Preclinical Studies with Digitalis Lanata:
A Bibliographic Review
Garcia Metz Soraya Katine1*, Carvalho Alex Aparecido de1, Antunes Da Silva Carina Fabricia1, Moraes Elton de1, Kaefer Fernanda1, Dias Maxwell Maximiano1, Lopes Ricardo Letycia2 and Pires Galan Vanessa2
1Pharmacy Student, Uniamérica, College Biopark, Brazil
2Guiding Professors Biopark Faculty, Brazil
Submission: June 02, 2022; Published: June 23, 2022
*Corresponding author: Garcia Metz Soraya Katine, Pharmacy Student, Uniamérica, College Biopark, Toledo, Brazil
How to cite this article:Garcia M S K, Carvalho A A d, Antunes D S C F, Moraes E d, Kaefer F, et al. Preclinical Studies with Digitalis Lanata: A
Bibliographic Review.Glob J Pharmaceu Sci. 2022; 9(5): 555772. DOI: 10.19080/GJPPS.2022.09.555772.
Popular knowledge has always served as a guide for scientific medical study. For over 200 years, the plant known as foxglove has contributed to the treatment of cardiac pathologies. This plant contains more than 80 cardenolide compounds, with digitalis glycosides being the main ones. Even with unquestionable benefits, its use has always been surrounded by care due to its high toxicity, even at low concentrations, requiring researchers to carry out preclinical studies to prove safe doses. In this sense, the present work aims to carry out a bibliographical review in order to compile works that present pre-clinical studies using the active principal digoxin, seeking to understand the procedures carried out by the researchers and the results obtained in their studies. This is a literature review article whose research was carried out in August 2021 and covered the areas of botany, pharmacognosy, biology and pharmaceutical sciences. Databases such as SciELO, PubMed and Academic Google were used, which provided more than 28,000 works. After passing the inclusion and exclusion criteria, four articles were selected, summarized, and compared. Of these, two studies presented the assessment of digoxin in cardiac pathologies, with results confirming the dosages and treatment times previously stipulated for the drug. The other two selected works present new perspectives for the use of drugs already available on the market containing digoxin for the treatment of visceral leishmaniasis and for fighting inflammation in the liver and cancer, respectively. Thus, the highlighted works demonstrate that the use of animal models to carry out tests with digoxin helps in studies to prove the drug’s safety and efficacy in cardiac pathologies. On the other hand, they also significantly contribute to the medical profession, patients, and the pharmaceutical industry by increasing the possibility of treating other already known pathologies, with a focus on improving existing treatments.
Keywords: Digoxin; Digitalis glycosides; Heart diseases; Pharmaceutical industry; Drug safety
One of the oldest traditions of humanity is the use of some plants to cure and prevent diseases Veiga Junior et al. . This popular knowledge, over time, is becoming study material as a valuable source of active natural components, which can generate the discovery of new drug molecules Argenta et al. . In the Renaissance period, there was an increase in interest in medicinal plants, with publications in the English language, which perpetuated for approximately 400 years. The reports present prescriptions made by many doctors, relating the plants used and including the species Digitalis purpurea Costa . Digitalis is among the most important plant drugs for the treatment of congestive heart failure. The class encompasses Digitalis purpurea L. (digitoxin) and Digitalis lanata E. (digitoxin, digoxin, lanatoside C and deacetyl-lanatoside C=deslanoside) Simões . At the beginning of its medicinal use, the species used for the extraction of digoxin was D. purpurea, but due to its high toxicity even at
low concentrations, the substance began to be extracted from D. lanata which is less toxic and promotes the same therapeutic effects Silva . D lanata is responsible for 90% of the production of cardioactive heterosides Simões . The plant D. lanata is popularly known as yellow-flowered digitalis and belongs to the Scrophulariaceae family. It is found in the Mediterranean basin and central Europe and comprises about 20 species Bruneton . The D. lanata plant has more than 80 cardenolide compounds, with digitalis glycosides being the main constituents [7,8]. Chemically, digoxin extracted from the plant Deladeira - D. Lanata, has its molecule composed of a sugar and a cardenolide, molecular formula C41 H64 O14 and molecular mass 780.95 g/mol Edwards . The digoxin molecule can be seen in Figure 1.
