Leonard Amaral- .
- Professor Emeritus at Institute of Hygiene and Tropical Medicine, Universidade Nova de Lisboa
Leonard Amaral
- .
- Professor Emeritus at Institute of Hygiene and Tropical Medicine, Universidade Nova de Lisboa
About
377
Publications
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Introduction
Development of drugs that promote killing of intracellular Mycobacterium tuberculosis infection by non-killing human macrophages; new methods for evaluation of efflux pumps of multi-drug resistant bacteria infections and multi-drug resistant cancers; drugs with activity against mdr bacteria and mdr cancers.Collaborates with 29 scientists from Europe, India, China, Japan, USA, South Africa and Argentina. Received the Medal Of Merit from the Universidade Nova de Lisboa on 8 November 2018 for work that resulted in reducing the frequency of MDR Mtb infections of the Greater Lisbon area from 28% of all clinical isolates in 1999 to 4%. in 2008.
Current institution
Institute of Hygiene and Tropical Medicine, Universidade Nova de Lisboa
Current position
- Professor Emeritus
Additional affiliations
September 2012 - present
University of Szeged, Szeged, Hungary
Position
- Professor Emeritus
Description
- Collaborate in research and teaching grad and post-grad students in infectious disease and cancer.
May 1968 - January 1977
Position
- Managing Director
Description
- Directed the research activities in the field of leukemia/basic research/drug development and assisted in the direction and operation of the Department of Anatomic and Clinical Pathology.
May 1968 - June 1992
Position
- Professor (Associate)
Description
- Directed research conducted at Methodist Hospital of Bklyn.
Education
September 1964 - August 1967
Publications
Publications (377)
Background/aim: One of the most studied bacterial resistance mechanisms is the resistance related to multidrug efflux pumps. In our study the pump activity of the Escherichia coli K-12 AG100 strain expressing the AcrAB-TolC pump system was investigated at pH 7 and pH 5 in the presence of the efflux pump inhibitor (EPI) promethazine (PMZ).
Material...
Background/aim:
One of the most studied bacterial resistance mechanisms is the resistance related to multidrug efflux pumps. In our study the pump activity of the Escherichia coli K-12 AG100 strain expressing the AcrAB-TolC pump system was investigated at pH 7 and pH 5 in the presence of the efflux pump inhibitor (EPI) promethazine (PMZ).
Materia...
Phenothiazines have been used in many areas of medicine, mainly in psychopharmacology. These compounds are able to effectively inhibit dopamine, histamine, serotonin, acetylcholine, and α-adrenergic receptors; thus, their effect and side-effect profiles are extremely diverse. Besides their antipsychotic activity, phenothiazines have a significant a...
Multidrug resistance (MDR) has appeared in response to selective pressures resulting from the incorrect use of antibiotics and other antimicrobials. This inappropriate application and mismanagement of antibiotics have led to serious problems in the therapy of infectious diseases. Bacteria can develop resistance by various mechanisms and one of the...
![Structures of the phenothiazines thioridazine and chlorpromazine [9].](publication/312316915/figure/fig1/AS:11431281332640920@1743265275636/Structures-of-the-phenothiazines-thioridazine-and-chlorpromazine-9_Q320.jpg)
This review presents the evidence that supports the use of thioridazine (TZ) for the therapy of a pulmonary tuberculosis infection regardless of its antibiotic resistance status. The evidence consists of in vitro and ex vivo assays that demonstrate the activity of TZ against all encountered Mycobacterium tuberculosis (Mtb) regardless of its antibio...
The focus of this mini-review is to identify non-toxic compounds isolated from natural sources (plants) that exhibit specific activity against efflux pumps of specific multidrug-resistant (MDR) cancer cell lines, inhibit proliferation of the MDR cancer cell lines and inhibit the activity of overexpressed efflux pumps of the MDR cancer cell line.
Thioridazine (TZ) is an antipsychotic drug renders multidrug resistant (MDR) cancer cells susceptible to cytotoxic agents to which they were initially resistant, has antiprolilferative activity and apoptotic inducing properties in various tumor cell lines and cancer stem cells. Whereas the antiproliferative activity takes place at high concentratio...
