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Clay Minerals, (2011) 46, 295309

A critical reconsideration of biomedical


and veterinary applications of natural
zeolites
C. COLELLA*
Dipartimento dIngegneria dei Materiali e della Produzione, Universita` Federico II, Piazzale V. Tecchio 80, 80125
Napoli, Italy

(Received 17 December 2010; revised 11 March 2011; Editor: George Christidis)

AB ST R ACT : Natural zeolites have traditionally been used as supplements in animal nutrition with
positive effects in terms of either faster growth or reduced incidence of diseases and death. The
discovery that natural zeolites may act as drugs or coadjutants in pharmaceutical preparations has
greatly enlarged the field of their applications in many sectors of biology and medicine, opening
unexpected horizons for either basic or applied research. This review updates the state of the art of
research in this sector, focusing on clinoptilolite-rich materials, with two main purposes: (1) trying to
rationalize this subject, which is extremely variable and heterogeneous, and (2) raising doubts about
unsuitable uses of natural zeolites in the light of their known properties and expected behaviour.

KEYWORDS: natural zeolites, clinoptilolite, animal feeding, veterinary science, biomedicine, pharmacology,
health care.
The first experiments on surface-active materials
for biomedical uses concerned animal nutrition.
Several publications, from the early 1950s, reported
that dietary clay supplements (bentonite and
kaolin), used as binding and lubricating agents in
the production of pelleted feeds for poultry, resulted
in evident improvements in animals performance.
Later studies demonstrated that improvements did
not depend on the way feed was administered, but
just on the presence of clay, resulting in a
slowdown of feed passage rate through the
intestinal tract and therefore in better nutrient
assimilation and calorific efficiency (Quisenberry,
1968).
The use of natural zeolites, namely clinoptiloliteand mordenite-rich tuffs, for animal nutrition began
in Japan in the mid 1960s in imitation of the

* E-mail: carmine.colella@unina.it
DOI: 10.1180/claymin.2011.046.2.295

successful use of clay. Tests were initially made


with swine and poultry, but they were then
extended to other animals. The results were, in
general, good to excellent, as faster growth was
observed with consequent increase of productivity
(Torii, 1974, 1978; Mumpton, 1978).
Actually, natural zeolite (or clay) administration
led also to a reduced incidence of diseases and
death in livestock. It was therefore suspected that
these minerals might have also a prophylactic
effect. In fact, suitable experiments, carried out
during the 1970s by Japanese scientists on calves
and pigs, demonstrated a statistically significant
reduction of some diseases, in particular diarrhoea,
in animals treated with several percent of
clinoptilolite-rich tuff (indicated from now
onwards as CPT), in comparison to control
animals. Moreover, CPT proved to be effective
even on livestock (piglets) already suffering from
severe diarrhoea, which means that zeolite administration had also a therapeutic effect (Papaioannou
et al., 2005).

# 2011 The Mineralogical Society

296

C. Colella

The possibility of direct biological activity of


zeolites, in particular CPT, stimulated research on
their bio-medical properties. This resulted in the
publication of some hundreds of papers on this
subject over the last thirty years. Research was
initially directed to improve zeolite effectiveness in
animal feeding and husbandry (Pond & Mumpton,
1984) but was later extended significantly, shifting
gradually towards biology and medicine (Pavelic &
Hadzija, 2003). This situation was also favoured by
the birth and rapid growth of medicine on a small
scale, i.e. that particular branch of the medical
science which is based on the interaction of
molecules of biological significance with nanostructures (Kralj & Pavelic, 2003).
At present, literature reports cover a large
number of proposed (or supposed) zeolite applications, spread over many areas of biology and
medicine. Analyses are made difficult by their
fragmentary character and the presence of investigations based on empiricism, mostly because they
have been carried out by scientists who are not
familiar with the zeolite materials and their relevant
properties. However, a non-exhaustive list of
functions, in which zeolites, in general, have been
claimed to have a positive effect, includes: (1) antibacterial agents, (2) anti-diarrhoeal agents, (3) antitumour adjuvants, (4) biosensors, (5) detoxicants
and decontaminants, and (6) vaccine adjuvants. In
addition, CPT (and a few other zeolites) have been
proved active in (7) bone formation, (8) contrast in
magnetic resonance, (9) delayed drug delivery, (10)
diabetes mellitus, (11) enzyme mimetics, (12)
external application, and (13) haemodialysis (Kralj
& Pavelic, 2003).
Many thorough reviews have been published on
most of the aforementioned topics in recent years,
specifically on natural zeolites, either as regards
animal feeding, see, e.g. Pond (1995), Bartko et al.
(1995), Papaioannou et al. (2005), Colella (2011),
or concerning applications in medicine (Pavelic et
al., 2001a; Pavelic & Hadzija, 2003). This review
intends, however, to critically reconsider this
subject, starting from a different standpoint. In
order to avoid giving much consideration to
preliminary, explorative or premature investigations, the analysis of the specific literature will be
strictly connected to the zeolite properties, which
are supposed to be responsible for the successful
claimed applications. In addition, the search will be
limited to clinoptilolite-rich materials.
Clinoptilolite, a siliceous form of heulandite

(Armbruster, 2001; Baerlocher et al., 2007),


formally (Na,K)6[Al6Si30O72]nH2O, is, in fact, the
only sedimentary zeolite with worldwide distribution and therefore the only one for which a
comparative analysis of the available data is
possible. Other natural zeolites, which may be of
interest in biomedical applications, are chabazite,
mordenite and phillipsite. Literature data on these
zeolites are sporadic and fragmentary and can be
found mainly in review papers (e.g. Pond, 1995;
Papaioannou et al., 2005; Andronikashvili et al.,
2009) and online reports (Waiora, 2011; Leu,
2011).

