| Current
Drug Targets
ISSN: 1389-4501
Current Drug Targets
Volume 7, Number 9, September 2006
Contents
Functional Phenothiazines and Related Compounds
Guest Editor: Noboru Motohashi
Editorial Pp. 1053
N. Motohashi
Cytotoxic Potential of Phenothiazines Pp.
1055-1066
N. Motohashi, M. Kawase, K. Satoh and H. Sakagami
[Abstract]
Fluorescence Studies of Anti-Cancer Drugs –
Analytical and Biomedical Applications Pp. 1067-1081
J.-J. Aaron and S. Trajkovska
[Abstract]
Luminescence and Photophysical Properties of Benzo[α]phenothiazines
- Therapeutic, Physico-Chemical, and Analytical Applications
Pp. 1083-1093
M.D. Gaye-Seye, J.-J. Aaron, C. Párkányi
and N. Motohashi
[Abstract]
Interactions of Phenothiazines with Lipid Bilayer
and their Role in Multidrug Resistance Reversal Pp.
1095-1105
K. Michalak, O. Wesolowska, N. Motohashi, J.
Molnar and A. B. Hendrich
[Abstract]
Application of Phenothiazine Derivatives and other
Compounds for the Determination of Metals in Various Samples
Pp. 1107-1121
J. Seetharamappa, N. Motohashi and D. Kovala-Demertzi
[Abstract]
Phenothiazines and Structurally Related Compounds
as Modulators of Cancer Multidrug Resistance Pp.
1123-1134
I. Tsakovska and I. Pajeva
[Abstract]
Photosensitization of Biomolecules by Phenothiazine
Derivatives Pp. 1135-1154
G. Viola and F. Dall’Acqua
[Abstract]
Trypanosoma cruzi Dihydrolipoamide Dehydrogenase
as Target for Phenothiazine Cationic Radicals. Effect of Antioxidants
Pp. 1155-1179
J. Gutiérrez-Correa
[Abstract]
Phenothiazine: The Parent Molecule Pp.
1181-1189
S.C. Mitchell
[Abstract]
Psychotropic Medications and Leukopenia
Pp. 1191-1194
K. Sedky and S. Lippmann
[Abstract]
The Guanylyl Cyclase Inhibition by MB as Vasoplegic
Circulatory Shock Therapeutical Target Pp. 1195-1204
P.R.B. Evora and F. Viaro
[Abstract]
Evolution of Antipsychotic Intervention in the
Schizophrenic Psychosis Pp. 1205-1215
D.L. Garver
[Abstract]
Antipsychotic Medications in the Treatment of
Bipolar Disorder Pp. 1217-1224
A.A.S. Surja, R.L. Tamas and R.S. El-Mallakh
[Abstract]
A Critical Review of Rating Scales in the Assessment
of Movement Disorders in Schizophrenia Pp. 1225-1229
U. Taksh
[Abstract]
Abstracts
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to top]
Editorial
N. Motohashi
The present issue of Current Drug Targets is about bioactive
phenothiazines, which have been both experimentally used or
tested as drugs for treating or improving conditions in some
diseases in various branches of medicine. The issue mainly
concerns, how phenothiazine’s molecular features could
play a role of therapeutic nature and the side effects phenothiazines
could produce. The volume also provides the general introductions
to the topics in each chapter, with the intention that the
researchers easily understand the current knowledge of each
phenothiazine region. It contains information from both basic
and preclinical investigations, highlighting the selectivity
of their pharmacokinetic and metabolic processes. I strongly
hope that the issue provides information to anyone who seeks
to know more details about basic and therapeutic phenothiazines.
The credit however, is shared by the various contributor’s
who conducted these studies as an international teamwork,
focusing their researches on the phenothiazines.
I thank all contributors of review papers of the phenothiazine’s
special issue from the bottom of my heart and it is hoped
that the issue will serve as a stimulus for both further researchers
and research studies in the phenothiazine therapeutics region.
