| Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 12, Number 26, 2006
Contents
An Update on the Diagnosis of Allergic and Non-Allergic
Drug Hypersensitivity
Executive Editors: M.T. Ventura and A. Romano
Editorial Pp. 3305-3307
Drug Hypersensitivity: Epidemiology and Risk Factors Pp.
3309-3312
L. Guglielmi, P. Guglielmi and P. Demoly
[Abstract]
Hypersensitivity Reactions to Quinolones Pp.
3313-3326
D.A. Schmid, P. Campi and W.J. Pichler
[Abstract]
Immediate Hypersensitivity Reactions to Penicillins
and Other Betalactams Pp. 3327-3333
C. Antúnez, E. Martín, J.A. Cornejo-García,
N. Blanca-Lopez, R. R-Pena, C. Mayorga, M.J. Torres and M.
Blanca
[Abstract]
IgE-Mediated Hypersensitivity to Cephalosporins
Pp. 3335-3345
J.-L. Guéant, R.-M. Guéant-Rodriguez, M. Viola,
R.L. Valluzzi and A. Romano
[Abstract]
Hypersensitivity to Aspirin and Other Nonsteroidal
Anti Inflammatory Drugs (NSAIDs) Pp. 3347-3358
A.L. de Weck, P.M. Gamboa, R. Esparza and M.L. Sanz
[Abstract]
Hypersensitivity Reactions to Iodinated Contrast
Media Pp. 3359-3372
R.-M. Guéant-Rodriguez, A. Romano, A. Barbaud, K. Brockow
and J.-L. Guéant
[Abstract]
Hypersensitivity to Aromatic Anticonvulsants:
In Vivo and In Vitro Cross-Reactivity Studies
Pp. 3373-3381
A. Romano, R. Pettinato, M. Andriolo, M. Viola, R.-M. Guéant
Rodriguez, R.L. Valluzzi, C. Romano, M. Elia, M.T. Ventura
and J.-L. Guéant
[Abstract]
Cross-Reactivity in Cell-Mediated and IgE-Mediated
Hypersensitivity to Glucocorticoids Pp. 3383-3391
M.T. Ventura, G.F. Calogiuri, L. Muratore, E. Di Leo, R. Buquicchio,
A. Ferrannini, O. Resta and A. Romano
[Abstract]
Hypersensitivity Reactions to Complementary
and Alternative Medicine Products Pp. 3393-3399
M.T. Ventura, M. Viola, G. Calogiuri, F. Gaeta,
O. Pesole and A. Romano
[Abstract]
Hypersensitivity Reactions to Ophthalmic Products
Pp. 3401-3410
M.T. Ventura, M. Viola, F. Gaeta, E. Di Leo, R. Buquicchio
and A. Romano
[Abstract]
General Articles
Dehydroepiandrosterone and Its Derivatives:
Potentially Novel Anti-Proliferative and Chemopreventive Agents
Pp. 3411-3421
Y. Matsuzaki and A. Honda
[Abstract]
Kinins and Cardiovascular Diseases Pp.
3423-3435
J.B. Su
[Abstract]
Abstracts
[Back
to top]
Editorial
An Update on the Diagnosis of Allergic and Non-Allergic
Drug Hypersensitivity
This volume is dedicated to hypersensitivity reactions to
drugs, which are increasing, partly because of indiscriminate
consumption of the latter. In fact, in industrialized countries
drug abuse represents one of the greatest problems of public
health.
The revised nomenclature for allergies [1], which is based
on the mechanisms that initiate and mediate hypersensitivity
reactions, classifies such reactions to drugs as either allergic
or non-allergic. The former are mediated by immunologic mechanisms,
either antibodies or cells; all other reactions should be
referred to as non-allergic drug hypersensitivity. In addition,
allergic reactions to drugs are classified as IgE-mediated
or non-IgE-mediated; some of the latter are cell-mediated.