This paper deals with the rapid molecular changes induced by laser radiation on two novel hydantoin derivatives, generically named SZ-2 and SZ-7, having promising pharmaceutical properties as Szymanska et al. in 2002 and Subtelna et al. in 2010 have reported. Hydantoins solutions with concentration of 10−3M in dimethyl sulfoxide were exposed both i...
The cell membrane P-glycoprotein (P-gp; MDR1, ABCB1) is an energy-dependent efflux pump that belongs to the ATP-binding cassette (ABC) family of transporters, and has been associated with drug resistance in eukaryotic cells. Multidrug resistance (MDR) is related to an increased expression and function of the ABCB1 (P-gp) efflux pump that often caus...
The increasing occurrence of multidrug resistant tuberculosis exerts a major burden on treatment of this infectious disease. Thioridazine, previously used as a neuroleptic, is active against extensively drug resistant tuberculosis when added to other second and third line antibiotics. By quantitatively studying the proteome of thioridazine treated...
Given the ability of M. tuberculosis to survive as an intracellular pathogen and its propensity to develop resistance to the existing antituberculosis drugs, its treatment requires new approaches. Here the antimycobacterial properties of verapamil, thioridazine, chlorpromazine, flupenthixol and haloperidol were investigated against a panel of drug...
Effect of the ion channel blockers against human monocyte-derived macrophages.
Cells were treated with different concentrations of the compounds for 3 days; 10% of AlamarBlue was then added and the cells were further incubated during four hours at 37°C, 5% CO2. For the subsequent intracellular assays, the concentrations used were those that gave mo...
Genetic characterization of the efflux transporters studied.
(DOCX)
Primers used in the RT-qPCR assays.
(DOCX)
Concentrations required to inhibit M. tuberculosis in vitro versus that needed to produce similar effects on macrophages.
(DOCX)
This review presents the evidence that supports the use of thioridazine (TZ) for the therapy of a pulmonary tuberculosis infection regardless of its antibiotic resistance status. The evidence consists of in vitro and ex vivo assays that demonstrate the activity of TZ against all encountered Mycobacterium tuberculosis (Mtb) regardless of its antibio...
This paper deals with the rapid molecular changes induced by laser radiation on two novel hydantoin derivatives, generically named SZ-2 and SZ-7, having promising pharmaceutical properties as Szymanska et al. in 2002 and Subtelna et al. in 2010 have reported. Hydantoins solutions with concentration of 10-3 M in dimethyl sulfoxide were exposed both...
Ecdysteroids are known as regulators of moulting and reproduction in arthropods, and they can also be found in many plants as defensive agents against herbivores [1]. Our research group has recently reported their adjuvant antitumor activity in combination with various chemotherapeutics on several cancer cell lines, by studying fourteen 20,22-, sev...
Tuberculosis presenting severe resistance, defined as extensively drug resistant tuberculosis (XDR TB) continues to increase world-wide to the point that resistance to all available drugs, defined as totally drug resistant tuberculosis (TDR TB) is now significantly present in India, Iran, and other countries (ex. China) and regions (ex. Central Asi...
A series of amine derivatives of 5-aromatic imidazolidine-4-ones (7–19), representing three subgroups: piperazine derivatives of 5-arylideneimidazolones (7–13), piperazine derivatives of 5-arylideneimidazolidine-2,4-dione (14–16) and primary amines of 5-naphthyl-5-methylimidazolidine-2,4-diones (17–19), was evaluated for their ability to improve an...
A series of amine derivatives of 5-aromatic imidazolidine-4-ones (7-19),
representing three subgroups: piperazine derivatives of 5-arylideneimidazolones
(7-13), piperazine derivatives of 5-arylideneimidazolidine-2,4-dione (14-16) and
primary amines of 5-naphthyl-5-methylimidazolidine-2,4-diones (17-19), was
evaluated for their ability to improve a...
The most common mechanism that reduces the efficacy of anticancer agents is overexpression of ATP-binding cassette (ABC) drug transporters. Phenothiazines and structurally-related compounds can sensitize multidrug-resistant (MDR) cells to chemotherapeutics.