ZEOLITE PROPERTIES USEFUL


FOR BIOMEDICAL APPLICATIONS
The use of natural zeolites in biomedicine and
veterinary science is affected by the presence of
impurities and coexisting zeolitic phases. Such
materials may have, therefore, different compositions, also within the same deposit, and variable
chemistry (Colella, 2002). That is why, apart from a
limited number of cases of local significance,
general applications of natural zeolites should be
subjected to standardization rules concerning either
the quality level or the processing procedures.
Recommendations should be given for careful
purification and suitable conditioning before use.
Depending on structure, mineralogical and
petrographical features and chemistry, natural
zeolites exhibit a series of properties which are
directly or indirectly relevant to their applications
in medicine. The main zeolite properties involved
in reactions and/or processes of biochemical
relevance are: (i) alkaline nature, (ii) cation
exchange, (iii) physical sorption and (iv) external
surface activity.

Alkaline nature
Depending on their structure and chemistry, the
zeolites are subjected to hydrolysis, which can be
regarded also as a cation exchange reaction with the
hydronium ion, giving rise to alkaline pHs,
according to the following main equilibrium:
MZ + n H2O > HnZ + Mn+ + n OH
n+

(1)

where M is a generic extraframework cation,


mainly Na+, K+, Ca2+ and Mg2+ in the zeolite
structure. The pH level depends also on other
simultaneous equilibria, such as possible hydrolysis

Biomedical and veterinary applications of zeolites

of Mn+ with formation of hydroxy complexes, e.g.


Ca(OH)+, possible precipitation of Mn+ as hydroxide, e.g. Mg(OH)2, dissolution of MZ, interactions
of the above ionic species with other electrolytes
present in solution, presence of impurities in the
original material, etc.
Clinoptilolite, in particular, undergoes rapid
hydrolysis, attaining equilibrium in a few minutes.
In a test, in which 2.5 g of a Croatian CPT,
containing roughly 50% clinoptilolite, was mixed
with 250 ml of bidistilled water, the pH reached a
value of 9 at ~10 min (Peric et al., 1999). Similar
results were obtained with a Cuban CPT, containing
roughly 70% zeolite (clinoptilolite + mordenite),
when it was added to water at a ratio of 100 mg per
200 ml H2O and a temperature range between 32
and 42C (Rivera et al., 2000).
Having an alkaline nature, zeolites are unstable in
an acid environment. Zeolite breakdown, due to
long exposure to low pHs, is usually preceded by
partial replacement of indigenous cations with
hydronium ions and then by dealumination.
Resistance to acids strongly depends on the Si/Al
ratio, increasing with increasing Si content. The
high-silica clinoptilolite is particularly acid resistant: it resists acid attack for several months at pH
even lower than zero (Dyer, 1988).
Because of their siliceous nature, zeolites are
unstable also in basic environments. OH favours
dissolution, yielding silicate and aluminate species,
possible precipitation of gels and, lastly, recrystallization of more stable tectosilicates (Dyer, 1988).

Cation exchange
Zeolites are the most important inorganic cation
exchangers. Ion exchange arises from the presence
of extraframework cations located in the regular
array of channels and cages of the rigid anionic
framework. Cations are bound to the lattice and to
water molecules, which normally fill the zeolite
micropores. When a zeolite is put into contact with
an electrolyte solution, the extraframework cations
are removed from their sites and replaced by other
cations from the solution, according to the
following equilibrium reaction:
AnZ + m Bn+(s) > BmZ + n Am+(s)

(2)

where Am+ and Bn+ are two cations; Z and s stand


for zeolite and solution, respectively. The concentration of cations present in the zeolite structure and
available for exchange is defined as the cation

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exchange capacity (CEC) and is expressed in


milliequivalents per gram (meq g 1).
The above equilibrium is more or less shifted to
the right, according to several parameters, among
them the cation exchange selectivity, referred to as
the measure of the preference that zeolite exhibits
for one cation (Bn+), compared with the other (Am+).
This parameter is a function of both the energy of
ion-lattice interaction and the hydration energy
(ion-solution interaction) (Colella, 1996). The
overall exchange selectivity for a cation couple is
usually measured by the relevant equilibrium
constant (K BA ). Considering all the available
equilibrium constants, this allows the so-called
selectivity pattern to be worked out, namely a
qualitative sequence of cations from the most to the
less preferred by the zeolite. Note that equation 2 is
strongly affected also by the nature and the
concentration of interfering cations present either
in the zeolite or in the contact solution.
Clinoptilolite, with a Si/Al ratio >4 (up to ~5.5),
has CEC values 2.0 2.6 meq g 1 although, due to
the presence of impurities, this value rarely reaches
the value of 2. The preferred extraframework
cations are Na+ and K+, with subordinate Ca2+. A
tentative selectivity pattern for clinoptilolite, based
on the available KBA literature data (Sherman, 1978;
Colella, 1996; Pabalan & Bertetti, 2001; Caputo &
Pepe, 2007), is the following:
Cs > K > Rb > NH4 > Pb > Ag > Na > Ba > Sr > Ca >
Mg > Cd > Li > Zn & Cu
(3)
Cation exchange selectivity data for additional
cations, e.g. Cr3+, Fe3+, Co2+, are also available in
the literature (Chmielewska-Horvathova & Lesny,
1992; Inglezakis et al., 2002), but they have not
been included in the selectivity series, because they
have been obtained using different experimental
approaches.
Finally, zeolites in general and CPT in particular
can exchange also H+, according to the following
schematic reaction:
AZ + m H+(s) > HmZ + Am+(s)

(4)

Physical sorption
This is a key property of zeolites, which enables
functionality in operations of great industrial
relevance, such as molecular sieving and catalysis.
The interaction of molecules with the extended
internal surface of zeolites (several hundred m2g 1)

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C. Colella
TABLE 1. Quantitative X-ray analysis of three clinoptilolite-bearing rocks (wt.%).

