea de productos OMS.
DERMOMEGA® cuenta hasta este momento con tres productos:
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Sativa. Con Manteca de Karité y Pantenol. Previene problemas dermatológicos en
pieles secas y ayuda a la pronta recuperación de la piel favoreciendo el crecimiento de
tejido nuevo y la producción de colágeno. Presentación: envase por 190 ml.
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Salvia Chía + Avena Sativa. Con manteca de Karité y
Acido Hialurónico. Fórmula especialmente desarrollada para las necesidades del rostro. Ofrece
una protección localizada en la zona más expuesta. Acelera y mejora la regeneración celular,
posibilitando un mayor nivel de hidratación y la reconstitución de las fibras que sostienen los
tejidos, incrementando su elasticidad y previniendo signos de envejecimiento. Presentación:
envase por 50 g.
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Aceite de baño para rostro y cuerpo: Salvia Chía +
Avena Sativa. Con tensioactivos ultrasuaves. Creado para facilitar la higiene de las
pieles atópicas, sensibles y frágiles. Su delicada fórmula favorece la higiene de todo
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tipo de piel. Limpia, suaviza, calma irritaciones y restaura la barrera de protección
natural. Presentación: envase por 250 ml.
DERMOMEGA®
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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]
“AMIGOS DE LO NATURAL”
LA HORA DE LA NATURALEZA LLEGO A LA RADIO!
Desde junio del año pasado, todos los miércoles de 15 a 16 horas, “AMIGOS
DE LO NATURAL”, programa radial de FM 94.7 (RADIO PALERMO),
conducido por la Dra. Elba Albertinazzi y el Farm. Fernando Estevez
Castillo, sale al aire, abordando temas tales como: Alimentación, Salud,
Ecología y Hábitos saludables, entre otros, tratados siempre por
profesionales y ofreciendo a los oyentes la posibilidad de hacer preguntas e
informarse en relación a la temática abordada.
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Fueron muchos los invitados que hasta el momento participaron en “AMIGOS
DE LO NATURAL”, destacando entre otros a: Dr. Jorge Alonso (médico
especialista en fitomedicina), Ing. Agr. Mónica Romero (especialista en
aromaterapia), Farm. Elena Ruiz Luque (Farmacéutica, Jefa de Producción de
Laboratorios Dr. Madaus) Dr. Horacio Galitelli (odontólogo naturista), Lic.
Susana Zurschmitten (Lic. en Nutrición), Dr. Guillermo Armesto (veterinario
homeópata), Dr. Ricardo Alvarez (médico infectologo y homeópata), Dr.
Alberto Gurni (Profesor Titular de Farmacobotánica de la Facultad de
Farmacia y Bioquímica (UBA), Dr. José Luis Feldman (médico pediatra y
homeópata), Dr. Horacio Alcorta (médico urólogo y naturista), Dr. Angel
Fusaro (médico legista), Dra. Ana Soerensen (médica naturista), Dra. Perla
Aizemberg (médica acupunturista), Dra. Cristina Solórzano (médica
ginecóloga, obstetra y homeopata), Dra. Raquel Ferrazano (médica
homeópata especialista en técnicas E.M.D.R.), Dra. Patricia Pilheu (médica
pediatra especialista en medicina biológica).
También fueron muchas las entrevistas realizadas, entre las cuales podemos
citar: Dr. Juan Velazco, Ministro de Medio Ambiente de la Ciudad
Autónoma de Buenos Aires (Gestión Telerman), por la verificación del
cumplimiento de la Ley de Contaminación Sonora de la Ciudad; Dr. Adolfo
Weimberg, médico especialista en Pneumonología e integrante de la
Asamblea Ambientalista de Gualeguaychú, respecto a los problemas de
salud que podrían aparecer con la instalación de la pastera Botnia en Fray
Bentos (Uruguay); Ing. Pedro Carlos Brunetto, Director del Programa de
Ensayos y Asistencia Técnica (INTI), respecto al informe publicado relativo a
la calidad de las distintas marcas de puré de tomate (en envase tetrabrick)
comercializados en la actualidad; Dr. Miguel Quintabani (abogado de la
Asociación vecinal Pro-Vicente López), por su denuncia referida a la
contaminación ambiental por cromo, proveniente de una empresa que afectaría
las napas freáticas de la zona; Ing. Jorge Luis Ferrari (Ingeniero en
Telecomunicaciones) de la Defensoría del Pueblo de la Ciudad Autónoma
de Buenos Aires, por la instalación de antenas de celulares y su relación con
ciertos problemas de salud en la población que vive en las adyacencias; Lic.
Guillermo Caille, Biólogo marino y coordinador de las áreas técnicas de la
Fundación Patagonia Natural, para informar sobre la contaminación
provocada por el derrame de petróleo en Caleta Córdoba (Comodoro
Rivadavia) y sus consecuencias sobre el medio ambiente y la fauna local.
Otros momentos destacados son las columnas ofrecidas por Liliana Caputo,
especialista en Cocina Natural, y René Larrea, cosmiatra de OMS,
Cósmética Natural”.