Phenothiazine derivatives were investigated regarding their anticancer and MDR-reversing eff...
A series of amine derivatives of 5-aromatic imidazolidine-4-ones (7-20), representing three subgroups: piperazine derivatives of 5-arylideneimidazolones (7-13), piperazine derivatives of 5-arylideneimidazolidine-2,4-dione (14-16) and primary amines of 5-naphthyl-5-methylimidazolidine-2,4-diones (17-19), was evaluated for their ability to improve an...
Ecdysteroids, analogs of the insect molting hormone, are known for their various mild, nonhormonal bioactivities in mammals. Previously, we reported that less-polar ecdysteroids can modulate the doxorubicin resistance of a multidrug resistant (MDR) mouse lymphoma cell line expressing the human ABCB1 transporter. Here, we describe the ability of 20-...
The study reports an investigation of the photoproducts obtained by exposure of chlorpromazine hydrochloride in ultrapure water (concentration 2 mg/mL) to a 266-nm laser beam obtained by fourth harmonic generation from a Nd:YAG laser (6-ns full time width at half maximum, 10-Hz pulse repetition rate). The photoproducts were analyzed by steady-state...
Objectives Chlamydiae are Gram-negative obligate intracellular bacterial pathogens responsible for a range of diseases of clinical and public health importance. C. trachomatis D is of great public health significance because of the impacts of untreated diseases on reproductive outcomes. Ascending uterine infections can lead to pelvic in?ammatory di...
Commentary It is estimated that most of the medicinal compounds developed during the 20th century have their origins in phenothiazines [1]. Among these medicinal compounds is the first neuroleptic chlorpromazine (CPZ) introduced in 1957. The wide use of CPZ resulted in many published observations that indicated activity against a wide variety of mi...
Over-expressed efflux pumps of cancer cells frequently contribute to the failure of cancer chemotherapy. These proteins are responsible for the extrusion of a large variety of unrelated chemically distinct compounds that are toxic to the cell. Hence their increased presence leads to a multi-drug resistant (MDR) phenotype. Ecdysteroids are analogues...
Bacteria and cancer cells frequently increase their resistance to chemotherapeutics as a consequence of therapy. Whenever studied, refractory response to chemotherapy is due to the over-expression of efflux pumps that render the bacterium or cancer cell resistant not only to the agent used for therapy, but to many, if not all other agents as well....
We have recently reported the set-up of an experimental system for the laser-induced photochemical modification of bioactive substances, where two ecdysteroids, 20-hydroxyecdysone (20E) and its diacetonide derivative served as probes. As a direct continuation of our previous work, three new compounds together with five other ecdysteroid derivatives...
Background: Phenothiazines have anticancer properties and are able to reverse the multidrug resistance
of neoplastic cells by inhibiting the ATP-binding cassette, sub-family B (MDR/TAP), member 1 protein (ABCB1 or Pglycoprotein) activity. Materials and Methods: A series of new phenothiazine derivatives was investigated regarding their ABCB1-modulat...
Advances recently introduced into the Clinical Mycobacteriology Laboratory of the Institute of Hygiene and Tropical Medicine, such that a multi-drug resistant infection of pulmonary tuberculosis (MDR TB) can be identified within one day of receiving the sputum specimen, have greatly contributed to the reduction of the frequency of these infections....
The mechanisms by which antibiotic resistance of bacteria takes place are discussed in detail. Among the
mechanisms that have been recently elucidated are overexpressed efflux pumps that render the bacterium multidrug resistant; down-regulation of porins; target modification; quorum sensing; biofilm production and
secretion and plasmids that carry...
This review discusses the relationship of the efflux pump (EP) system of Gram-negative bacteria to other antibiotic resistance mechanisms of the bacterium such as quorum sensing, biofilms, two component regulons, etc. The genetic responses of a Gram-negative to an antibiotic that render it immune to an antibiotic are also discussed. Lastly, the met...
Abstract
Four large groups of antibiotics were developed for different targets of bacterial cells which differ from those of
human cells. Uncontrolled use of antibiotics, resistance soon followed. Today, the majorities of bacterial infections are caused by multidrug resistant bacterial isolates and result in serious treatment difficulties. The main...