Sample
PEN1
SCL2
MIC3

CLI

O-CT

QTZ

FEL

BIO

SME

92
66
71

2
5
4

5
19
16

1
2
1

4
8

From de Gennaro et al., 2005. 2 From de Gennaro et al., 2010. 3 This study.
Legends: PEN = Pentalofos (Thrace, Greece); SCL = St. Cloud (NM, USA); MIC = Michoacan (SW Mexico).
CLI = clinoptilolite; O-CT = Opal-CT; QTZ = quartz; FEL = feldspar; BIO = biotite; SME = smectite.

is governed by two parameters: the dimension of


the entering windows, which represents the upper
limit for admittance of molecules, and the polarity
of molecules, which ensures the formation of more
or less strong ion-dipole bonds inside the structure.
The molecule which is definitely preferred by any
type of zeolite is H2O. This is the main reason why
zeolites are hydrated minerals.
Sedimentary zeolites, i.e. zeolitic tuffs, exhibit a
hierarchical porosity. In fact, in addition to zeolite
microporosity (diameters within 1 nm), an intergranular meso-/macro-porosity (diameters from
~0.01 10 mm) is also observed in the rock.
Macroporosity allows molecules to diffuse easily
and reach zeolite crystals for possible sorption; in
the meantime it is also a potential repository of
absorbed water.
The clinoptilolite structure contains an array of
three groups of channels. Two of these are confined
by ten-membered (0.7560.31 nm) and eightmembered tetrahedral rings (0.4660.36 nm)
respectively, and are parallel to the c-axis. An
additional group of eight-membered ring channels
(0.4760.28 nm), runs parallel to [100] and [102]
and cross-links the former channels within (010),
giving rise to a two-dimensional channel system
parallel to (010) responsible for a layer-like
structure (Armbruster, 2001; Baerlocher et al.,
2007). The void volume, expressed as cm3 of
liquid water per cm3 of crystal, is equal to 0.34
(Barrer, 1978).
The meso- and macro-porosity, which may be
important in some biomedical applications, depends
on the conditions under which the zeolitic rock
formed (nature, grain size, and compaction of the
original volcanic material; geological features of the
zeolitization system, temperature, pressure, etc.). To
emphasize how a different genesis may affect
porosity, porosimetric data by mercury intrusion

were measured on three CPT samples, coming from


Pentalofos (Thrace, Greece) (de Gennaro et al.,
2005), St. Cloud (New Mexico, USA) (de Gennaro
et al., 2010), and Michoacan (SW Mexico)
(Ostrooumov & Colella, 2010) (Table 1), using a
Micromeritics Autopore III porosimeter. Table 2
summarizes the results obtained. A comparison of
these data emphasises the great variability of
zeolitic tuff constitution and porosity and the
absence of a clear relationship between mineralogical and microstructural data.

External surface activity


Apart from the internal extended surfaces,
zeolites exhibit medium-sized (a few tens m2g 1),
negatively charged, external surfaces, balanced by
hydrated inorganic cations. This results in possible
external interactions either with polar molecules or
with other cations, provided that they both are large
enough to prevent entry into the zeolite structure.
Most of these molecules or cations are organic. This
allows the formation of a variety of organo-mineral
aggregates, characterized in some cases by notable
stability.
The key parameters to evaluate the external
surface activity of zeolites are (1) the external

TABLE 2. Mercury intrusion porosimetry of three


clinoptilolite-bearing rocks.
Sample
PEN1
SCL1
MIC1
1

Porosity (%)

Mean pore size (mm)

13.0
33.2
28.4

0.04
0.25
0.21

See Table 1 for sample identification.

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Biomedical and veterinary applications of zeolites

surface area (ESA), (2) the external cation


exchange capacity (ECEC) and (3) the external
surface charge density (ESCD = ECEC/ESA).
These parameters depend, besides the zeolite
nature and structural features, on several other
variables, such as grain size, framework charge
density, i.e. Si/Al ratio of the zeolite, extraframework cation composition and, in the case of zeoliterich rocks, on zeolite content, mineral composition,
etc. ESA and ECEC were measured on the CPT
samples referred to in Tables 1 and 2.
The estimation of ESA is based on the BET
adsorption method, which accepts that the N2
molecule does not enter the microporous structure
of clinoptilolite (Hernandez et al., 2000). The values
obtained, using a Micromeritics ASAP 2020
instrument, are reported in the second column of
Table 3. The ECEC is measured by exchange of the
extraframework cations of the zeolitic component of
the tuff by a large organic cation, unable to enter the
microporous zeolite structure, usually tert-butylammonium (TBA+) or hexadecyltrimethylammonium
(HDTMA+). The ECEC values, obtained by exhaustively treating the three CPT samples with a TBABr
solution (cf. Colella, 2007), are reported in the third
column of Table 3.
The calculated ESCD values are finally reported
in the fourth and the fifth columns of Table 3. It is
evident that the external surface parameters of the
three clinoptilolite-rich tuffs are rather variable and
that there is no clear relationship between them and
zeolite contents (Table 1).