El espacio que la Naturaleza recuperó en la Radio
Homeonews
FM 94.7 RADIO PALERMO
MIÉRCOLES 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
CURSOS Y CONGRESOS
CURSOS
CURSOS A DISTANCIA
“FITOMEDICINA (2008)” Y “FITODERMATOLOGIA Y FITOESTÉTICA (2008)”
Asociación Argentina de Fitomedicina
¿En qué consisten los Cursos?
80
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Se trata de un Curso a Distancia consistente en el envío de 40 módulos (Fitomedicina) ó 16 módulos
(Fitodermatología y Fitoestética) en formato Acrobat PDF totalmente ilustrados, a la dirección mail del
cursista. Durante el mismo, se verá un repaso fisiopatológico orientado a resaltar los aspectos más
importantes que hacen al diagnóstico de las principales dolencias del ser humano, para luego avanzar en
el abordaje fitoterapéutico, indicándose los mecanismos de acción de las diferentes especies vegetales,
sus dosificaciones, diferencias con medicamentos de síntesis, y formulaciones respaldadas por las
principales farmacopeas e instituciones académicas mundiales.
El alumno podrá, a su vez, dirigir sus preguntas o dudas al director del curso, así como pedir
ampliaciones de temas, y solicitud de papers o trabajos científicos sobre las áreas de interés que
considere relevantes.
¿Cuándo iniciar?
El curso en Abril de 2008.
¿Cuándo y cómo es la evaluación?
La evaluación del alumno será realizada a partir de los seis meses de recibido todo el material. El examen
consiste en la redacción de una Tesis sobre un tema o planta en particular. El alumno propondrá tres
temas y la dirección del curso elegirá una de esas opciones para redactar la tesis. La misma podrá ser
remitida por medio de Correo certificado a la sede de Av. Santa Fe 3553 – 2° “8” Capital Federal (1425) –
República Argentina; o por documento en attach remitido al mail: [email protected]. Llegado
el momento de rendir el examen, el alumno solicitará las condiciones y el formato de presentación de la
tesis. A partir del envío de todo el material del curso, el alumno dispondrá de 12 meses para presentar su
tesis.
¿Quiénes pueden inscribirse?
Únicamente profesionales de la salud con matrícula universitaria, correspondientes a las siguientes
carreras: Medicina, Farmacia y Bioquímica, Odontología, Veterinaria, Nutrición, Biología. También son
aceptados los alumnos que cursen el último año de las respectivas carreras. En todos los casos, se
remitirá por mail, fax o de modo personal, el certificado o carnet habilitante.
Director del Curso
Dr. Jorge Rubén Alonso. Médico y Presidente de la Asociación Argentina de Fitomedicina.
Inversión en los Cursos
El valor total de inscripción (contado) es el siguiente:
1. Para la República Argentina: El Curso de Fitomedicina tiene un valor de $ 450, pudiéndose
también abonar en dos cuotas consecutivas de $ 250 cada una. En el primer caso, el alumno
recibe al momento los 40 módulos que son enviados a su servidor; en el segundo caso, recibirá
20 módulos el primer mes y los restantes 20 módulos el segundo mes.
Para el Curso de Fitodermatología y Fitoestética, el valor es de $ 370 (o dos cuotas
consecutivas de $ 200). Los módulos se envían a razón de uno cada 14 días encualquiera de las
dos formas de pago.
Los inscriptos podrán realizar su pago directamente en la sede de la AAF: Av. Santa Fe
3553 – 2° “8” Capital Federal, de lunes a viernes de 10 a 19 hs. También mediante
depósito en la caja de ahorros de Banco Galicia n° 4049945/5-032-2 (CBU 0070 0 320
3000 4049 9455 23 – CUIT 20-11702990-6) o por medio de envío de dinero por giro
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postal de Correo Argentino a nombre de Jorge Rubén Alonso, con domicilio Av. Santa Fe
3553 – 2° “8” Capital Federal.
2. Para los alumnos extranjeros de Latinoamérica, el valor del Curso de Fitomedicina es de
u$s 170 (dólares norteamericanos ciento setenta), y el Curso de Fitodermatología y
Fitoestética es de u$s 140, pudiéndose abonar por medio de la empresa Western Union o
Money Pocket o similares, a nombre de Jorge Rubén Alonso, con domicilio Av. Santa fe 3553 –
2° “8” Capital Federal – República Argentina. Los alumnos de Bolivia y Perú, podrán contar
además, con el sistema de pago a través de la empresa “Perú Services Courier” (consultar
método de pago en [email protected] o en [email protected] ).
En cualquiera de los casos, notificar su inscripción a: [email protected] y
[email protected] acompañando los siguientes datos: nombre y apellidos completos,
dirección completa incluyendo código postal, profesión y especialidad (si la hubiere), institución donde
trabaja, teléfono de contacto, edad, estado civil y mail o blog de contacto.
PROGRAMA OFICIAL CURSO DE FITOMEDICINA
MÓDULO 1: Presentación. Breve introducción a la Fitomedicina.
MÓDULO 2: Fitoterapia: Antecedentes Históricos (Egipto, China, India, Grecia, etc). Análisis histórico de las figuras
de Teofrasto, Hipócrates, Galeno, Dioscórides, Plinio, Avicena, Paracelso, etc, sus influencias, obras y legados. La
Medicina en la Edad Media, Renacentista, Contemporánea y actual.