In IgE-mediated reactions, the drug or drug metabolite reacts
with IgE bound to the surface of mast cells and leads to the
activation, degranulation, and release of mast-cell vasoactive
mediators like histamine and tryptase. In cell-mediated allergic
reactions, CD4+ and CD8+ T cells recognize drugs through their
αβ
receptors. Drug-specific T cells generate inflammatory reactions,
mainly cutaneous, through the release of various cytokines
(e.g., interleukin-5, interferon) and chemokines (e.g., interleukin-8).
Non-allergic immediate hypersensitivity reactions to drugs
(i.e., occurring less than one hour after drug administration)
are frequent, and their symptoms are similar to those observed
in IgE-mediated allergic reactions. Non-allergic reactions
may involve different pathogenic mechanisms, such as the capability
of iodinated contrast media (ICM) of releasing mediators through
a non-immunologic mechanism and the inhibitory effect on cyclooxygenase-1
of nonsteroidal anti-inflammatory drugs (NSAIDs).
This volume contains articles by researchers and clinicians
belonging to the European Network for Drug Allergy (the European
Academy of Allergology and Clinical Immunology’s interest
group on drug hypersensitivity). In preparing this issue,
we have tried to meet the needs of readers who wish to learn
about the latest developments regarding this subject, particularly
those concerning pathogenic mechanisms and diagnostic aspects.
In the first article, Guglielmi and coworkers [2] focus their
attention on the risk factors of hypersensitivity reactions
to drugs, which are related to the latter and the treatment
regimens, as well as to the host. As far as genetic factors
are concerned, most studies regard HLA haplotype association
or polymorphisms in genes encoding drug-metabolising enzymes.
There are also studies concerning single nucleotide polymorphisms,
which may be involved in multifactorial and multigenic diseases,
and aimed at enabling patients at risk for hypersensitivity
reactions to be identified.
The following three articles [3-5] provide data on hypersensitivity
reactions to antibacterial drugs such as quinolones and β-lactams.
The review by Schmid and coworkers [3] analyzes the different
pathogenic mechanisms involved in hypersensitivity reactions
to quinolones, with special attention to T cell-mediated ones.
The authors also provide data on IgE-mediated reactions, such
as anaphylactic shock, urticaria and angioedema, and highlight
the usefulness of the sepharose radioimmunoassay of serum-specific
IgE against quinolones in the diagnosis of such reactions.
They also stress that cross-reactivity among quinolones at
both the IgE- and T-cell level is clinically well documented.
Therefore, patients with hypersensitivity reactions to any
quinolone should not be re-exposed to any antimicrobial agents
of that class.
The paper by Antúnez and coworkers [4] focuses its
attention on diagnostic tests for IgE-mediated hypersensitivity
reactions to β-lactams,
mainly penicillins. Diagnostic work-ups for such reactions
include skin tests, serum-specific IgE assays, flow cytometric
basophil activation tests and, in case of negative responses
to these in vivo and in vitro tests, controlled
administrations of suspect antibiotics. The authors emphasize
the importance of the side-chain antigenic determinants of
the various β-lactams
and thus the need to use in diagnosis the suspect β-lactams
themselves. In fact, hypersensitivity reactions to β-lactams
may not be detected by tests performed only with penicillin
determinants in cases where side-chain determinants play an
important role in sensitization.
The article by Guéant et al. [5] demonstrates
the usefulness of skin testing with responsible cephalosporins,
the sepharose radioimmunoassay of serum-specific IgE against
cephalosporins, and challenges in diagnosing immediate reactions
to these β-lactams.
In their allergologic work-up, performing allergologic tests
with cephalosporins other than the culprit, as well as with
penicillin reagents, allows the identification of cross-reactivity
with penicillins, selective responses, or cross-reactivity
among cephalosporins. In the latter group, cross-reactivity
is more frequently related to R1 than to R2
side-chain recognition. The authors highlight that cephalosporin
IgE-mediated hypersensitivity may be a temporary condition;
therefore, it is advisable to repeat allergologic exams in
subjects with negative initial work-ups, including challenges.