Professor and Dr. Noboru Motohashi
Meiji Pharmaceutical University
2-522-1 Noshio, Kiyose-shi
Tokyo 204-8588
Japan
[Back to top]
Cytotoxic Potential of Phenothiazines
N. Motohashi, M. Kawase, K. Satoh and H. Sakagami
Phenothiazines, a kind of sulfur-containing tricyclic
compounds, have diverse biological activities including tranquilizer,
antibacterial, antitumor and antihelmintic activities due
to the relatively lower cytotoxicity. Phenothiazines have
been used for clinical treatments as psychotropics. In contrast
to the psychotropic preparations, their information of other
biological activities of phenothiazines and their related
compounds has been limited. This review article summarizes
the interaction with DNA (using quantum calculation), antitumor
activity, differentiation or apoptosis-inducing activity,
tumor necrosis factor (TNF)-induction, antiproliferative activity,
radical scavenging activity, antimutagenic activity, antiplasmid
activity, antibacterial activity, reversal of multidrug resistance
(MDR), blast transformation activity of phenothiazines, benz[c]acridines
and benzo[a]phenothiazines.
[Back to top]
Fluorescence Studies of Anti-Cancer Drugs
– Analytical and Biomedical Applications
J.-J. Aaron and S. Trajkovska
The fluorescence properties of anticancer drugs (ACDs),
including steady-state native fluorescence, time-resolved
fluorescence, fluorescence polarization, excimer and exciplex
emission, laser-induced fluorescence (LIF) with one- or two-photon
excitation are reviewed, as well as the use of fluorogenic
labels and fluorescent probes for the non-fluorescent ACDs.
The interest of monitoring the fluorescence spectral changes
to study the interactions of ACDs with biomolecules, such
as DNA, proteins, vesicles, and the formation of complexes
is discussed. The fluorescence methodologies used for ACDs
studies, including fluorescence with two-photon excitation,
liquid chromatography and capillary electrophoresis with fluorescence
and laser-induced fluorescence (LIF) detection, and fluorescence
microscopy, are also surveyed. Analytical and bioanalytical
applications of fluorescence, indicating good selectivity
and very low limits of detection at the nanomolar and picomolar
level for most ACDs, are described. Biomedical and clinical
applications of the fluorescence methods, mostly oriented
towards the evaluation of the cytoxicity and anti-tumor potential
of ACDs in single cells as well as in biological fluids, including
blood, serum, plasma, cerebrospinal fluid, urine and feces,
are also discussed in detail. This review is based on selected
literature published in the last decade (1994-2003).
[Back to top]
Luminescence and Photophysical Properties
of Benzo[α]phenothiazines
- Therapeutic, Physico-Chemical, and Analytical Applications
M.D. Gaye-Seye, J.-J. Aaron, C. Párkányi
and N. Motohashi
Luminescence studies on a series of new 12H-benzo[a]phenothiazines
(BPHTs), possessing potentially useful antitumor therapeutic
properties, are reviewed. The electronic absorption and fluorescence
spectral properties of BPHTs, as well as their triplet- and
singlet-excited states luminescence quenching are reviewed.
Ground-state and singlet-excited state dipole moments and
solvatochromic relationships are also described for these
compounds. Studies on the formation of inclusion complexes
between BPHTs and cyclodextrins (CDs), including CD-enhanced
fluorescence, and thermodynamic constants and molecular geometry
of these complexes, are discussed. The BPHTs antitumor properties
in relation to their π-electron
density, and the physico-chemical and analytical applications
based on their fluorescence and photophysical properties are
also presented. This review article is based on selected literature
data published in the last ten years (1993-2004).
[Back to top]
Interactions of Phenothiazines with Lipid
Bilayer and their Role in Multidrug Resistance Reversal
K. Michalak, O. Wesolowska, N. Motohashi,
J. Molnar and A. B. Hendrich
The mechanism of multidrug resistance (MDR) reversal
is not fully understood yet. Interaction of MDR modifiers
with lipid bilayer of cell membranes and alterations of fluidity
or other biophysical properties of plasma membrane might be
an important factor in mechanism of MDR modulation and reversal.
In this review we focus on phenothiazines which belong to
the group of drugs known to modify MDR in different types
of cells, from cancer cells up to various kinds of microorganisms.
First, the aggregation properties of phenothiazines and their
interactions with lipid bilayers are described. The localization
of phenothazine derivative molecules in bilayers and alteration
of membrane properties are discussed. Apart from the influence
on model bilayers also the interactions of phenothiazines
with cellular membranes (especially of erythrocytes) are reviewed.
In subsequent sections the anti-MDR activity of phenothiazine
derivatives observed in microorganisms and in cancer cells
is described. The possible molecular mechanisms involved in
MDR reversal by these compounds are presented. The direct
interactions of phenothiazines with multidrug transporters
and other effects of these modulators on plasma membranes
are discussed. Finally, the structural features of phenothiazine
derivatives essential for their optimal MDR reversal activity
are described.