MÓDULO 3: Evolución Histórica de la Fitoterapia en Latinoamérica. El chamanismo. Significado y consecuencias
del Descubrimiento de América. Conocimiento e introducción de nuevas especies. Culturas aborígenes de
Latinoamérica. Las obras herbolarias de la época.
MÓDULO 4: Botánica General. Origen de las Especies. Clasificación de Linneo. Fisiología vegetal. Clasificación
general de las plantas. Las plantas con flores y las plantas sin flores. Su importancia medicinal. Plantas de cultivo,
plantas alimenticias y plantas de uso industrial. Su importancia. Recolección de Plantas Medicinales. Conservación
(poscosecha).
MÓDULO 5: Control de calidad para materias primas y fitoterápicos. Concepto de calidad. Variabilidad de la misma.
Concepto de seguridad y eficacia. Pasos a seguir en el control de calidad. Análisis macroscópico y microscópico
(breves nociones).
MÓDULO 6: La importancia del Suelo y el Clima y sus influencias en la obtención de principios activos. Tipos de
suelo y especies mejor adaptadas a cada uno de ellos. Bosques tropicales, templados, praderas, herbazales y
desiertos. Flora adaptada a cada situación.
MÓDULO 7: Técnicas de comprobación de actividades biológicas. Ensayos in vitro, en animales y humanos. Tests
para antimicrobianos, antitumorales, hipoglucemiantes, antiinflamatorios, antiulcerosos gástricos, espasmolíticos,
antiasmáticos, hepatoprotectotres, antihipertensivos, antiagregantes, antitrombóticos, antiagregantes, sedantes,
afrodisíacos, etc. Estudios de toxicidad (aguda, subaguda, crónica, teratogenicidad, mutagenicidad).
MÓDULO 8: Farmacognosia general, Galénica. Formas de Identificación, Extracción, Preparación y Aislamiento de
los Principios Activos Vegetales. Noción de Droga vegetal, Fitomedicamento o Medicamento Fitoterápico.
Legislación vigente. Preparados a base de droga trozada (Tisanas). Infusión, Decocción, Maceración, Digestión.
Preparados a base de droga pulverizada (polvos para encapsular). Métodos extractivos: maceración, destilación.
Tratamiento con diferentes disolventes. Productos extractivos obtenidos por medio de diferentes disolventes:
tinturas, alcoholaturas, extractos secos, fluidos, blandos, nebulizados, glicólicos, crioextractos, jarabes, elixires,
pomadas, unguentos, etc.
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MÓDULO 9: Principios activos I. Rutas biosintéticas. Metabolitos primarios y secundarios. Hidratos de Carbono
(glúcidos en general), Lípidos (ácidos grasos polinsaturados, Omega), y Proteínas (papaína, bromelaína, etc).
MÓDULO 10: Principios activos II. Cardiotónicos (digitales y alternativas al digital: el espino albar), Saponinas
(escina de Castaño de Indias, Ginseng, Hiedra, Regaliz), Cumarinas (Meliloto), Fenoles (salicílicos y no salicílicos),
Compuestos cianogénicos (laurel cerezo, almendras amargas, etc).
MÓDULO 11: Principios activos III. Antraquinonas (cáscara sagrada, sen, aloe, ruibarbo, frángula, etc), Flavonoides
(Clasificación, su importancia medicinal, casos concretos: Ginkgo biloba, Vitis vinifera, etc), Taninos (sus
propiedades astringentes y utilidad en aparato digestivo y dermatología, casos concretos: Te, Roble,
Proantocianidinas, etc).
MÓDULO 12: Principios activos IV. Los aceites esenciales. Historia. Métodos de destilación y obtención.
Clasificación general de aceites esenciales según sus componentes. Ejemplos en cada caso. Propiedades
Medicinales. Toxicidad de los aceites esenciales. Bases de la Aromaterapia.
MÓDULO 13: Principios activos V. Alcaloides. Clasificación según el origen o ruta biosintética. Actividad en las
plantas. Potencialidades terapéuticas, toxicidad. Algunos ejemplos: atropina, alcaloides del cornezuelo de centeno,
efedrina, berberina, boldina, vincristina, vinblastina, sanguinarina, fisostigmina, etc.
MÓDULO 14: Principios activos VI. Quinonas (ubiquinonas, naftoquinonas). Importancia medicinal. El caso de la
Drosera. Las piretrinas (pelitre de Dalmacia), iridoides (harpagofito, llantén, valeriana), carotenoides (curcumina,
azafrán), lignanos (su presencia en hongos), vitaminas (hidrosolubles, liposolubles, vitaminoides), terpenos (usos
medicinales).
MÓDULO 15: Aparato Digestivo I. Dispepsias. Concepto. Eupéticos, antiflatulentos o carminativos (importancia de
los aceites esneciales de angélica, menta, coriandro, alcaravea, manzanilla, etc). Antiulcerosos gástricos. Concepto,
fisiopatología. Investigaciones clínicas y biológicas con Regaliz, Congorosa, Cayena, Sangre de Drago, etc.
Formulaciones útiles en cada caso.