Surface modification by interaction with


surfactant cations
Surface properties of zeolites can be modified by
replacing indigenous surface cations with longchain organic cations having surfactant properties,
mainly tetra-substituted ammonium ions, e.g.,

HDTMA+. The process may yield two different


products (Haggerty & Bowman, 1994):
(1) formation, via cation exchange, of a
monolayer or hemimicelle at the solid aqueous
interface. The surfactant sorption capacity (SSC) is
numerically equal to ECEC. The zeolite retains
most of its total CEC, and simultaneously it
becomes enriched in organic carbon and acquires
additional capacity to adsorb or dissolve non-polar
organic molecules;
(2) if the surfactant concentration in solution is
sufficiently high (over the so-called critical
admicelle concentration), a second layer is
formed by association of the hydrophobic tails of
the surfactant molecules to form a bilayer or
admicelle. In this case, the SSC becomes
roughly twice as much as the ECEC. As a result,
the modified zeolite, besides the capability to
exchange cations and to interact with hydrophobic
organic molecules, is also able to exchange anions,
as the second layer is provided by ammonium
heads, positively charged and balanced by hydrated
inorganic anions (usually Cl or Br ).

BIOMEDICAL ZEOLITE
APPLICATIONS
With reference to the properties described above,
natural zeolites present a wide spectrum of possible
applications in bio-medicine. Zeolite application as
a drug, coadjutant in medicine or supplement in
animal feeding is, however, subjected to preliminary assessments of its toxicological effects.
Many studies can be found in the literature
demonstrating that zeolite (mainly CPT) administration, even for several months, to animals or
humans showed no evidence of harmful reaction or
adverse change of their biochemical and haematological profiles (see, e.g. Martin-Kleiner et al., 2001
[and references therein]; Anonymous, 2003,

TABLE 3. Surface features of three clinoptilolite-bearing rocks.


Sample
PEN1
SCL1
MIC1

ESA (m2g 1)

ECEC (meq kg 1)

ESCD (e nm 2)

ESCD (C m 2)

14.0
11.4
18.3

149
102
135

6.4
5.4
4.6

1.0
0.9
0.7

1
See Table 1 for sample identification. ESA = External surface area; ECEC = External cation exchange capacity;
ESCD = external surface charge density. e = elementary charge; C = Coulomb.

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C. Colella

Alexopoulos et al., 2007). In addition, clinoptilolite


crystals, having a non-fibrous morphology, contrary
to erionite, are completely safe as regards the
zesmi et al.,
possible induction of mesothelioma (O
1985; Temel & Gundogdu, 1996; Adamis et al.,
2000). For this reason CPT has been accepted in the
pharmacopoeias of several countries and allowed
for specific drug production and marketing.
The zeolite effectiveness in biomedical applications, either as ion-exchanger or as adsorber (see
below), is strongly connected to the integrity of its
structure. Considering that the pH of the stomach is
very low, acid resistance of zeolite is an imperative
pre-requisite, especially in oral administrations.
This is the main reason for the preference of
siliceous zeolites, such as clinoptilolite and
mordenite, in bio-medicine compared to the more
aluminous phillipsite and chabazite.
Studies of natural zeolites in life sciences should
involve a preliminary characterization of the
material to evaluate the specificity of its use and
to plan, when possible, suitable modifications.
Unfortunately, most studies do not pay attention
to this point. The zeolitic material is often used in
its original form, collecting unreliable results which
are, on one hand, of no general significance and, on
the other hand, irreproducible if other similar
materials are used. In a few studies and/or
applications, attention is paid, however, to the
characterization and standardization of the material.
A protocol is usually set up to obtain, through
suitable treatment (e.g. through ion exchange,
exhaustive grinding, etc), a product, which can be
used safely and with the certainty of results.
Commercial products presenting a higher grade of
standardization, e.g. a tribomechanically activated
zeolite, are available in the market and are
sometimes used for experiments (see Ivkovic et
al., 2004).

Applications based on the alkaline character


One of the earliest applications of CPT for
medical use is associated with its alkaline character.
According to equations 1 and/or 4, CPT may in fact
act as an antacid drug for patients suffering from
hyperacidity produced by gastric dyspepsia and
gastric-duodenal ulcer. Moreover, it has been
proved that the neutralization of excess acidity
occurs without negative effects on the structural
stability of gastric enzyme pepsin (Llanio et al.,
1993; Rodrguez-Fuentes et al., 2006). Antacid

effects can be enhanced through the use of a


CPT-based drug, obtained by hydrothermal treatment of zeolite with a 0.5 M Na2CO3 solution
(temperature: 100C, solid-to-liquid ratio: 0.5, time:
1 h). The improved neutralizing properties might be
due to zeolite enrichment in Na+ (Rivera et al.,
1998).
A Cuban CPT-based product, having antacid
properties is available on the market under the
trade name Neutacid.