Various aspects of hypersensitivity reactions to acetylsalicylic
acid and other NSAIDs are reviewed in the paper by de Weck
et al. [6]. With regard to the pathogenic mechanisms,
they hypothesize that NSAID hypersensitivity is due to both
a localized inflammatory processes causing a non-specific
basophil hyperreactivity and an abnormal pharmacogenetic reaction
to NSAIDs resulting in a hyperproduction of LTC4 and other
mediators by activated mast cells, basophils and eosinophils.
For this reason, the authors consider the leukotriene release
test and the basophil activation test as reliable in vitro
tools to diagnose NSAID hypersensitivity. Therefore, the routine
use of these tests might reduce the performance of provocation
tests in diagnosing such hypersensitivity.
The article by Guéant-Rodriguez et al. [7]
analyzes various aspects of ICM-induced hypersensitivity reactions,
particularly the pathogenic mechanisms, diagnosis, and prevention.
On the basis of literature data and their experience, some
immediate reactions, especially severe ones, appear to be
IgE-mediated, while a T-cell-mediated pathogenic mechanism
is involved in most non-immediate reactions, particularly
maculopapular rashes. As far as diagnostic tests are concerned,
skin tests and specific IgE assays are useful for diagnosing
immediate hypersensitivity reactions, while both delayed-reading
intradermal tests and patch tests, as well as the lymphocyte
transformation test, are useful for evaluating non-immediate
reactions.
Our article regarding hypersensitivity reactions to aromatic
anticonvulsants [8] provides both personal and literature
data on this topic, focusing its attention on cross-reactivity
among these drugs. Although several hypersensitivity reactions
to sequential exposure to more than one aromatic anticonvulsant
(i.e., clinical cross-reactivity) have been reported, the
immunologic cross-reactivity (i.e., diagnosed on the basis
of responses to patch tests and/or lymphocyte transformation
tests) rate among these drugs appears to be low in studies
evaluating at least 10 subjects with hypersensitivity reactions
to them. In addition, data concerning the toxic cross-reactivity
(i.e., assessed by lymphocyte toxicity assays, which expose
the patient’s lymphocytes to arene oxides) are also
contradictory. Therefore, further in vivo and in
vitro studies in large samples of subjects are needed
to evaluate cross-reactivity among aromatic anticonvulsants.
The review concerning hypersensitivity reactions to glucocorticoids
[9] analyses the clinical and diagnostic aspects of both cell-mediated
and IgE-mediated reactions to these drugs. Particular attention
is addressed to the problem of allergenic cross-reactivity
among glucocorticoids. In this regard, substitutions at the
C16/C17 positions of the glucocorticoid
D ring are crucial in influencing such cross-reactivity, although
other rings (A-C) are also important in determining cross-reactions
among glucocorticoids.
The last two articles [10, 11] analyze literature data regarding
hypersensitivity reactions to products of complementary and
alternative medicine and to ophthalmic ones, respectively.
The first one emphasizes that alternative remedies may not
be as safe as they are generally thought to be. As far as
reactions to ophthalmic products are concerned – and
especially eyelid dermatitis – the second one stresses
that patch testing at the standard concentrations may be insufficiently
sensitive, and therefore the skin on the back could be scratched
and stripped to favor greater cutaneous absorption.
We hope this volume will be useful to those who work in the
complex field of drug hypersensitivity.
References
[1] Johansson SG, Bieber T, Dahl R, Friedmann PS, Lanier BQ,
Lockey RF, et al. Revised nomenclature for allergy
for global use: Report of the Nomenclature Review Committee
of the World Allergy Organization, October 2003. J Allergy
Clin Immunol 2004; 113: 832-6.
[2] Guglielmi L, Guglielmi P, Demoly P. Drug hypersensitivity:
epidemiology and risk factors. Curr Pharm Design 2006; 12(26):
3309-3312.
[3] Schmid DA, Campi P, Pichler WJ, Pichler MD. Hypersensitivity
reactions to quinolones. Curr Pharm Design 2006; 12(26): 3313-3326.
[4] Antúnez C, Martín E, Cornejo-García
JA, Blanca-Lopez N, R-Pena R, Mayorga C, et al. Immediate
hypersensitivity reactions to betalactams, mainly penicillins.