Editorial During the 1950’s, the consensus among infection disease practitioners was that pulmonary tuberculosis, as a consequence of the effectiveness of the two main anti-tuberculosis drugs, isoniazid (INH) and rifampicin (RIF), would soon be globally eradicated. However, as a consequence of civil unrest, wars, poverty and famine primarily in thi...
Fully treatable tuberculosis with isoniazid and rifampicin has progressed to multi-drug resistant tuberculosis (MDR TB) and to increasingly more severe status of drug resistance extensively drug resistant (XDR). Most recently, totally drug resistant (TDR) tuberculosis has arisen in India in large numbers. Although the threat to global health is rea...
Introduction: varicose ulcer is characterized by being a skin lesion that affects the lower third of the legs and can be triggered by vascular, metabolic and hematologic changes. Objective: to know the changes in the daily lives of people affected by varicose ulcer. Methods: descriptive and exploratory research with qualitative approach, held in ex...
At this moment, millions of patients are terminally ill with essentially incurable pulmonary tuberculosis. This herein mini-review provides the experimental and observational evidence that a specific phenothiazine, thioridazine, will cure any form of drug-resistant tuberculosis. Given that economic motivation can stimulate the use of thioridazine a...
At this moment, over half million patients suffer from multi-drug resistant tuberculosis (MDRTB) according to the data from the WHO. A large majority is terminally ill with essentially incurable pulmonary tuberculosis. This herein mini-review provides the experimental and observational evidence that a specific phenothiazine, thioridazine, will cont...
Ecdysteroids, molting hormones of insects, can exert several mild, non-hormonal bioactivities in mammals, including humans. In a previous study, we have found a significant effect of certain derivatives on the ABCB1 transporter mediated multi-drug resistance of a transfected murine leukemia cell line. In this paper, we present a structure-activity...
Cancer cells become refractory to chemotherapy as a consequence of their overexpression of multidrug transporters.
The anticancer and multidrug resistance (MDR) reversal effects of the racemic form and the two enantiomers of thoridazine were investigated on a mouse T-lymphoma cell line over-expressing the ATP-binding cassette, subfamily-B (MDR/TAP)...
Pulmonary tuberculosis (TB), once thought to be on track for complete elimination during the 1950’s as a consequence of improved social conditions, delivery of public health, diagnosis and therapy with the two most effective anti-tubercular agents Isoniazid (INH) and Rifampicin (Rif), has, as a consequence of social and political strife which reduc...
Phenothiazine exposed to white light or UV radiation undergoes a variety of reactions that result in the degradation of the parental compound and the formation of new species. Chlorpromazine exposed to the 266 nm laser beam of given energy levels yielded species derived from it, whose number increased with the exposure duration. At distinct time in...
Chlorpromazine (CPZ) was exposed to a 266nm laser beam for different periods of time ranging from minutes to 24 h. At intervals, the products from irradiation were evaluated by thin-layer chromatography (TLC) and evaluated for their activity against mycobacteria of human interest (Mycobacterium tuberculosis, M. avium, M. intracellulare and their co...
Efflux pumps are integral plasma membrane protein systems that recognize and bind noxious compounds present in the cytoplasm (toxic products produced by metabolism; compounds that have penetrated the cell), or periplasm of the bacterial cell and extrude it into the environment in which the bacterium resides. The efflux pump machinery gives the cell...
The use of light-activated bactericidal agents—photobactericides—is suggested in local infection in order to conserve conventional antibacterials for more systemic disease. Local administration of a photobactericide such as methylene blue coupled with locally-targeted red light illumination ensures the production of non-specific reactive oxygen spe...
After the publication of our study [1], we became aware that the mutations in the quinolone resistance-determining region (QRDR) of the gene grlA were incorrectly described for some of the Staphylococcus aureus clinical isolates studied in this work. In particular, isolates SM1, SM10, SM14, SM17, SM25, SM27, SM43, SM46, SM47 and SM48 carry the GrlA...