Applications based on cation exchange


Depending on (1) the nature and concentration of
extraframework cations in zeolite (usually Na+, K+,
Ca2+, and Mg2+), (2) the cation exchange capacity
and selectivity, and (3) the cationic environment of
the body fluids, a number of simultaneous
reactions, similar to that of equation 2, take place.
Accordingly, equilibria may have a favourable or
unfavourable course, i.e. they may favour the
removal of noxious (or beneficial) cations, and
introduce into the organism desired (or undesired)
species.
Considering the selectivity pattern of clinoptilolite, reported in equation 3, it is evident that a Narich form of CPT is able, for instance, to remove
NH+4 from a fluid. In contrast, a Zn-form of CPT is
able to release Zn2+ to the biological environment.
Of course, if we use a natural, unmodified CPT, it
is to be considered that, based on the selectivity
sequence of the indigenous extraframework cations,
i.e. K > Na > Ca > Mg, in equation 3, interferences
may occur during the exchange. Hence the
prevailing presence of K+ in clinoptilolite may not
favour NH+4 uptake and make CPT less effective.
CPT administration may also affect Na+ and K+
concentration in serum and/or the whole blood, so
that the levels of these two cations may change,
when feeding CPT to animals, e.g. cattle
(Hutcheson, 1984).
In summary, as regards cation exchange, the
following activities of natural zeolites have been
proposed and have a scientific foundation in biomedical fields, provided the zeolite is of the right
cationic form or has been modified by exchange in
order to improve its effectiveness.
Interaction with NH+
4 . Successful application of
CPT to control hyperammonemia in livestock, e.g.
in sheep, is reported in literature (Pond, 1984). A
number of positive effects on the dynamics of NH+4
exchange can be found in various studies of CPT

Biomedical and veterinary applications of zeolites

administration to livestock, presented at the


Zeoagriculture Conference in 1982 (Pond &
Mumpton, 1984). White & Ohlrogge (1974)
proved that NH+4 withdrawal from the circulation
by CPT and its later release allows a better
utilization of nitrogen by ruminants and therefore
a more complete conversion of feedstuff nitrogen to
animal protein. These results were confirmed by
later studies (e.g. Bergero et al., 1997). The
possibility of using natural zeolites has also been
considered in the removal of ammonium from the
dialysate of kidney patients in haemodialysis
(Andersson et al., 1975; Ash, 1986; Patzer et al.,
1995).
Release of cations with marked antibacterial and
antifungal effects. Ag+-, Cu2+- and/or Zn2+-enriched
CPT, proved to be effective in vitro against a
number of gram-negative (e.g. Pseudomonas
aeruginosa and Escherichia coli) and gram-positive
bacteria (e.g. various Streptococcus and
Enterococcus faecalis) and some fungi, such as
Candida albicans (Kirov & Terziiski, 1997; Rivera lku, 2004; De La RosaGarza et al., 2000; Top & U
Gomez et al., 2008). Zeolite effectiveness is
attributed to a gradual release of antibacterial and/
or antifungal cations in sufficient amounts to act,
avoiding useless or poisonous excesses. There is a
large patent literature on this subject, starting from
the middle 1980s (see references in Rivera-Garza et
al., 2000). Cation-exchanged CPT are proposed as
general-purpose and wide-spectrum disinfectant
(Rodrguez-Fuentes, 2004), also in the form of
coating material for topical use (Maeda, 1989).
Specific uses are suggested in dentistry, in analogy
with an already registered drug (Zeomic), based on
synthetic zeolite A (Matsuura et al., 1997;
Kawahara et al., 2000; Matsumura et al., 2003).
Clinoptilolite proved in fact to be less selective for
Ag+ than zeolite A and, therefore, more effective in
its release (Kirov & Terziiski, 1997). Associations
of Zn-exchanged CPT and erythromycin have been
successfully tested and are proposed for topical
treatments of acne (de Gennaro et al., 2002; Cerri
et al., 2004). Oil-based skin treatment compositions
containing natural (or synthetic) antibacterial
zeolites are also being considered (Araki &
Ishino, 2009).
Modulation of the presence of metal ions in the
organism. In principle, zeolite may either remove
specific noxious cations from the human or animal
body or release beneficial cations, remedying
microelement deficit morbidity. Considering,

301

however, that some 70 microelements have been


detected in the organisms and some tens are
normally present in any natural zeolite
(Andronikashvili et al., 2009), zeolitic species
may be involved in such a great number of cation
exchange equilibria making it practically impossible
to forecast the effect of its administration (which
might not be necessarily or completely positive).
Scientific literature is very uncommon in this sector
and is limited to tests in vitro. For instance, an
investigation on the action of CPT added in vitro to
rumen and abomasum juice of ruminants, proved
that clinoptilolite was able to take up As, Cd and
Pb. No information is available, however, on the
positive or negative effects towards other cationic
species (Vrzgula & Seidel, 1989). In a more recent
publication (Mohri et al., 2008), the ability of an
Iranian CPT to release beneficial ions, such as iron,
calcium and, indirectly, phosphorous is detailed but
there was also an undesired increase of sodium to
dairy calves. Of course, this situation might be
reversed or strongly modified, using CPT samples
with different extraframework cation composition.
Commercial literature online, on the contrary,
claims without proof constantly beneficial effects
of CPT in controlling and settling the global
balance of microelements in the human or animal
body.