Curr Pharm Design 2006; 12(26): 3327-3333.
[5] Guéant JL, Guéant-Rodriguez RM, Viola M,
Valluzzi RL, Romano A. IgE-mediated hypersensitivity to cephalosporins.
Curr Pharm Design 2006; 12(26): 3335-3345.
[6] de Weck L, Gamboa PM, Esparza R, Sanz ML. Hypersensitivity
to aspirin and other nonsteroidal anti-inflammatory drugs
(NSAIDs). Curr Pharm Design 2006; 12(26): 3347-3358.
[7] Guéant-Rodriguez RM, Romano A, Barbaud A, Brockow
K, Guéant JL. Hypersensitivity reactions to iodinated
contrast media. Curr Pharm Design 2006; 12(26): 3359-3372.
[8] Romano A, Pettinato R, Andriolo M, Viola M, Guéant-Rodriguez
RM, Valluzzi RL, et al. Hypersensitivity to aromatic
anticonvulsants: in vivo and in vitro cross-reactivity
studies. Curr Pharm Design 2006; 12(26): 3373-3381.
[9] Ventura MT, Calogiuri GF, Muratore L, Di Leo E, Buquicchio
R, Ferrannini A, et al. Cross-reactivity in cell-mediated
and IgE-mediated hypersensitivity to glucocorticoids. Curr
Pharm Design 2006; 12(26): 3383-3391.
[10] Ventura MT, Viola M, Calogiuri GF, Gaeta F, Pesole O,
Romano A. Hypersensitivity reactions to complementary and
alternative medicine products. Curr Pharm Design 2006; 12(26):
3393-3399.
[11] Ventura MT, Viola M, Gaeta F, Di Leo E, Buquicchio R,
Romano A. Hypersensitivity reactions to ophthalmic products.
Curr Pharm Design 2006; 12(26): 3401-3410.
Prof. Maria Teresa Ventura M.D.
Department of Internal Medicine,
Immunology and Infectious
Diseases (MIDIM),
University of Bari Policlinico,
70124 Bari, Italy
Prof. Antonino Romano, M.D.
UCSC, Unità di Allergologia
Complesso Integrato Columbus
Via G. Moscati, 31
00168 Rome, Italy
[Back to top]
Drug Hypersensitivity: Epidemiology and Risk Factors
L. Guglielmi, P. Guglielmi and P. Demoly
Drug allergies are heterogeneous and multifactorial diseases
and are always the consequence of an exaggerated immune-mediated
reaction. Previously described models of immunologic mechanisms
(mainly based on Gell and Combs' classification) cannot fully
explain the physiopathology of these diseases; it seems therefore
important to identify risk factors. Clinical and biologic
tests are helpful diagnostic tools but are limited in their
sensitivity and reliability and are certainly not predictive.
Epidemiologic data supply information concerning the prevalence
of drug hypersensitivity: female gender, concomitant infections
(HIV, herpes) and concurrent illnesses (systemic lupus erythematosus)
are all significant risk factors. Another host-related factor
is the genetic predisposition of patients and is currently
under investigation in our laboratory. Most genetic studies
concern HLA haplotype association or polymorphism in genes
encoding drug-metabolising enzymes. A current study by our
group seems to implicate polymorphisms within the promoter
of IL-10, a cytokine with anti-inflammatory properties. The
chemical properties of the drug and the treatment regimen
also influence the development of drug allergies.
[Back to top]
Hypersensitivity Reactions to Quinolones
D.A. Schmid, P. Campi and W.J. Pichler
Quinolones are one of the most important classes of antimicrobial
agents discovered in the recent years and one of the most
widely used classes of antibiotics in clinical medicine. Their
broad spectrum of activity and pharmacokinetic properties
make them ideal agents for treating a variety of infections.
Their clinical importance is further demonstrated by their
activity against a wide range of diseases of public health
importance such as anthrax, tuberculosis, bacterial pneumonia,
and sexually transmitted diseases.