MÓDULO 16: Aparato Digestivo II. Constipación : tipos, etiología. Plantas útiles. Laxantes de formadores de masa o
volumen, lubricantes, de contacto. Los casos de llantén, psyllums, fibras vegetales, aloe vera, frángula, sen,
ruibarbo, etc. Diferencias y utilidades. Diarrea: clasificación, tipos. Astringentes vegetales: plantas con taninos (te,
ratania, roble, etc). El caso de la Guayaba. Ensayos clínicos. Colon Irritable. Etiología, Sintomatología. Abordaje
fitoterápico: aceite de menta, los psyllum. Formulaciones útiles en cada caso.
MÓDULO 17: Aparato Digestivo III. Colagogos, coleréticos, hepatoprotectores. Los casos de: diente de león,
bardana, boldo, cardo mariano, cúrcuma, phyllantus, hongos medicinales, etc. EvidencIas científicas y casos clínicos
en hepatitis y cirrosis. Fórmulas apropiadas en cada caso.
MÓDULO 18: Aparato Respiratorio I. Generalidades (tipos de tos, expectoración y disnea). Principios activos útiles.
Plantas recomendadas en casos de resfríos, rinitis, sinusitis, faringitis. Ejemplos: equinácea, drosera. Formulaciones
útiles en cada caso.
MÓDULO 19: Aparato Respiratorio II. Antitusivos, expectorantes, antisépticos, antiasmáticos. Los ejemplos de:
eucalipto, hiedra, guaco, ambay, anacahuita, tomillo, unckaluabo, berros, etc. Formulaciones útiles en cada caso.
MÓDULO 20: Aparato Cardiovascular I. Cardiotónicos, antiarrítmicos. Fisiopatología de la Insuficiencia cardíaca
congestiva. Inotrópicos vegetales: digital, estrofanto, convalaria, adonis, etc. El caso del espino albar o cratageus.
Diferencias con el digital. Antiarrítmicos vegetales: retama, rauvolfia serpentina, árnica, etc. Formulaciones útiles en
cada caso.
MÓDULO 21: Aparato Cardiovascular II. Antihipertensivos – Antianginosos. Fisiopatología y clasificación de la
hipertensión arterial. Estudios experimentales y clínicos con ajo, crataegus o espino albar, rosa de Jamaica, etc. El
rol del espino albar en la angina de pecho. Formulaciones útiles.
MODULO 22: Aparato Cardiovascular III. Insuficiencia venosa crónica. Fisiopatología y clasificación de drogas
antivaricosas. Flebotónicos más importantes: castaño de Indias, meliloto, vid, ciprés, hiedra, centella asiática, rusco,
rutósidos provenientes del eucalipto, trigo sarraceno, sófora, etc). Hemorroides. Formulaciones útiles en cada caso.
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MÓDULO 23: Sistema Génitourinario I. Diuréticos. Nociones básicas de fisiología renal. Clasificación de los
agentes diuréticos. Diferencias en sus mecanismos de acción con drogas de síntesis. Principales diuréticos
vegetales: equisetos o colas de caballo, zarzaparrillas, diente de león, abedul, aceites esenciales, grama de las
boticas, etc. Fórmulas ütiles.
MÓDULO 24: Sistema Génitourinario II. Antisépticos urinarios. Drogas con aceites esenciales. Los casos de los
arándanos o mirtilos, gayuva o uva ursi, berberina, palo pichi, etc. Antiliátisicos urinarios. El caso del Phyllanthus
niruri (rompepiedras).
MÓDULO 25: Sistema Génitourinario III. Antiprostáticos. Fisiopatología de la Hipertrofia Benigna Prostática. Drogas
vegetales útiles: Serenoa repens (Sabal serrulata), ciruelo africano, Hipoxis rooperi, Ortiga mayor. Otros activos
útiles: polen, semillas de calabaza. Mecanismos de acción en todos los casos. Casos clínicos. Diferencias con el
tratameinto clásico convencional.
MÓDULO 26: Ginecología I. Menopausia y Climaterio. Síntomas asociados. Fitoestrógenos: clasificación y fuentes
alimenticias. Fitoestrógenos de la soja (daidzeína, genisteína, etc). Otros fitoestrógenos de importancia medicinal:
cimicífuga, trébol rojo, ñame, etc. Diferencias y virtudes frente a la terapia de reemplazo hormonal convencional.
Trabajos clínicos.
MÓDULO 27: Ginecología II. Sindrome premenstrual. Etiopatogenia, síntomas característicos. Abordaje fitoterápico
en base a aceite de onagra o prímula, agnocasto, etc. Fórmulas útiles.
MÓDULO 28: Aparato Locomotor I. Antiinflamatorios. Artrosis. Definición, clasificación. Etiopatogenia. Síntomas
característicos. Antiinflamatorios de origen vegetal: salicilatos (sauce, ulmaria, gaulteria, álamo, etc), iridoides
(harpagofito o garra de diablo), inhibidores de la COX-2 (el ejemplo de los curcuminoides de la Curcuma longa).
Formulaciones útiles.