Applications based on sorption


Molecules involved in biological processes are
usually too large to enter the zeolite framework.
That is why physical adsorption is a property of
limited interest for direct application of natural
zeolites in biomedicine. However zeolites may
interact with small molecules playing a role in
biomedical processes. Two examples are reported
here, regarding haemostatic and bactericidal activities, connected to water sorption. These examples
include surface (and possibly inner) adsorption on
zeolite crystals and absorption in the porous rock
matrix, and NO release, respectively. In addition, a
claimed application for the treatment of diabetes is
also described.
Uses as haemostatic and wound-healing accelerator. Literature on this topic, starting from the
1980s, is mostly of a patent nature (see, e.g. Hursey
& Dechene, 1989). It is claimed that zeolite
application to a wound or incision, usually together
with other drugs or coadjutants (for instance, with a
zeolite-based bactericide), helps to stop bleeding

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C. Colella

and to accelerate wound healing. A documented


case series on the successful application of a
commercial product, likely based on CPT, has
recently been published (Rhee et al., 2008). Water
sorption, and the consequent concentration of
coagulation factors, appears to be a possible
explanation of zeolite action. Recent results on the
positive effect of polar surfaces on haemostasis
suggest that the faster coagulation might also be
favoured by the charged outer zeolite surface
(Ostomel et al., 2007).
Bactericidal activity. According to a recent
investigation (Narin et al., 2010), CPT, loaded by
NO after thermal activation, is able to play a
bactericidal action, releasing gradually nitric oxide
to experimental E. coli and B. subtilis cultures
under physiological conditions. Medical applications are awaited, but doubts are raised on the
implications of NO release in the living being.
Antihyperglycemic activity. In vivo tests proved
that CPT, in its original form, displays positive
effects on many diabetic symptoms of sick laboratory
animals. Nevertheless, zeolites show a modest ability
to adsorb glucose, notwithstanding its polar character
(Pavelic & Hadzija, 2003). A remarkable selectivity
towards glucose is, on the contrary, claimed for a
CPT-based material, modified by a FeSO4 solution
under severe hydrothermal conditions (ConceptionRosabal et al., 1997). According to a second
publication (Conception-Rosabal et al., 2000),
glucose would be adsorbed (possibly chemisorbed)
into the clinoptilolite framework through formation
of a strong complex with exchanged Fe2+ and FeSO4,
occluded in the framework. All these data have been
collected in vitro; therefore they need to be
confirmed in vivo. Some doubts are raised also on
the adsorption mechanism, considering that the size
of the glucose molecule (0.88 nm) is rather larger
than the largest clinoptilolite channel. Most recently,
a positive action in controlling glucose concentration
in plasma has been reported also for Zn2+-exchanged
CPT, which has been attributed to a connection
between the Zn2+ presence and distribution in the
body and the oxidative stress associated with diabetes
(Torres Domnguez et al., 2010).

Applications based on external surface activity


Most of the prophylactic or therapeutic action
played by zeolite is connected to its external
surface activity. Whereas the external cation
exchange capability is only indirectly involved in

this action, as it serves essentially to modify zeolite


surfaces (e.g. through the use of surfactant cations)
and, therefore, to improve and to expand the field
of zeolite activity (see the sub-section Surface
modification), the external zeolite surface, either
original or surfactant-modified, is crucial for the
interaction with hydrophilic molecules or with both
hydrophilic and hydrophobic molecules, respectively. Depending on the different environments in
which natural zeolites operate, this results in a
series of possible uses in bio-medicine, ranging
from the withdrawal of noxious species to the
delayed release of drugs.
The most convincing applications of CPT,
depending mainly on its surface activity, are
summarized below.
Antidiarrhoeic activity. This is one of the first
effects observed in livestock when fed with zeolite
supplements. The therapeutic effect of a purified
CPT has been demonstrated also in humans by an
extended investigation, including microbiological
tests and pharmacological and clinical studies
(Rodrguez-Fuentes et al., 1997). It is likely that
zeolite acts through its extended, electrically
charged, external surface, having the capacity to
adsorb many endogenous and exogenous substances
responsible for this and other diseases. The antidiarrhoeic effect would be related in particular to
the adsorption of bilious acids. Improvement of
health conditions against diarrhoea might depend
also on the subtraction of mycotoxins (see below),
if any, from the gastro-intestinal tract. The results
of this investigation gave rise to the production of a
CPT-based drug named Enterex, which was
approved by the Cuban Drug Control Agency in
1995 and has been on the market since then.
A more recent investigation on CPT feeding to
calves (Sadeghi & Shawrang, 2008) suggests that
the positive action against diarrhoea may originate
either from alteration of metabolic acidosis, through
the effects on osmotic pressure in the intestinal
lumen, or from enhanced retention of some
enterotoxins, as demonstrated in vitro for
Escherichia coli (Ramu et al., 1997).
Hypocholesterolemic activity. The reduction of
cholesterol level in the blood of animals by feeding
them with a Ca2+-rich CPT (named Colestina) was
experimentally proved in mid 1990s (Simon et al.,
1995a,b). Further investigations in vitro showed that
the hypocholesterolemic action may be achieved
also in humans and is connected to the removal of
three major human bile components: bile acids,