Like other antibiotics, quinolones can cause various, sometimes
dangerous hypersensitivity reactions. The underlying pathomechanisms
are only poorly understood. Some are thought to be partly
non-immune mediated reactions, others are considered to be
IgE- or T cell-mediated reactions. This review gives an insight
into the different immunological mechanisms leading to the
diverse symptoms of quinolone-induced hypersensitivity reactions,
with special emphasis on the role of T cells in such reactions.
[Back to top]
Immediate Hypersensitivity Reactions to Penicillins
and Other Betalactams
C. Antúnez, E. Martín, J.A. Cornejo-García,
N. Blanca-Lopez, R. R-Pena, C. Mayorga, M.J. Torres and M.
Blanca
Immediate hypersensitivity reactions to betalactams are
IgE mediated and constitute the most frequent allergic reactions
mediated by specific immunological mechanisms. IgE responses
to benzyl penicillin (BP), the first antibiotic producing
the benzyl penicilloyl structure (BPO), are characterized
by a quick release of inflammatory mediators, resulting in
anaphylactic shock, urticaria and angioedema. With the progressive
appearance of other structures, comprising cephalosporins,
carbapenems, monobactams and clavulanic acid, IgE selective
responses and cross-reactivity reactions were observed. The
diagnosis of betalactam hypersensitivity, classically based
on skin testing with major and minor determinants of benzyl
penicillin or in vitro IgE antibodies to BP, has
been modified by the inclusion of different determinants generated
from these compounds, for which amoxicillin (AX) is the most
relevant, followed by cephalosporins. Some subjects develop
positive responses to several betalactams, mostly within the
same family, but others develop a selective response. These
are relevant for the appropriate selection of antimicrobial
drugs in patients who have immediate hypersensitivity to betalactams.
[Back to top]
IgE-Mediated Hypersensitivity to Cephalosporins
J.-L. Guéant, R.-M. Guéant-Rodriguez, M. Viola,
R.L. Valluzzi and A. Romano
Like penicillins, cephalosporins may cause IgE-mediated
reactions such as urticaria, angioedema, and anaphylactic
shock, which occur because of sensitization to determinants
shared with penicillins or to unique cephalosporin haptens.
In particular, side-chain structures may be responsible for
selective sensitization or cross-reactivity. For this reason,
individual free cephalosporins are usually employed in skin
testing, in addition to the classic penicillin reagents.
Cephalosporin skin tests are sensitive in diagnosing immediate
hypersensitivity to these betalactams. As far as in vitro
tests are concerned, IgE assays for cephalosporins, specifically
sepharose-radioimmunoassays, are a potentially useful tool
in evaluating immediate reactions and could be used as complementary
tests. In selected cases displaying negative results in both
skin tests and IgE assays, a graded challenge with the implicated
cephalosporin can be performed.
Cephalosporin IgE-mediated hypersensitivity may be a transient
condition; therefore, allergologic exams should be repeated
in patients with negative initial allergologic work-ups, including
challenges.
Performing allergologic tests with cephalosporins other than
the culprit, as well as with penicillin reagents, allows the
identification of cross-reactivity with penicillins, selective
responses, or cross-reactivity among cephalosporins. In the
lat-ter group, cross-reactivity is more frequently related
to R1 than to R2 side-chain recognition.
In assessing the selectivity of the response, negative results
in skin testing with cephalosporins other than the responsible
one appear to be a reliable indicator of tolerability.
[Back to top]
Hypersensitivity to Aspirin and Other Nonsteroidal
Anti Inflammatory Drugs (NSAIDs)
A.L. de Weck, P.M. Gamboa, R. Esparza and M.L. Sanz
Hypersensitivity to aspirin and other non steroidal anti-inflammatory
drugs (NSAIDs) manifesting in the airways (rhinosinusitis,
polyps, asthma) or in the skin (urticaria, angioedema) is
the second most frequent untoward allergic reaction to drugs.
Various aspects of this syndrome, such as its clinical features,
the cell types and mediators involved, the role of underlying
chronic inflammatory processes, the patterns of cross-reactivity
between NSAIDs, the major role of sulfidoleukotrienes (LTC4)
and of some other mediators such as prostaglandin E2 (PGE2)
and C5a are briefly reviewed.