[Back to top]
Application of Phenothiazine Derivatives
and other Compounds for the Determination of Metals in Various
Samples
J. Seetharamappa, N. Motohashi and D. Kovala-Demertzi
Phenothiazine derivatives (PDS) readily react with several
metal ions in acid or buffer media to yield colored species
which could be followed spectrophotometrically. Reaction conditions
have been optimized to get colored species of maximum stability
and intensity. The effects of foreign ions have been investigated.
The results of all the methods were supported by statistical
analysis. The proposed methods have been successfully applied
for the analysis of various samples containing the interested
metal ion(s). In addition, some extractive spectrophotometric
methods based on the formation of ion-association complexes
(extractable into organic solvents) and gravimetric methods
have been discussed.
[Back to top]
Phenothiazines and Structurally Related Compounds
as Modulators of Cancer Multidrug Resistance
I. Tsakovska and I. Pajeva
Phenothiazines and structurally related compounds alongside
their other biological activities are able to modulate multidrug
resistance (MDR) in tumor cells. The extensive investigations
on their MDR modulation effects consist part of the efforts
to overcome MDR – the major obstacle in cancer chemotherapy.
In this article we try to systematize the results collected
in the last two decades in two main aspects. The first one
comprises the mechanism of modulation by phenothiazine-type
MDR modulators. Two main possible mechanisms of MDR reversal
are reviewed: (i) direct interaction with Pgp; (ii) interactions
with membrane phospholipids. The second aspect relates to
the structural properties of phenothiazines and related compounds
responsible for their MDR reversing effect. The structural
alerts and physicochemical properties influencing anti-MDR
activity are considered as identified by structure –
activity (SAR) or quantitative structure – activity
relationship (QSAR) studies. Results discussed in the article
point to MDR modulation by phenothiazines and related compounds
as a complex process in which more than one mechanism are
certainly involved. Further investigations in this direction
should contribute to elucidation of the possible mechanisms
of MDR modulation by these compounds. On the basis of the
studies discussed the potential use of phenothiazine-type
MDR modulators as a model system in the further investigations
of the MDR phenomenon is outlined.
[Back to top]
Photosensitization of Biomolecules by Phenothiazine
Derivatives
G. Viola and F. Dall’Acqua
It is well known that many drugs act as photosensitizers
towards cells by interacting with various cellular components
such as lipids, proteins and nucleic acids. The structural
modifications of the cellular components may occur by direct
interactions of the excited states (singlets or triplets)
of the drugs with the biological substrate or indirectly,
through reactive species of oxygen sensitised by the drug
themselves. In particular, the phototoxic activity of various
drugs correlated with their potential photomutagenic and photocarcinogenic
effects, takes place through DNA modification.
Phenothiazines, a class of antihistaminic (anti-H1)
or neuroleptic drugs used in the therapy of mental illness,
such as schizophrenia, organic psychoses and other mental
disorders, are known to induce photosensitization of the skin
by systemic use or by topical applications as antiallergic
drugs.
In this review we have focused our attention on the photosensitizing
property of phenothiazines and related compounds both in
vitro and in vivo systems. Particular attention
has been given to the mechanism of photo reaction with biomolecules
such as lipids, proteins and DNA.
Moreover there is a growing interest in drugs having photobiological
effects because of their possible application as phototherapeutics.
It has been interesting in this context to mention briefly
the possible application of phenothiazine derivatives as new
photosensitizers for their therapeutic application in photodynamic
therapy (PDT) or in the light inactivation of viruses and
bacteria.
[Back to top]
Trypanosoma cruzi Dihydrolipoamide
Dehydrogenase as Target for Phenothiazine Cationic Radicals.
Effect of Antioxidants
J. Gutiérrez-Correa
Myeloperoxidase (MPO), myoglobin (Mb) and horseradish
peroxidase (HRP), catalyzed the generation of radical-cations
by one-electron oxidation of phenothiazines (PTZ). The transient
formation of these radicals (PTZ+.) was confirmed
by ESR and optical spectroscopy. These species are reactive
towards Trypanosoma cruzi LADH (T. cruzi LADH),
T. cruzi trypanothione reductase (T. cruzi TR)
and possibly other macromolecule targets. Both T. cruzi
enzymes were irreversibly inactivated. T. cruzi LADH
inactivation depended on: a) PTZ structure, peroxidase nature
and the rate production of PTZ+. radical cations;
b) incubation time; c) the presence of an antioxidant that
intercepts free radicals. The production of PTZ+.
radical cations, which is essential for T. cruzi
LADH inactivation, is correlated with the electron donor ability
of the substrates, as qualified by the Hammett σpara
constant for the subtituent in the 2-position of the PTZ.