Biomedical and veterinary applications of zeolites

phospholipids and bilirubin (Simon Carballo et al.,


2001). Colestina demonstrated a particular ability to
sequester them. The removal mechanism involves
adsorption of the surfactant-like phospholipids on
the external surface of clinoptilolite crystals. The
formation of admicelles through tail to tail
interaction of the phospholipid carbon chains
results in reversion of the surface charge of
zeolite from negative to positive. The organozeolite aggregate can therefore act as anion
exchanger, interacting in particular with the
carboxylic groups of bile acids and bilirubin
(Simon Carballo et al., 2001). A recent investigation showed that the synthetic zeolite Na-X displays
hypocholesterolemic activity too (Linares et al.,
2008).
Antitoxin activity. Much research has been
carried out since the end of the 1980s (see, e.g.
Dvorak, 1989; Harvey et al., 1993) on the use of
either original or modified CPT as a tool to
sequester mycotoxins accidentally ingested by
animals. Mycotoxins, a group of secondary
metabolites of different fungi, are common
contaminants of cereals, mainly feedstuff of farm
animals. They can initiate serious teratogenic,
carcinogenic, oestrogenic and immunodepressive
problems in livestock. The most poisonous mycotoxins are aflatoxins, especially aflatoxin B1, on
which research is mostly focused.
CPT proved to be a valuable adsorbent for
mycotoxins, especially the more polar aflatoxins
(Tomasevic-Canovic et al., 1997; Spotti et al.,
2005). Clinoptilolite and other zeolites are able to
form highly stable complexes with mycotoxins.
Given the dimensions of these molecules (kinetic
diameters of aflatoxins, for instance, range from
), they can not enter the microporous
5.18 to 6.50 A
structure of clinoptilolite (cf. sub-section on
Physical adsorption). Bond formation is therefore
credited to the hydrophilic environment created on
the external surface of these minerals by hydrated
extraframework cations. The adsorption capacity of
clinoptilolite for mycotoxins, which is of the order
of some hundred mg g 1, was demonstrated to be a
function of various parameters (apart from the
nature of adsorbent), such as temperature, pH, and
the presence and concentration of interfering
species. Also the specific properties of the
adsorbate, such as polarity, solubility, size, shape
and capacity to give rise to dissociation products
play a significant role in the adsorption process.
Adsorption capability of zeolites, in particular CPT,

303

for less polar mycotoxins (e.g. ochratoxins and


zearalenone), can be improved by the use of
surfactant-modified zeolites (Tomasevic-Canovic et
al., 2003).
Binding of aflatoxins to clinoptilolite in vitro, in
the presence of rumen fluids or solutions reproducing the gastric juice of animals, was usually more
effective than in vivo, because of a possible
interfering action of other components of biological
fluids. Results in vivo are anyway controversial (see
Table 2 in Papaioannou et al., 2005). For instance,
good performances of clinoptilolite against aflatoxins have in some cases been reported for broiler
chickens (Ortatatli et al., 2005), whereas in other
cases the absence of any influence (Harvey et al.,
1993) or even a negative activity has been reported
(Mayura et al., 1998).
The use of CPT as mycotoxin binder (but also as
anti-caking agent and coagulant) has been approved
by the European Commission for use in swine,
rabbit and poultry breeding (Directive 70/524/EEC,
Commission Regulation No. 1245/1999/16 June
1999). The Food and Drug Administration, on the
contrary, allows zeolite use in animal feeds, but
only as anti-caking agent (CFR 582-2727).
Antiviral and immunoenhancing activity. Virus
dimensions range roughly between 10 nm and
1 mm. They are therefore much larger than the
microporous window size of any zeolite, particularly of clinoptilolite (see sub-section on Physical
adsorption). By analogy with the action credited to
clay minerals (Anonymous, 2003), it has been
assumed that zeolites may act as antiviral agents
due to the activity of their external surface. Partially
positive responses were obtained using CPT as
antiviral agent, but the interpretation of the results
is controversial. It is certain that viruses are not
adsorbed to a great extent onto external zeolite
surfaces. In fact, at a pH value close to neutrality,
viruses and some pathogenic bacteria tend to be
negatively charged and are therefore rejected by the
zeolite surface. It has therefore been supposed that
the ability of CPT to suppress virus activity and/or
proliferation is due either to morphology destabilization by ion exchange (Grce & Pavelic, 2005) or
to neutralization of the immunosuppressive effect of
the viral infection (Ivkovic et al., 2004).
The ability to adsorb negatively charged pathogens is attained by CPT, if the zeolite is modified
with cationic surfactants in order to exhibit a
positive surface charge (see above). This introduces
the possibility of removing viruses and bacteria

304

C. Colella

from greywaters or contaminated ground water,


which has successfully been tested with a sewage
effluent from a constructed wetland, artificially
contaminated with E. coli and MS-2 bacteriophage
(Schulze-Makuch et al., 2003, 2007).
Drug carrier activity. Clinoptilolite proved to be
effective as a drug carrier mainly by means of its
active external surface. A great deal of research in
this sector has been and is being carried out at the
Zeolites Engineering Laboratory, Institute of
Materials and Reagents (IMRE), University of
Havana (Cuba) together with other medical or
biomedical Cuban institutions. Investigations have
been focused on the exploitation of a local CPT.
The first study of this series, at the end of 1990s,
aimed at evaluating the CPT-aspirin association,
assuming that the anti-acid properties of zeolite
could control the well known gastrointestinal side
effects caused by the drug in many patients (Lam
et al., 1998). It was demonstrated through a
theoretical approach that CPT is able to bind
aspirin molecules on its surface, allowing a
modulation of drug activity by its slow availability.
Analogous results were obtained by studying
binary and ternary mixtures of CPT with the
antibiotic drugs metronidazole and sulfamethoxazole, both of which also caused considerable
gastric side effects (Lam et al., 2001; Faras et al.,
2003; Rivera et al., 2003). As expected, the polar
zeolite surface interacted preferably with the more
hydrophilic metronidazole than with the more
hydrophobic sulfamethoxazole. In order to
enhance the CPT interaction with the latter drug,
research was direct towards clinoptilolite-surfactant
drug supports (Rivera & Faras, 2005). Three types
of surfactants (cationic, anionic and non-ionic)
were tested. Benzalkonium chloride, the only
(cationic) surfactant able to be strongly bound to
the zeolite surface, proved to be an excellent
adsorbent of sulfamethoxazole. This was demonstrated also by a theoretical study, using semiempirical calculations, in which the interaction of
some organic molecules with the external surface
of clinoptilolite was modelled (Lam & Rivera,
2006). Research is proceeding aimed at finding
further applications of CPT, e.g. as support of
cations of pharmaceutical interest (Li+, K+) (Faras
et al., 2009a), or to deepen and optimize the
mechanism of micellar solubilization of metronidazole and sulfamethoxazole in the CPT-benzalkonium chloride composite (Faras et al., 2009b,
2010).