It has been assumed for a long time that there were no reliable
in vitro tests for that condition and that diagnostic
confirmation can only be ascertained by provocation challenge.
This appears no longer to be true, since several recent studies
using a leukotriene release test (CAST) or a basophil activation
test (BAT) on blood basophils, or a combination of both tests,
yields positive results (70 – 75%) in a sizeable number
of clinically validated cases, with a high specificity (above
85%).
The finding in that syndrome of hyperreactive basophils suggests
that the NSAID hypersensitivity syndrome is due to the associated
effect of several factors : 1) Localized inflammatory processes
causing a non specific cellular hyperreactivity; 2) An abnormal
pharmacogenetic reaction to NSAIDs resulting in a hyperproduction
of LTC4 and other mediators by activated mast cells, basophils
and eosinophils.
[Back to top]
Hypersensitivity Reactions to Iodinated Contrast
Media
R.-M. Guéant-Rodriguez, A. Romano, A. Barbaud, K. Brockow
and J.-L. Guéant
Adverse reactions after iodinate contrast media (ICM)
administration have been observed, which can be classified
as immediate (i.e., occurring within one hour after administration)
and delayed or non-immediate (i.e., occurring more than one
hour after administration). Even though the incidence of ICM
adverse reactions has been significantly reduced by the introduction
of non-ionic compounds, immediate reactions still occur in
about 3% of administrations. Different pathogenic mechanisms
have been suggested for ICM reactions, including immunologic
ones. Basophils and mast cells participate in immediate reactions
through the release of mediators like histamine and tryptase,
whereas a T-cell-mediated pathogenic mechanism is involved
in most non-immediate reactions, particularly maculopapular
rashes. Skin tests and specific IgE assays are carried out
to diagnose immediate hypersensitivity reactions, while both
delayed-reading intradermal tests and patch tests are usually
performed to evaluate non-immediate reactions. However, in
vitro specific IgE assays are not commercially available.
As far as in vitro tests are concerned, a response
involving ICM-related T-cell activity may be assessed by the
lymphocyte transformation test.
Allergologic evaluation appears to be indicated in hypersensitivity
reactions to ICM, although the sensitivity, specificity, and
predictive values of allergologic tests have not yet been
established.
This paper summarizes the current state of the art and addresses
the research that is still needed on the pathogenic mechanisms,
diagnosis, and prevention of ICM-induced hypersensitivity
reactions.
[Back to top]
Hypersensitivity to Aromatic Anticonvulsants:
In Vivo and In Vitro Cross-Reactivity Studies
A. Romano, R. Pettinato, M. Andriolo, M. Viola, R.-M. Guéant
Rodriguez, R.L. Valluzzi, C. Romano, M. Elia, M.T. Ventura
and J.-L. Guéant
Aromatic antiepileptic drugs (phenytoin, carbamazepine,
oxcarbazepine, and phenobarbital) are frequently associated
with cutaneous eruptions. A cell-mediated pathogenic mechanism
has been demonstrated in most of such reactions on the basis
of positive responses to patch tests and/or lymphocyte transformation
tests. Therefore, such tests are useful tools for evaluating
anticonvulsant hypersensitivity reactions. Moreover, an in
vitro lymphocyte toxicity assay, which exposes the patient’s
lymphocytes to arene oxides, has detected lymphocyte susceptibility
to toxic metabolites in a large percentage of patients with
hypersensitivity reactions to aromatic anticonvulsants.
Although several hypersensitivity reactions to sequential
exposure to more than one aromatic anticonvulsant (i.e., clinical
cross-reactivity) have been reported, there are few studies
performed with patch tests and/or lymphocyte transformation
tests assessing immunologic cross-reactivity, and their data
are contradictory. In any case, considering studies performed
in samples of at least 10 patients, the immunologic cross-reactivity
rate among aromatic anticonvulsants appears to be low. On
the other hand, the reported rate of the toxic cross-reactivity
(i.e., assessed by lymphocyte toxicity assays) is high.
