Current Drug Targets - Volume 7, Issue 9, 2006

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.

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.

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).

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).

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.

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.

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.

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.

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 spara 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 trifluophenothiazines with CF3⊂ group at 2-position (Trifluoperazine (TFP), fluphenazine (FFZ) and trifluopromazine (TFPZ)), and propericyazine (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.

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.

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.

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.

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 secondgeneration 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.

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.

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.