Promazine (PZ), trimeprazine (TMPZ) and thioridazine (TRDZ)
were the most effective inactivating agents, whereas trifluo-phenothiazines
with CF3 group at 2-position (Trifluoperazine (TFP),
fluphenazine (FFZ) and trifluopromazine (TFPZ)), and propericyaz-ine
(PCYZ) with CN group at 2-position, were much less active
or inactive, all in close agreement with their higher or lowest
electron donor ability, respectively. Comparison of inactivation
values for T. cruzi LADH and mammalian heart LADH
demonstrated a greater sensitivity of T. cruzi LADH
to various PTZ studied. Thiol compounds, tyrosine, dopa, tryptophan,
NADH, ascorbate and trolox prevented T. cruzi LADH
inactivation by the peroxidase/H2O2
systems in agreement with their ability to suppress PTZ+.
radical cations. The role of these radicals as enzyme inhibitors,
or as generators of secondary free radicals and metabolite
depletors may contribute to explain the trypanocidal effect
as well as other chemotherapeutic actions of PTZ.
[Back to top]
Phenothiazine: The Parent Molecule
S.C. Mitchell
Phenothiazine is an aromatic tricyclic compound that
first emerged from the furtive chemical activity surrounding
the aniline dye industry at the latter half of the 19th
century. It contains both nitrogen and sulphur atoms and is
the parent molecule of a multitude of drugs that have enjoyed
varied and extensive use throughout medical and veterinary
practice. The compound itself is not without biological activity
and has been shown to possess insecticidal, antifungal, antibacterial
and anthelmintic properties. It was this latter vermifugal
application that has earned the molecule a place alongside
penicillin and DDT for its colossal impact on mankind. Following
its extensive usage over many years, unwanted reactions including
neuromuscular incoordination, photosensitization and haemolytic
anaemia have been reported and these have limited its use
in the present climate. Investigations into the mode of action
of phenothiazine and its underlying biochemical properties
have been undertaken but the molecule has yet to reveal its
secrets and still poses problems of understanding at the molecular
level. This article reviews the literature, both established
and current, and presents a contemporary view on phenothiazine
and its interaction with biological systems.
[Back to top]
Psychotropic Medications and Leukopenia
K. Sedky and S. Lippmann
Neutropenia and/or agranulocytosis are among the medicinal
side-effects induced by many psychotropic drugs. Clozapine
and carbamazepine cause the highest incidence of this side-effect
and require long-term blood cell monitoring. Bone marrow suppression
can have an allergic, hypersensitivity etiology (e.g., clozapine),
which mandates the causative drug discontinuation. It can
also be a direct, toxic effect (e.g., carbamazepine), which
calls for dosage reduction or a medication change. Other treatment
options may include filgrastim, sargramostim, or lithium.
Blood cell count monitoring is encouraged on patients receiving
clozapine as long as the drug is continued. Such evaluation
is also advised on those medicated with other psychotropics,
especially carbamazepine.
[Back to top]
The Guanylyl Cyclase Inhibition by MB as
Vasoplegic Circulatory Shock Therapeutical Target
P.R.B. Evora and F. Viaro
There were strong evidences that NO has capital importance
in the progressive vasodilatation that associates to the varied
circulatory shock forms. The decreased systemic vascular resistance
observed in irreversible hemorrhagic (hypovolemic) and septic
shock may be due to the excess production of nitric oxide.
Other forms of shock associated to anaphylaxis (anaphylactic
shock, SIRS) and ischemia reperfusion injury (cardiogenic
shock, organ transplants), may involve nitric oxide overproduction.