Andrade  describes that the extraction of primary cardiotonic glycosides is performed with fresh plants or by submitting the plants to an enzymatic inactivation process so that the sugar molecules that integrate them are conserved. For
the elimination of secondary cardiotonic glycosides, the drying
process is performed. According to the author, a hydroalcoholic
solution, such as 50% or 70% ethanol at high temperatures,
should be used. Then, the macromolecules of the extract must be
precipitated. For this, lead acetate can be used and separated using
a medium polarity solvent, such as chloroform. Finally, with the
acidification of the hydroalcoholic solution, hydrolysis is carried
out, thus obtaining only the aglycones of the compound. In this
context, desiccated leaves are used, which may contain a content
greater than 1% of cardiotonic heterosides, mainly lanatosides
A, B, C and D. Bruneton . D. lanata, currently commercialized
in Brazil, is the industrial source of digoxin and lanatosides C.
Both are used in the treatment of congestive heart failure. The
composition of digoxin as a raw material for the manufacture of
medicines is characterized by odorless white crystals that are
insoluble in water or ether, slightly soluble in alcohol and freely
soluble in pyridine. As drugs, digoxin is supplied as tablets in
dosages of 125 μg (0.125 mg) or 250 μg (0.25 mg), as capsules in
dosages of 100 μg (0.1 mg) or 200 μg (0.2 mg), as elixir at 50 μg/
mL (0.05 mg/mL), or for intravenous injection as a sterile solution
in ampoules of 2 mL at 250 μg (0.25 mg) per mL or 100 μg (0.1 mg)
per mL Edwards . In the body, digoxin acts in several ways, and
the action of cardenolides is based on the inhibition of Na+/K+-
ATPase ions, involved in the sodium/potassium pump mechanism
dependent on these ions and their relationship with myocardial
cells [9,11]. Digitalis glycosides produce positive ionotropic
effects and are often used for the treatment of heart failure.
Increased intracellular calcium (Ca++) causes ionotropic action
forming the basis for arrhythmias related to digitalis intoxication
Horto Didático . In addition, it also acts on the sympathetic
nerve promoting an increase in vagal tone (vagomimetic effect),
thus contributing to the treatment of heart failure. These results
are also beneficial for the control of supraventricular arrhythmias
Edwards . In general, the plant is used in cardiac treatment,
but it has also had activity cited as anti-inflammatory, antitumor,
antioxidant, anti-aging, among others [8,12,13]. Due to the diverse
possibilities of treatment, before the introduction of a drug on the
market, it is necessary to conduct pre-clinical studies involving
animals in order to obtain data that demonstrate the effects,
limits and safety conditions of the drug being studied Brasil .
In this context, the present work aims to carry out a literature
review in order to compile studies performed with digoxin in
animals, seeking to understand the procedures performed by the
researchers and the results obtained in their studies.
This is a literature review, carried out in August 2021. The
search for theoretical material took place in the SciELO, PubMed
and Google Scholar databases, using the descriptors: “digitalis
lanata”, “digoxina”, “digoxina ratos”. From this search, more
than 28,000 results were found, which were submitted to the
selection criteria. Research was also carried out on websites of
Universities and scientific research institutions, in addition to
books and journals in the field of botany and pharmacognosy. As
inclusion criteria, studies were selected that presented studies
with cardioactive heterosides and pre-clinical trials involving
the drug digoxin and animals, both for cardiac pathologies and
investigations into new treatments. Then, as exclusion criteria,
studies that presented association with other drugs and did
not detail the concentrations of digoxin used were chosen. The
selected works were read in full, summarized and their findings
detailed in the present work.
Digoxin is the best-known molecule and has been used for
more than two centuries in the treatment of heart failure (HF).
However, its effectiveness has been questioned due to its short
therapeutic margin Botelho . In order to present the main data
of each selected work, Table 1 was prepared with the summary of
each experience. Source: Self elaboration (2021).