Further in vivo and in vitro studies in
large samples of subjects are needed to evaluate cross-reactivity
among aromatic an-ticonvulsants.
[Back to top]
Cross-Reactivity in Cell-Mediated and IgE-Mediated
Hypersensitivity to Glucocorticoids
M.T. Ventura, G.F. Calogiuri, L. Muratore, E. Di Leo, R. Buquicchio,
A. Ferrannini, O. Resta and A. Romano
In the last few decades, glucocorticoids have received
increasing attention for their capability of provoking systemic
hypersensitivity reactions, when administered orally, parenterally,
or intralesionally, as well as allergic skin and mucosal symptoms,
when applied locally to the skin in patients with contact
dermatitis or to the mucosa in patients with asthma and/or
rhinitis. However, because of their anti-inflammatory and
immunosuppressive properties, glucocorticoids are often not
suspected of such hypersensitivity reactions. In addition,
because glucocorticoids retain their anti-inflammatory potential,
even if they act as sensitizers, the signs and symptoms of
allergic reactions are not always obvious, particularly when
they overlap with those caused by the very diseases glucocorticoids
are used to treat. Moreover, interpretation of diagnostic
tests, specifically that of patch-test reactions, can be difficult.
In this review, particular attention is addressed to the problem
of allergenic cross-reactivity among topical and systemic
glucocorticoids.
We also look at the clinical and practical aspects of both
cell-mediated and IgE-mediated hypersensitivity reactions
to glucocorticoids and their consequences on anti-inflammatory
therapeutic choices.
[Back to top]
Hypersensitivity Reactions to Complementary
and Alternative Medicine Products
M.T. Ventura, M. Viola, G. Calogiuri, F. Gaeta,
O. Pesole and A. Romano
Complementary and alternative medicine (CAM) is becoming
increasingly popular, and is often used for treating hypersensitivity
diseases. Virtually all alternative remedies can cause hypersensitivity
reactions, but the most frequently involved ones are tea tree
oil, members of the Compositae family, propolis, oils used
in aromatherapy, substances responsible for photosensitization,
and metal-containing compounds. The main target organ is skin,
with manifestations ranging from contact dermatitis (the most
common) to urticaria-angioedema, maculopapular eruptions,
photosensitivity reactions, and the Stevens-Johnson syndrome.
Other types of reactions are possible, including respiratory
and anaphylactic ones. Different pathogenic mechanisms have
been suggested for CAM product reactions, including immunologic
ones. Basophils and mast cells participate in IgE-mediated
reactions through the release of mediators like histamine
and tryp-tase, whereas a T-cell-mediated pathogenic mechanism
is involved in most delayed reactions, particularly contact
dermatitis and maculopapular eruptions. Skin tests and serum
specific IgE assays are carried out to diagnose immediate
hypersensitivity reactions, while patch tests and lymphocyte
transformation tests are usually performed to evaluate delayed
hypersensitivity reactions.
Thus clinicians should know about the potential of CAM products
for causing adverse reactions. Our study is aimed at highlighting
the risk of hypersensitive reactions to CAM remedies on the
basis of the numerous cases reported in the literature.
Because little is known about adverse reactions to CAM products,
further systematic studies and an appropriate regulation by
heath authorities are necessary.
[Back to top]
Hypersensitivity Reactions to Ophthalmic Products
M.T. Ventura, M. Viola, F. Gaeta, E. Di Leo, R. Buquicchio
and A. Romano
Adverse reactions after administration of ophthalmic
products have frequently been observed. These reactions can
be provoked by both active principles and excipients. Different
pathogenic mechanisms have been suggested for such reactions,
including immunologic ones. Basophils and mast cells participate
in IgE-mediated reactions through the release of mediators
like histamine and tryptase, whereas a T-cell-mediated pathogenic
mechanism is involved in most delayed reactions, particularly
conjunctival ones and eyelid dermatitis. Prick tests and immediate-reading
intradermal tests are carried out to diagnose immediate hypersensitivity
reactions, while patch tests are usually performed to evaluate
delayed reactions. Other diagnostic tests, such as serum-specific
IgE assays in immediate reactions, as well as delayed-reading
intradermal tests and/or lymphocyte transformation tests in
delayed ones, are rarely performed.