Cancer grows at the expense of the host as a parasite or superparasite following the second law of thermodynamics (conservation of energy). When the cancer cell progresses via replication to the special state called “spheroid”, a new phase begins with its intimiate interaction and development of responses from the stroma which together assist in th...
Morpholino-disiloxane (ALIS-409) and piperazino-disiloxane (ALIS-421) compounds were developed as inhibitors of multidrug resistance of various types of cancer cells. In the present study, the effects of ALIS-409 and ALIS-421 compounds were investigated on cancer promotion and on co-existence of tumor and normal cells. The two compounds were evalua...
The effect of prolonged and repeated exposure of mice to low levels of ozone was studied during a 120-day period. During this time, severe alterations were observed in the synthesis of lung DNA (decreased), RNA (decreased), and protein (increased).
The major priority for tuberculosis control programmes is the rapid and accurate diagnosis and treatment of individuals with active tuberculosis. This approach is intended to cut the chain of transmission of the bacillus
and provide appropriate therapy to the tuberculosis patient. In this context, the mycobacteriology laboratory has a crucial role...
This chapter to provides the rationale and experimental basis for thioridazine and its consideration as a new effective anti-XDR-TB.
drug.
![Multiple reactions monitoring (MRM) was performed for [M+H+] = 285,...](profile/Leonard-Amaral-2/publication/235605424/figure/fig13/AS:202554655940634@1425304201521/Multiple-reactions-monitoring-MRM-was-performed-for-M-H-285-301-317-319-and-335_Q320.jpg)
Phenothiazines when exposed to white light or to UV radiation undergo a variety of reactions that result in degradation of parental compound and formation of new species. This process is slow and may be sped up with exposure to high energy light such as that produced by a laser.
Varying concentrations of Chlorpromazine Hydrochloride (CPZ) (2-20 mg/...
Acquisition of resistance is one of the major causes of failure in therapy of bacterial infections. According to the World Health Organization (WHO), thousands of deaths caused by Salmonella sp., Escherichia coli, Staphylococcus aureus or Mycobacteria tuberculosis are due to failure in therapy caused by resistance to the chemotherapeutic agents. Un...
The emergence of infections caused by multi- or pan-resistant bacteria in the hospital or in the community settings is an increasing health concern. Albeit there is no single resistance mechanism behind multiresistance, multidrug efflux pumps, proteins that cells use to detoxify from noxious compounds, seem to play a key role in the emergence of th...
It is known that bacteria showing a multi-drug resistance phenotype use several mechanisms to overcome the action of antibiotics. As a result, this phenotype can be a result of several mechanisms or a combination of thereof. The main mechanisms of antibiotic resistance are: mutations in target genes (such as DNA gyrase and topoisomerase IV); over-e...
Phenothiazines have their primary effects on the plasma membranes of prokaryotes and eukaryotes. Among the components of the prokaryotic plasma membrane affected are efflux pumps, their energy sources and energy providing enzymes, such as ATPase, and genes that regulate and code for the permeability aspect of a bacterium. The response of multidrug...
Resistance mediated by efflux has been recognized in Staphylococcus aureus in the last few decades, although its clinical relevance has only been recognized recently. The existence of only a few studies on the individual and overall contribution of efflux to resistance phenotypes associated with the need of well-established methods to assess efflux...
Plasmid pSM52 was isolated from SM52, a sequence type 8
(ST8) meticillin-resistant S. aureus (MRSA) strain collected in a Portuguese
hospital. SM52 was the only strain found to carry the smr
gene among a collection of 52 ciprofloxacin-resistant S. aureus clinicalisolates
Cancer grows at the expense of the host as a parasite or superparasite following the second law of thermodynamics (conservation of energy). When the cancer cell progresses via replication to the special state called “spheroid”, a new phase begins with its intimiate interaction and development of responses from the stroma which together assist in th...
Varying concentrations of Chlorpromazine Hydrochloride (CPZ) were exposed to a 266 nm laser beam for varying periods of time ranging from 4 to 24 hrs and the products of irradiation were evaluated for activity against a panel of bacteria that consisted of representatives of Gram-positives and Gram-negatives that expressed different degrees of efflu...