MÓDULO 29: Aparato Locomotor II. Artritis Reumatoidea. Etiopatogenia. Sintomatología. Hallazgos radiológicos e
histológicos. Tratamiento convencional: sus peligros y limitaciones. Abordaje fitoterápico. Los casos de Oenothera
biennis (onagra) e Incienso (Boswellia serrata). Mecanismos de acción. Trabajos clínicos. Productos en el mercado
farmacéutico. Formulaciones.
MÓDULO 30: Sistema Nervioso I. Ansiedad e Hipnosedantes. Tipos de ansiedad. Fobias y ataques de pánico.
Teorías fisiopatológicas. Drogas vegetales útiles: valeriana, kava-kava, melisa, pasionaria (pasiflora), tilo, naranjo
amargo, amapola de California, etc. Diferencias respecto a drogas benzodiacepínicas sintéticas. Trabajos clínicos.
Dosis en cada caso.
MÓDULO 31: Sistema Nervioso II. Sindrome depresivo. Repaso fisiopatológico. Incidencia poblacional.
Sintomatología. Drogas vegetales útiles. El caso de la hierba de San Juan (Hipérico). Casos en los cuales está
indicado. Difererencias con los tratamientos convencionales. Ensayos clínicos.
MÓDULO 32: Sistema Nervioso III. Circulación cerebral. El caso del Ginkgo biloba. Actividades en casos de déficit
irrigatorio, pérdida de memoria, etc. Dosis en cada caso. Enfermedad de Alzheimer. Utilidad del Ginkgo bilob en los
déficits cognitivos de estos pacientes. El caso del galanto (Galanthus nivalis, planta de donde procede la
galantamina).
MÓDULO 33: Sistema Nervioso IV. Alucinógenos o drogas enteógenas. Su significado dentro de las cosmovisiones
indigenistas. Estudio sistemático de la hoja de coca, el Cannabis (marihuana), el peyote, la ayahuasca, la Salvia
divinorum, hongos alucinógenos, etc. Posibilidades terapéuticas. Debate legal.
MÓDULO 34: Metabolismo I. Diabetes. Clasificación, incidencia mundial, sintomatología. Nutrientes útiles (fibras,
ajo, cebolla, arándanos, etc). Plantas investigadas como hipoglucemiantes: higuera, momórdica, sarandí
(Phyllanthus sellowianus), pezuña de vaca, Gymnema sylvestre, eucalipto, estevia o yerba dulce, etc. Plantas útiles
en diabetes tipo I. Investigaciones. Ensayos clínicos y preclínicos.
MÓDULO 35: Metabolismo II. Obesidad. Tipos, clasificación. Recientes investigaciones en el área de la
etiopatogenia. Plantas útiles (garcinia, fucus, naranjo amargo, Hoodia sp, Phaseolus sp, etc). Su verdadera utilidad.
Dosis, formulaciones. Ensayos clínicos.
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MÓDULO 36: Metabolismo III. Hiperlipidemias. Clasificación. Ácidos grasos. Aceites Omega. Plantas investigadas:
ajo, mirra, berenjena, fitoesteroles, chía, etc. Trabajos preclínicos y clínicos.
MÓDULO 37: Fitodermatología – Fitocosmética. Breve reseña de las principales afecciones de la piel y anexos:
acné, psoriasis, vitiligo, alopecías, manchas cutáneas, etc. Abordajes terapéuticos en cada caso.
MÓDULO 38: Inmunología. Inmunomoduladores e inmunoestimulantes. Repaso fisiológico. Plantas destacadas:
equinácea, lapacho, ginseng coreano y siberiano, hongos medicinales (shiitake, maitake, etc).
MÓDULO 39: Antitumorales vegetales. Ciclo celular y modus operandi de las principales plantas estudiadas. Drogas
clásicas (vincristina, vinblastina, etopósido, taxol, tenopósido, Cataranthus sp, etc). Drogas vegetales en
experimentación: cúrcuma, azafrán, lapacho, graviola, uña de gato, celidonia, etc. Ensayos preclínicos y clínicos.
MÓDULO 40: Interacciones entre hierbas y medicamentos de síntesis. El rol del sistema citocromal p-450.
Principales interacciones de drogas sintéticas y ajo, cardo mariano, hipérico, ginseng, ginkgo, yohimbo, etc.
PROGRAMA CURSO A DISTANCIA DE
FITODERMATOLOGÍA Y FITOESTÉTICA (2008)
Módulo 1: Generalidades de la piel.
Histología. El estrato córneo: su importancia. El rol del manto hidrolipídico. Función de barerra y
emuntorial. Tipos de piel. Lesiones primarias, lesiones secundarias y lesiones especiales de piel.
Terminología empleada en fitodermatología: astringentes, emolientes, demulcentes, exfoliantes, etc.
Módulo 2: Envejecimiento Cutáneo - Arrugas.