In this review, particular attention is addressed to the clinical
and practical aspects of both cell-mediated and IgE-mediated
hypersensitivity reactions to ophthalmic products.
[Back to top]
Dehydroepiandrosterone and Its Derivatives: Potentially
Novel Anti-Proliferative and Chemopreventive Agents
Y. Matsuzaki and A. Honda
Dehydroepiandrosterone (DHEA) is the most abundant adrenal
androgenic steroid in young adult humans. The physiological
functions of DHEA in preventing human carcinogenesis are still
controversial, but a lot of reports have shown that pharmacological
doses of DHEA show chemopreventive and anti-proliferative
effects on tumors in rodents. Although a therapeutic dose
of DHEA has been reported to promote hepatocarcinogenesis
in rats due to peroxisomal pro-liferation, it remains unclear
whether DHEA is a peroxisome proliferator in human liver.
The chemopreventive and anti-proliferative effects of DHEA
are not explained by a single mechanism, and at least four
mechanisms seem to contribute to these effects: 1) depletion
of NADPH and ribose-5-phosphate due to the inhibition of glucose-6-phosphate
dehydro-genase activity, 2) suppression of cholesterol biosynthetic
pathway by inhibition of HMG-CoA reductase, 3) interference
with cell proliferation signaling pathways, and 4) suppression
of nitric oxide generation through down-regulation of nitric
oxide synthase II. In addition to studies of the mechanisms
underlying the anti-neoplastic effects, searches for more
potent and less androgenic DHEA derivatives are ongoing. A
small amount of DHEA is endogenously metabolized to 7-oxygenated
DHEA, and this may represent a metabolic pathway to more potent
steroid hormones. Androsterone, epian-drosterone and etiocholanolone
have been considered to be merely inactive end products of
DHEA, but may in fact be physiological effectors in their
own right. In addition, DHEA analogs such as 3β-methyl-5-androsten-17-one,
16α-fluoro-5-androsten-17-one
and 16α
fluoro-5α-androstan-17-one
have been synthesized and shown to be more effective inhibitors
of tumor growth, compared with DHEA itself. However, to design
potent and safe DHEA derivatives, identification of the DHEA
receptor and clarification of the mechanisms of DHEA action
are required.
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Kinins and Cardiovascular Diseases
J.B. Su
Kinins are synthesized from their precursors by different
enzymes and participate in the regulation of cardiovascular
function through bradykinin (BK) B1 and B2 receptors. They
modulate blood coagulation by exerting antithrombotic and
profibrinolytic actions. By activating B2 receptors that results
in the release of nitric oxide and prostacyclin, kinins inhibit
vascular smooth muscle growth and neointima formation, which
may play an inhibitory role on the atherosclerosis development,
while through the activation of B1 receptors, they may play
a deleterious role in this disease. Kinins are potent endogenous
vasodilators that are involved in the regulation of coronary
vascular tone. However, due to their metabolic characteristics,
these peptides act mainly as an autocrine/paracrine factor
to locally regulate blood perfusion of organs. By modulating
cellular energy metabolism and myocardial oxygen consumption,
they protect cardiac and vascular endothelial function in
myocardial ischemia and heart failure. Finally, mounting evidence
indicates that kinins are involved in the actions of some
drugs actually used in the treatment of cardiovascular diseases
such as angiotensin-converting enzyme inhibitors and angiotensin
AT1 receptor antagonists. Taken together, the kinin system
constitutes a potential therapeutic target for cardiovascular
diseases. Experiments in animals attempted to explore the
kinin system as a therapeutic means, including the mobilization
of endogenous kinins using pharmacological agents, searching
BK analogs with long-acting properties and gene therapies.
However, the potential values of the kinin system have not
been taken into consideration in clinical practice for cardiovascular
indications.
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