Phenothiazines have their primary effects on the plasma membranes of prokaryotes and eukaryotes. Among the components of the prokaryotic plasma membrane affected are efflux pumps, their energy sources and energy providing enzymes, such as ATPase, and genes that regulate and code for the permeability aspect of a bacterium. The response of multidrug...
Bacteria have the capacity, as all living cells, to escape harm from a noxious agent by extruding the agent before it reaches its target and harms to the cell. This initial response is intrinsic and involves plasma membrane bound efflux pumps which have the capacity to recognise and extrude a large variety of structurally unrelated molecules. When...
This mini-review provides the entire experimental history of the development of the old neuroleptic thioridazine (TZ) for therapy of antibiotic resistant pulmonary tuberculosis infections. TZ is effective when used in combination with antibiotics to which the initial Mycobacterium tuberculosis was resistant. Under proper cardiac evaluation procedur...
Tuberculosis is one of the major causes of infection globally. The emergence of multi, extensively and totally-drug resistant strains contributes to the lack of therapeutic options available. The mechanisms associated with this resistance could involve mutations of several gene targets, decreased permeability, increased efflux, etc. Resistance-medi...
Tuberculosis is one of the major causes of infection across the world. The emergence of multi-, extensively- and totally drug-resistant strains of Mycobacterium tuberculosis contributes to the lack of therapeutic options available. The mechanisms associated with this resistance could involve mutations in genes coding for target proteins, decreased...
This book, inclusive of 22 chapters, describes novel approaches currently used for antimicrobial drug discovery, focusing on agents for use against bacterial and fungal pathogens. Specific chapters discuss: (1) concepts relevant to drug resistance; (2) microbial mechanisms related to efflux pumps and studies on their potential inhibitors; (3) impac...
Over a period of 14 years, the authors have studied thioridazine, an old neuroleptic, that has been shown to have in vitro activity against intracellular Mycobacterium tuberculosis, regardless of its antibiotic resistance status, thioridazine cures infected mice of antibiotic-susceptible and multidrug-resistant tuberculosis (TB) infections and, whe...
Quorum Sensing (QS) systems of bacteria consist of a producer of the QS signal and the responder. The
generation of a QS signal provides the means by which a population can behave in a concerted manner such as swarming, swimming and secretion of biofilm, etc. Because concerted bahaviour bestows protection to the bacterial species, and hence factors...
Protoapigenone (PA), a natural flavonoid possessing an unusual p-quinol moiety on its B ring, is a prospective novel lead compound against cancer currently in development, together with WYC0209, a potent synthetic PA analog. Structure activity relationships (SAR) concerning different 1'-O-alkyl side-chains were also studied on two sets of derivativ...
Bacteria and cancer cells frequently increase their resistance to chemotherapeutics as a consequence of therapy. Whenever studied, refractory response to chemotherapy is due to the over-expression of efflux pumps that render the bacterium or cancer cell resistant not only to the agent used for therapy, but to many, if not all other agents as well....
N-dienylphenothiazines synthesized from tetrazolo[1,5-a]pyridinium salts by treatment with phenothiazine were subjected to catalytic hydrogenation to yield N-butylphenothiazines, whereas transformation of these dienes with borane dimethyl sulfide (BH(3) × Me(2)S) resulted in selective hydroboration of one double bond and full reduction of the other...
Multidrug resistant (MDR) tuberculosis is caused by Mycobacterium tuberculosis resistant to isoniazid and rifampicin, the two most effective drugs used in tuberculosis therapy. Here, we investigated the mechanism by which resistance towards isoniazid develops and how overexpression of efflux pumps favors accumulation of mutations in isoniazid targe...
Photochemical transformation of certain bioactive compounds for the purpose of obtaining derivatives with increased bioactivity is a prospective area of synthetic chemistry. Ecdysteroids, analogs of the insect molting hormone, which can also exert several beneficial effects in mammals including humans, contain an enone moiety in their B ring, and,...
Thioridazine (TDZ) in combination with antibiotics to which extensively drug-resistant Mycobacterium tuberculosis (XDR-TB) is initially resistant yields a cure. This is due to the fact that TDZ enhances the killing of intracellular M. tuberculosis by non-killing macrophages, inhibits the genetic expression of efflux pumps of M. tuberculosis that ex...