In these situations, the nitric oxide-induced loss of vascular
sensitivity to catecholamines and myocardial depression contributes
to lethal hypotension. As NO vasodilatation is cyclic GMP
– mediated, there were two therapeutical options: a)
The unspecific NO synthesis inhibition by L-arginine analogs,
iNOS-specific inhibition by corticoids and/or aminoguanidine
and; b) Guanylyl cyclase inhibition by MB. As the NO synthesis
inhibition is associated to tissue necrosis and adverse hemodynamic
effects and its clinical use was associated with high mortality,
the second option using MB is safer and more rational. The
elaboration of this text was motivated to suggest the guanylyl
cyclase inhibition by MB as vasoplegic circulatory shock therapeutical
target.
[Back to top]
Evolution of Antipsychotic Intervention in
the Schizophrenic Psychosis
D.L. Garver
The accidental discovery (in the 1950s) and subsequent
development of antipsychotic drugs have revolutionized the
care of many patients with the schizophrenic psychoses. The
first-generation antipsychotics, though effective for hallucinations,
delusions, as well as a treatment of the disorder in two-thirds
of patients with schizophrenia, burdened many patients with
extrapyramidal effects (EPS), including dystonias, akathisia,
and pseudo-Parkinsonian morbidity. Moreover, they had little
or no effect on the most disabling, core symptoms associated
with withdrawal of interests and interpersonal relationships.
The second-generation antipsychotics, which began to appear
in the late 1980s with the introduction of clozapine, had
strikingly less morbidity, contributing little or no EPS and
providing at least modest promise of reduction of negative
symptoms and enhancement of some aspects of cognition. However,
some second-generation antipsychotics have induced considerable
weight gain, and appear to lower the threshold for the development
of the metabolic syndrome, which increases cardio-vascular
morbidity.
The actual mechanism(s) of action of the antipsychotic drugs
is still in dispute. Direct and indirect effects on dopamine
transmission have been supported by much of the evidence.
Direct blockade of dopamine hyperactivity and partial restoration
deficient dopamine has been the standard explanation of their
effects. However, dysfunctional intracellular signal transduction
and dysfunction of myelin are emerging as competing pathologies
upon which antipsychotics act. It is likely that the next
generation of antipsychotics will act more directly and more
specifically on such underlying neuropathology.
[Back to top]
Antipsychotic Medications in the Treatment
of Bipolar Disorder
A.A.S. Surja, R.L. Tamas and R.S. El-Mallakh
Antipsychotic medications have been used to treat acute
phases, and prevent relapses in, bipolar illness since their
introduction into psychiatric practice. With the introduction
of second generation antipsychotic medications, there has
been renewed interest in the utility of this class of medications
in managing manic-depression. It appears that all antipsychotic
agents investigated have a potent acute antimanic property.
This has been shown both in monotherapy and in combination
with traditional mood stabilizing medications. The first generation
antipsychotics appeared to worsen depression or induce a depressive-like
state, but the second generation agents do not have this property
and may have some antidepressant properties in bipolar patients.
There is a dearth of controlled long term studies, but in
open studies, both first and second generation agents appear
to have a beneficial effect. Second generation antipsychotic
agents appear to be a useful tool that may benefit bipolar
patients. Adverse consequences of this group of medications
appear to be the major limiting factors to their use.Antipsychotic
medications play a very important role in the treatment of
bipolar illness. This has become especially true since the
introduction of second generation agents. There is a wealth
of data documenting the use of these agents in bipolar mania.
There are fewer studies examining relapse prevention. Finally,
there are a small number of interesting studies suggesting
utility in bipolar depression. This paper will critically
review available randomized clinical trials utilizing antipsychotic
agents in bipolar disorder.
[Back to top]
A Critical Review of Rating Scales in the
Assessment of Movement Disorders in Schizophrenia
U. Taksh
Tardive dyskinesia (TD) has been recognised for nearly
50 years. It is associated with antipsychotic drugs and is
usually persistent with no satisfactory treatment. It is believed
to be under-documented in medical records. Many rating scales
have been devised to measure TD. Studies have demonstrated
variability between the rating scales on the measures of reliability
and validity, the clinical setting used, the raters involved
in the ratings and the provision of definitions and instructions.
Scales that include too many items to be comprehensive become
cumbersome and difficult to use. A compromise is to reduce
the number of items and have add-in items for individual patients.
A good example of this approach is the Abbreviated Dyskinesia
Scale (ADS). Rating scales continue to be the best available
methods to evaluate dyskinesia but in view of the shortcomings
of validity, reliability and utility for clinical use, more
efforts need to be done to improve current rating scales and
to develop new ones.
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