Etiopatogenia. Papel de los radicales libres, la luz ultravioleta y la dieta. Abordaje integral en pieles
envejecidas. Protectores UV. Hidratantes. Revisión de abordajes convencionales: beneficios y perjuicios
del Botox, adenoxine, argilerina, DMAE, octamioxyl, myoxinal, etc. Actividad de los compuestos similBOTOX, algas marinas (Padina pavonica, etc), ácido beta-boswélico (Boswellia serrata), flavonoides
(quercetina, kaempferol, etc), alfa-hidroxiácidos frutales (ácidos glicólico, málico, láctico, tartárico, etc),
vitaminas, oligoelementos. ácido hialurónico (glucosaminoglicanos), beta-glucanos, ácido ursólico,
extractos de Phoenix dactylifera, Kigelia africana, derivados de proteínas del trigo, etc. Sustancias
antiage: raifortasa, antoxina, HPDR sodium, tiotaurina, etc. Plantas con propiedades anti-filtro solar.
Módulo 3: Fitonutrientes y productos naturales en piel y faneras.
Investigaciones científicas sobre ácido lipoico, ácido ursólico, avena (Avena sativum), manzanilla
(Matricaria recutita), aceites esenciales (albahaca, enebro, melaleuca, azahar, etc), ceramidas, ácido
glutámico, coenzima Q-10, silicio, carotenos, isoflavonas, metalotioneínas endógenas. Antiirritantes
cutáneos. Sustancias naturales emolientes, rubefascientes, astringentes y demulcentes.
Módulo 4: Alopecías.
Etiopatogenia. Causas hormonales y medicamentosas involucradas. Clasificación (difusa, androgénica,
traumática, etc). Revisión de los tratamientos medicamentosos convencionales (minoxidil, finasteride,
etc). Investigaciones científicas en base a suplementos dietarios, vitaminas, minerales y oligoelementos.
Plantas medicinales útiles: vasodilatadores (Ginkgo biloba, Capsicum sp), antiandrógenos (Sabal
serrulata, Urtica dioica). Rol del ácido ursólico. Formulaciones.
Módulo 5: Pediculosis
Etiología. Datos epidemiológicos. Abordaje convencional. Permetrina (riesgos, resistencia). Plantas
medicinales útiles: Quassia amara, Picrasma crenata, Melia azedarach (paraíso), Schinus molle (molle),
Allium sativum (ajo), aceites esenciales de cítricos, etc. Formulaciones.
Módulo 6: Caspa – Seborrea
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Etiopatogenia de la caspa y seborrea. Clasificación. Revisión del abordaje convencional (beneficios y
perjuicios de queratolíticos, citostáticos, antimicrobianos, brea de Hulla o Coaltar, etc). Plantas
medicinales útiles. El rol de los aceites esenciales. Formulaciones útiles.
Módulo 7: Despigmentantes cutáneos
Clasificación de hipercromías. Agentes blanqueadores de la piel. Inhibidores de la tirosinasa (fenoles,
hidroquinonas y derivados, catecoles, ácido ascórbico, ácido kójico, luteolina-7-glucósido, arbutina, etc).
Inactivadores y competidores de la tirosina (ácido azelaico, nicotinamida, etc). Fórmulas útiles.
Módulo 8: Cupersosis – Rosácea
Cuperosis: definición y etiopatogenia. Desencadenantes internos y externos. Productos cosméticos útiles.
Plantas medicinales más empleadas: Melilotus officinalis (meliloto), Glycyrrhiza glabra (regaliz), Ruscus
aculeatus (rusco), Aesculus hippocastanum (castaño de Indias), Matricaria recutita (manzanilla), etc.
Rosácea. Definición, etiopatogenia. Factores de riesgo. Sintomatología clínica. Plantas medicinales útiles.
Formulaciones.
Módulo 9: Acné
Etiopatogenia. Clínica. Clasificación. Tratamientos convencionales (beneficios y perjuicios). Tratamientos
tópicos y sistémicos. Plantas medicinales y principios activos útiles: alfa-hidroxiácidos frutales, bardana
(Arctium lappa), fenogreco (Trigonella foenum-graecum), pensamiento (Viola tricolor), Aloe (Aloe vera),
aceite de melaleuca (Melaleuca alternifolia), etc. Normas higiénico-dietéticas. El rol de las arcillas y el
ácido lipoico. Fórmulas útiles.
Módulo 10: Psoriasis
Etiopatogenia. Datos epidemiológicos. Clasificación. Localizaciones más frecuentes. Clínica. Abordaje
convencional (ventajas y desventajas de corticoides, metrotexato, ciclosporina, hidroxiurea, antimitóticos,
tratamientos P-UVA, etc). Investigaciones científicas en base a calaguala (Polypodium leucotomos),
Bardana (Arctium lappa), plantas con cumarinas, crisarobina, vitaminas A, D y derivados, etc. Fórmulas
útiles.
Módulo 11: Vitiligo
Definición. Datos epidemiológicos. Etiopatogenia. Localizaciones más frecuentes. Clínica. Tratamiento
convencional (ventajas y desventajas de maquillajes, tratamientos P-UVA, tratamiento cubano con
melagenina, etc ), Rol de las melaninas en la pigmentación cutánea.Plantas útiles. Investigaciones
cientificas con cumarinas, calaguala (Polypodium leucotomos), Citrus bergamota, etc.
Módulo 12: Dermatitis atópica
Definición. Etiopatogenia. Localizaciones más frecuentes. Manifestaciones clínicas. Factores agravantes.