Neves et al.  grouped the animals into groups of four
individuals, having conducted their study as follows:
a) Control (C): application of saline solution
b) Trained (T): application of saline solution; physical
adaptation for 7 days on a treadmill with a speed of 10 m/min
lasting 15 minutes per day. Then, they underwent maximum
effort, where saline solution was reapplied 30 and 60 days after
the beginning of the training.
c) Digoxin (DIGO): administration of 30.0 μg.kg-1 of
digoxin once a day for 75 days
d) Trained plus digoxin (TDIGO): administration of 30.0
μg.kg-1 of digoxin once a day for 75 days, physical adaptation for
7 days on a treadmill with a speed of 10 m/min lasting 15 minutes
per day. Then, they underwent maximal effort, where digoxin was
reapplied 30 and 60 days after the start of training.
The proposed training rules aimed to enable actions to benefit
cardiac function and hypertrophy. As a conclusion of the study
Neves et al.  emphasize that even using doses above those
recommended, the levels of creatinine, TGO, TGP and total proteins
remained stable in the animals. They also cite that digoxin alone
or associated with IAT has not been shown to harm the kidneys
or liver of the animals but favored cardiomyocyte hypertrophy in
sedentary and/or trained rats. On the other hand, Botelho 
separated the animals into three groups with four rats and carried
out their study for 21 days, applying the drugs subcutaneously.
a) Group control: NaCl 0,9%.
b) Group DIG 50: administration of 50 μg/kg of digoxin.
c) Group DIG 100: application of 100 μg/kg of digoxin.
Clinical evaluation was performed daily by the author
based on the normal behavior of the species. Sensitivity at the
application site and possible signs of heart failure were evaluated.
The treatment was conducted with digoxin, and in the same
period three animals from each group received heparin. The
results of the work of Botelho  pointed out that the group
of rats that received a higher dose of digoxin, after the seventh
application, showed a small sensitivity at the application site.
However, the researchers pointed out that there were no clinical
changes in the rats and no symptoms of adverse reactions due to
intoxication were observed. There was also no arrhythmia during
the three weeks of study, and it can be concluded that the doses
administered, and the time used were sufficient to induce cardiac
alterations without altering the autonomic modulation in the
Both studies were initiated with the purpose of evaluating
cardiac pathologies, having as results the confirmation of the
dosages and treatment times previously stipulated for the drug.
In contrast, Freitas  sought improvements in the treatment of
visceral leishmaniasis since the drugs used in the treatment are
highly toxic, painful to administer and/or therapeutic failure,
in addition to their high cost. The animals were infected by the
subcutaneous route by L. Infantum and after 60 days the treatment
was started. Each drug was applied once a day every other day for
10 days. The author concluded that Digitoxigenin and β-acetyldigitoxin
showed selective action against L. infantum both in
their free form and when incorporated into a delivery system
composed of micelles, thus demonstrating that they are effective
in the treatment of visceral leishmaniasis. The study published by
Teijeiro et al. , carried out monitoring of obese mice, where at
first the initial objective was to fight inflammation in the liver and
check possible treatments for cancer, but they observed a loss of
up to 40% of weight in them during the study period, of 8 months.
These overweight mice were treated with digoxin and, even while
maintaining a high-fat diet, were cured of metabolic disorders
often linked to obesity, a major inflammatory disease. These
authors concluded that digoxin could be used for the treatment
of obesity, for a short period, until they managed to stabilize the
weight reduction and, later, adhere to a healthier diet. In addition,
they emphasize that their findings proved that Digoxin improves
insulin sensitivity and/or hypercholesterolemia, contributing
to the aforementioned treatment. Works such as those carried
out by [7,17] present new perspectives for the use of drugs
already available on the market, contributing significantly to
the pharmaceutical industry  and patients by increasing the
possibility of treatment for already known pathologies.
From the bibliographic survey it was possible to perceive
the importance of carrying out pre-clinical studies with the use
of animals. This type of study contributes both to confirm the
recommended dosage, duration of treatment and drug safety,
as well as to evaluate the use of the drug in new treatments,
since animal models represent the real capacity of physiological
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