ZEOLITES IN ANTICANCER
THERAPY
This is the most recent field of potential application
of natural zeolites: research started in fact at the
end of the 1990s. The subject is treated separately
because of the complexity of the biological
processes involved. At present, the action mechanisms of zeolites are unknown and only hypotheses
have been made. It is recognized, however, that
zeolites must be considered only as adjuvants in a
possible anticancer therapy.
Most research on the use of clinoptilolite in
oncology has been carried out in the laboratories of
the Division of Molecular Medicine, Ruer Boskovic
Institute, Zagreb (Croatia) (Poljak-Blazi et al.,
2001; Pavelic et al., 2001b, 2002; Zarkovic et al.,
2003; Katic et al., 2006). The CPT sample used in
all the studies was a Slovakian material, finely
powdered by tribomechanical micronization. Either
in vitro or in vivo experiments were carried out.
Experiments in vivo on mice and dogs, suffering
from a variety of tumour types, resulted in
improvement of the overall health status, prolonged
life-span, and decrease in tumour size. In addition,
local application of CPT to skin cancers in dogs
effectively reduced tumour formation and growth.
Experiments in vitro on tissue cultures helped to
interpret these results through the analysis of
various medical and biochemical parameters.
These appeared to be distinct in the cancer
evolution with and without CPT treatment.
Initially, the positive results were explained in
terms of attenuation of survival signals and
induction of tumour suppressor genes in the
treated cells (Pavelic et al., 2001b). Further
research in vivo demonstrated antimetastatic and
immunodepressive effects of clinoptilolite (Pavelic
et al., 2002). Treatment of animals with CPT in
combined cancer therapy (specifically with an
antibiotic used in chemotherapy) resulted in strong
reduction of the pulmonary metastasis count, giving
indications in terms of interference of CPT with
lipid peroxidation (Zarkovic et al., 2003). In
contrast to the previous papers, which did not
mention the effective role of clinoptilolite, in the
most recent paper of the group (Katic et al., 2006),
the positive results of CPT is credited, at least
partially, to adsorption of growth factors from
serum (with the presumable involvement of external
surface activity of the zeolite) and to modification
of ion concentrations in the cellular microenviron-

Biomedical and veterinary applications of zeolites

ment, which may affect Ca2+ levels and calciumdependence, signalling pathways through ion
exchange. Results coherent with those of the latter
paper have been obtained more recently with a
Cuban CPT (Martn et al., 2010).
In summary, this field of investigation needs
further research to find more strict connections
between the results obtained and the action actually
played by the zeolite.

CONCLUSION AND OUTLOOK


This review showed that natural zeolites, which are
usually considered as poor materials with a
limited number of applications, actually display a
wide range of activities in biomedicine and
veterinary science, connected to their peculiar
nature and unique properties. With reference to
original or modified clinoptilolite-rich materials, it
has been demonstrated that ion exchange and
adsorption capabilities allow actual or potential
applications of zeolites, and specifically of CPT, as
(1) active supplements in animal diets, (2) antiacids, (3) coadjutants in haemodialysis, (4) antibacterial and antifungal agents, (5) haemostatic and
wound-healing accelerators, (6) antihyperglycemic
agents, (7) antidiarrhoeal agents, (8) hypocholesterolemic agents, (9) antitoxin agents, (10) antiviral
agents and immunoenhancers, (11) drug delivery
retarders, and (12) anti-tumour adjuvants.
Whilst supplementing animal diet with natural
zeolites is a common practice today, which is
recognized and admitted by several national or
supranational regulations, research on possible
zeolite administration to human being is mostly
preliminary, i.e. it has essentially been carried out
in vitro. Effort is therefore needed to test in vivo
most of the above potential applications and check
if the positive performance of laboratory experiments is confirmed in living organisms, where
possible interfering actions of several natural
compounds may occur.
Finally, it is important to emphasize that a
preliminary complete characterization and/or modification of the zeolitic materials before use in the
biomedical field is particularly important. The
various clinoptilolite-rich rocks are different
materials and they cannot be proposed for any use
as identical materials. Moreover, standardization
would be necessary and suitable criteria should be
issued for each specific application. These should
include (1) purity and mineral composition of the

305

rock, i.e. minimum content of the specific zeolitic


phase and absence of undesired minerals, (2) grain
size distribution and procedure to obtain it,
(3) cationic composition of the zeolitic phase and
ion exchange process to obtain it, and (4) any other
modification, e.g. surface modification with a
surfactant, hydrothermal treatment, etc.
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