Tratamiento convencional (ventajas y desventajas de corticoterapia, antihistamínicos, antibióticos de uso
tópico, etc). Plantas medicinales útiles. Investigaciones científicas en base a la calaguala (Polypodium
leucotomos), breas y queratolíticos vegetales (salicilatos), rusco (Ruscus aculeatus), aceite de onagra
(Oenothera biennis), manteca de karité, etc).
Módulo 13: Celulitis
Definición. Clasificación. Etiopatogenia. Unidades matriciales (intersticial, neurovegetativa,
microcirculatoria, lipídica). Factores incidentes y desencadenantes. Metabolismo de los lípidos y su rol en
la génesis de la celulitis. Tratamientos tópicos. Plantas medicinales útiles. Investigaciones científicas en
base a saponinas (de Hedra helix, Centella asiatica, beta-escina del castaño de Indias, ruscogenina del
rusco, etc), metilxantinas (cafeína, teofilina, etc), citroflavonoides, etc. Otras alternativas: Hibiscus
sabdariffa, Garcinia cambogia, Glycyrrhiza glabra, estimulantes de la lipasa, vitamina A, quimotripsina,
hialuronidasa, etc. Formulaciones útiles.
Módulo 14: Úlceras dérmicas – Escaras de decúbito - Quemaduras
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Etiopatogenia, localizaciones más frecuentes, clasificación y cuidados paliativos de úlceras de piel,
escaras de decúbito y quemaduras. Empleo de ácidos grasos hiperoxigenados. Plantas re-epitelizantes y
cicatrizantes: centella asiática, cola de caballo, caléndula, rosa mosqueta. Tipos de apósito. Limpieza de
las zonas afectadas.
Módulo 15: Miscelánea
La importancia de los excipientes en las formulaciones dermatológicas. Dermatitis de pañal, grietas de
pezón: abordaje fitoterápico. Preparados fitoterápicos para piernas cansadas, telangiectasias, verrugas,
condilomas, lepra, leishmaniasis, cicatrizaciones imperfectas, etc.
Módulo 16: Formulaciones
Fórmulación de preparados para la piel y las enfermedades más relevantes vistas durante el curso.
CURSO SUPERIOR DE MEDICINA NATURISTA PARA PROFESIONALES
AÑO 2008
El Curso Superior de Medicina Naturista tiene como objetivo formar a profesionales del área de la Salud
en:
- el uso de técnicas no agresivas para prevenir y retardar la aparición de las enfermedades a
través del equilibrio nutricional que nos proporciona una alimentación sana;
- la incorporación de diversos métodos terapéuticos que la naturaleza nos ha proporcionado para
recuperar la salud en forma suave y muy efectiva;
- individualizar por parte del profesional el tipo de terapéutica más útil y económica para el
paciente y para la sociedad.
La duración del Curso es de 2 años, divididos en 4 módulos teóricos y 8 clases prácticas de Cocina
Natural; las clases teóricas se dictarán una vez por semana, con una duración de 2 hs., se pide una
presencia del 75% de cada parte; al finalizar cada parte se realizará una evaluación. Las clases de
Cocina Natural se dictarán en horarios y fechas establecidas, que se notificarán antes del comienzo del
curso. Los alumnos participarán de ateneos mensuales en horarios a determinar. Al finalizar el Curso, con
todos los temas aprobados se tomará un examen final. Podrán inscribirse profesionales universitarios del
área de la Salud: médicos, nutricionistas, odontólogos, psicólogos, psicopedagogos, enfermeros,
farmacéuticos, biólogos, químicos, bioquímicos, etc. o alumnos de los últimos años de estas carreras.
Horarios:
Primer año: Lunes de 18 a 20 hs.- Inicia: lunes 9 de abril de 2008
Segundo año: Miércoles de 18 a 20 hs. – Inicia miércoles 31 de marzo de 2008
PROGRAMA 2008
Módulo 1: ALIMENTACIÓN NATURAL: Nutrición y biología celular – macro y micronutrientes desnutrición y desnutrición. Hidratos de carbono: absorción y metabolismo – características nutricionales
de los cereales – necesidades dietarias - beneficios para la salud.
Grasas saturadas y colesterol:
absorción y metabolismo – excreción – importancia de sus funciones nutricionales – necesidades
dietarias. Grasas insaturadas: omega 3-6 y 9 – importancia de su incorporación dietaria – funciones
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inmunológicas y constitutivas - grasas trans: problemas metabólicos surgidos a partir de su utilización
masiva. Proteínas: absorción y metabolismo – características nutricionales de las Proteínas – excreción aminoácidos esenciales – necesidades dietarias.
Vitaminas hidrosolubles: necesidad, funciones y
absorción, alimentos que las contienen, suplementación. Vitaminas liposolubles: necesidad, funciones y
absorción, alimentos que las contienen, suplementación.
Minerales y oligoelementos: necesidad,
funciones y absorción, alimentos que los contienen, suplementación – interacciones. Radicales libres del
oxígeno (ROL) – oxidación y antioxidantes – relación con el metabolismo. Método Kousmine para
protección del Sistema inmune. Nutracéuticos, prebióticos y probióticos. Alimentación sana, completa y
compatible.