The antimicrobial action of a number of non-antibiotic drugs has been demonstrated in recent years, for example the antimycobacterial activity associated with the phenothiazine neuroleptic class. However, as with other classes of non-antibiotics, such activity may be traced back to common precursor structures such as the phenothiazinium dye, methyl...
Development of a non-toxic, fluorescent-based, agar system for the screening of overexpressed bacterial efflux pump systems with common, inexpensive UV accessories.
Wild type Gram-negative and positive bacteria expressing intrinsic efflux pumps and their progeny that overexpress a specific efflux pump were selected for evaluation of efflux pump act...
To evaluate a new series of 16 hydantoin derivatives for activity against the intrinsic and overexpressed efflux pumps of the ATTC 25923 Staphylococcus aureus and the clinical Staphylococcus aureus HPV-107 strain, respectively.
The hydantoin compounds were evaluated for activity against the efflux pumps of the ATTC 25923 S. aureus and the clinical...
Questions
Questions (24)
It seems to me that it would be extremely useful for the RG members to be able to have their citations by descending and ascending order much like Scopus. Companies can use this added criterion for evaluating the candidate for a given position.
Thioridazine is cheap, and it inhibits the replication of all encountered Mtb strains regardless of their antibiotic resistance status , it enhances intracellular killing of MDR Mtb and XDR Mtb , it cures the mouse of a pulmonary Mtb infection and it has cured 17 XDR TB patients without producing any serious side effects . So why has it not been seriously considered and used now for therapy of problematic TB infections that cannot be readily cured with other available drugs especially in countries where MDR, XDR TB and now TDR TB infections are present in huge numbers? I welcome your thoughts and involvement.
References that discusses all of the above:
Amaral L, Boeree M, Gillespie SH, Udwadia Z, van Soolingen D. Editorial: Thioridazine cures XDR TB: The need for Global Clinical Trials For therapy of XDR TB is now. Int J Antimicrob Agents 2010; 35:524-526.
Amaral L, Udwadia Z, Abbate E and van Soolingen D. The added effect of Thioridazine in treatment of resistant TB. Int J Tuberculosis and Lung Disease. 2012;16:1706-1708.
Strangely enough, the isolation of Mtb and analysis of its genome from autopsy subjects who do not present with active disease, has not been a subject of investigation. Because a parasite does not kill its host (normally) and because Mtb is a steadfast human pathogen, it seem reasonable to suspect that those who are infected and never progress to active disease are infected with a benign strain of Mtb. Any thoughts on this or have I missed something in the literature?
From discussions with colleagues, I get the impression that a single TB infection involves a single strain. This cannot be unless there is a preventive mechanism that renders the acquisition of another Mtb strain by the already infected person. Years ago I began to look into this question with specimen received from a Portuguese prison whose inmates share cells. Many of these inmates acquire the infection in prison and it seems that the opportunity to acquire another infecting organism is present. What are your thoughts or ideas on this topic?
Peer review is not all things to everyone and the process and the items within the process vary considerably from journal to journal. If the publication of work is to be judged as many believe it is by the use of the IF of a journal, should specific criteria be used as the fundamental absolute basis that together constitutes a standard review process? If this is achieved, then the "objective" standardized process of review may serve to further define quality.
Reviewers perform an important role that results in the improved quality of a publication. However, with the exception of a few proceedings and books, they are not identified in the peer reviewed publication. Moreover, some reviewers pass on the job of reviewing to a Post-Doc who, in attempting to impress his/her mentor, will exceed the responsibility of a reviewer. Among the items such "replacements" usually impart of the required revision, is the identification of additional experiments which fall beyond the question posed by the author(s) of the submitted study. In addition, if the review process was less than required, and yet the submission is recommended for publication, that reviewer would be associated publicly with that "faux pas". If the identity of the reviewer is prominent in an published study, some of the negative aspects of peer review might be reduced given the need for receiving credit for a job well done. I welcome the "pros and cons" relevant to the question asked in order that the question may be tabled or pursued as a common process in scientific publications.