Módulo 2: TERAPÉUTICA NUTRICIONAL y SUPLEMENTOS: Tratamiento nutricional de las
dislipidemias. Tratamiento nutricional de la DBT y la obesidad. Síndrome metabólico, X o del “caos
metabólico”. Estrés: aumento de las necesidades nutricionales. Alimentación en embarazo y lactancia.
Alimentación infantil: trastornos del aprendizaje y la conducta - ADD – hiperactividad. Alergias
alimenticias: dietas de eliminación. Alimentación en el adolescente: cómo cubrir las necesidades
nutricionales. Alimentación del deportista. Candidiasis. Acidosis alimentaria y su relación con SFC,
fibromialgias, fibroartrosis. Envejecimiento y restricción calórica.
Módulo 3: CLÍNICA MÉDICA NATURISTA: DISTINTAS TERAPÉUTICAS: Fitoterapia: Reseña Histórica
y Actualidad. Aspectos Botánicos de las plantas. Principios Activos: clasificación. Preparaciones
farmacéuticas de plantas Medicinales, recolección y conservación, preservación y control de calidad.
Preparaciones herbales de uso popular, especias, condimentos, germinados y brotes. Terapéuticas
naturales: agua, aire y luz: baños (métodos e indicaciones). Cataplasmas y compresas: uso de la arcilla.
Aromaterapia Tradicional Médica: las plantas aromáticas según el uso a través de los tiempos y su
relación con el reino vegetal - las tres reglas básicas que deben cumplir los aceites esenciales (AE).
Extracción de moléculas aromáticas: destilación - propiedades físicas y químicas de los AE - principios
activos (P.A): reconocimiento práctico de los aceites esenciales: colores, olores, densidad. Desarrollo de
cada uno de los aceites más importantes: vías de administración y aplicación terapéutica - precauciones,
toxicidad y posología. Principales propiedades: calmantes, sedantes, energizantes, estimulantes, mío
relajantes, anti-inflamatorios, anti-infecciosos, anti-histamínicos, inmunoreguladores, estimulantes
hormonales, antibióticos, antivirales, - antifúngicos, etc. - formulaciones específicas.
Psiconeuroendocrinología. Enfermedades de la mujer: modulación hormonal - alimentación y fitoterapia –
fitoestrógenos.
Módulo 4: MEDICINA NATURISTA: TRATAMIENTOS: Desintoxicación por el ayuno. Piel: función
desintoxicante y protectora, patologías más comunes: psoriasis, dermatitis; nutrientes de la piel: AGPI, vit.
Liposolubles. Intestino y aparato digestivo: gastritis, dispepsias, intolerancias alimentarias, constipación y
diarrea, hemorroides. Hígado: función depurativa y digestiva, bilis y digestión, protección hepática.
Páncreas: función endo y exócrina. Riñón: función depurativa y filtrado renal. HTA, artrosis y gota, nefritis
y nefrosis. Pullmón: función desintoxicante y respiración; sind. nasales y de senos, broncopatías,
enfisema.
Boca: prevención de caries por la alimentación, higiene bucal y dental con remedios
naturales. Encías y mucosa bucal: gingivitis, aftas, tipos de lengua. Sistema músculo-ósteoarticular:
ejercicio físico: ventajas y beneficios - tendinitis y bursitis, artrosis, dolores musculares. Termalismo:
indicaciones y beneficios, características de las distintas fuentes termales del país. Sistema nervioso
central: depresión, insomnio, memoria. Sistema inmunológico: prevención y tratamiento, alimentación,
fitoterapia.
Informes e inscripción:
Freire 2169 – Ciudad Autónoma de Buenos Aires
Tel.: (54-11) 4541-0207 Fax: (54-11) 4541-3707
E.mail: [email protected]
www.aamenat.org.ar
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CONGRESOS
VIII CURSO – 1º SIMPOSIO INTERNACIONAL DE INMUNONUTRICION
Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires
16 al 19 de Abril de 2008.
HORARIO: 8:30 a 19:00 hs.
DIRIGIDO A: Farmacéuticos. Farmacéutico, Bioquímico, Químico, Biólogo (con conocimientos
básicos de nutrición), Nutricionista-Dietista, Médico Clínico, Médico especialista en nutrición, Lic. en
Enfermería
TEMARIO: Alimentación a lo largo de la vida. Generalidades del sistema inmune. Nutrientes e
inmunidad: aminoácidos condicionalmente esenciales. Nucleótidos, ácidos grasos esenciales, ácido
oleico, alcohol, vitaminas, oligoelementos, antioxidantes prebióticos: mecanismos de inmunomodulación,
utilidad de los prebióticos en cáncer. Terapia nutricional en diferentes situaciones fisio-patológicas,
alergias alimentarias.
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 a Viernes
de 13 a 18 horas ó a [email protected] Tel.: (54-11) 4546-3566
www.inmunonutricion.com.ar
63º CONGRESO DE LA LIGA MEDICA HOMEOPATICA INTERNACIONAL
Ostende, Bélgica
20 al 25 de Mayo de 2008
La Homeopatía basada en la evidencia – Verificación de los síntomas homeopáticos
Para más información:
www.medicongress.com/homeopathy
Homeonews
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Nombre y Apellido:...........................................................................................................
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Domicilio particular:
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