Papers by Igor Makarovsky
Journal of Nanomedicine & Nanotechnology, 2013
Polymeric nanoparticles have been widely investigated as carriers for drug delivery, as they can ... more Polymeric nanoparticles have been widely investigated as carriers for drug delivery, as they can effectively deliver the drug to a target site and thus increase the therapeutic benefit, while minimizing side effects. Triclosan (Irgasan ®) is a broad-spectrum antimicrobial agent, possessing mostly antibacterial, but also some antifungal and antiviral properties. In order to synergize the advantages of the delivery of antimicrobial molecules of triclosan by a nanoscaled system, we tested antimicrobial nanosized polymeric formulations containing triclosan. Triclosan was derivatized using acrylolyl chloride and then subjected to a radical dispersion polymerization. The polymeric nanoparticles were obtained, namely PTA-NPs, in the range of 100 nm. The characterization of these polymeric nanoparticles as well as the appropriate monomer has been accomplished by nuclear magnetic resonance, scanning and transmitting electron microscopy, elemental and thermal analyses. PTA NPs' electron microscopy examination presents a spherical morphology and a smooth topology. These nanoparticles exhibit very high antimicrobial activities against common pathogens involved in nosocomial infections. We demonstrate the importance of a direct contact of our nanoparticles and the bacterial cell as the trigger to triclosan releasing. Our results emphasize the advantages of a nanoscaled system in a covalently-linked delivery of a biocide and the limitations in utilizing the "free" biocide. Journal of Nanomedicine & Nanotechnology J o u rna l of N a n o m ed icine & N a n o te chnolo g y
Scientific Reports, Oct 27, 2022
that non-human primates poisoned with 3-5 LD 50 of soman and treated with a mixture of an oxime, ... more that non-human primates poisoned with 3-5 LD 50 of soman and treated with a mixture of an oxime, atropine, and benactyzine (TAB), showed remarkable recovery 15,16. Benactyzine is a compound with mixed anti-cholinergic and anti-glutamatergic properties, approved for emergency use in Israel in OP poisoning 17,18. Numerous studies have shown that exposure to different OPs at different doses produces a neuronal loss in various CNS structures, particularly in the entorhinal and piriform cortex, amygdala, and the CA1 and CA3 subfields of the hippocampus 19,20. It was recently suggested that the degree of brain damage and ensuing cognitive deficits depend on the severity of convulsions 14,21. Spatial learning and memory impairments are two major detrimental consequences of OP poisoning, with ensuing neuronal degeneration in CNS structures (e.g., hippocampus). Indeed, cognitive weakness, such as impaired learning and memory resulting from exposure to OPs, was reported in humans and animals 22,23. Raveh et al. 24,25 , demonstrated that caramiphen, a drug with a mixed anticholinergic and antiglutamatergic profile, affords better protection when compared to that provided by scopolamine, a pure anticholinergic agent when given in a pretreatment paradigm, and that TAB and caramiphen given to soman-exposed animals offered cognitive protection as reflected with the Morris water maze test 26. These results show that drugs with a pharmacological profile consisting of anticholinergic and antiglutamatergic properties such as caramiphen and benactyzine have an advantage as post-exposure therapies against poisoning by OP agents 27. The lack of a side-effect-free anticonvulsant prompts current research efforts aimed at developing better MCMs for OP-induced seizures. Any such drug should be devoid of behavioral side effects as possible, to diminish incapacitation of the casualty and since the drug may be taken inadvertently. Therefore, it is critical to identify drugs that not only counteract the effects of nerve agents but also produce minimal behavioral effects when administered alone. Gama-Amino-Butyric-Acid (GABA) is the major inhibitory neurotransmitter in the brain and was found to be involved in the reduction of convulsions 28. It is known that benzodiazepines that bind allosterically to GABA-chloride channels, display anticonvulsant activity and are commonly administered to patients affected by OP agents. Moreover, the benzodiazepine drug midazolam was shown to be superior over other compounds in terminating OP-induced seizures, with some neuroprotective qualities. However, GABA itself does not readily cross the blood-brain-barrier (BBB) and is therefore ineffective when systemically administered. Therefore, a concept of a prodrug of an anticholinergic compound acting in the CNS together with GABA activity may offer a novel therapeutic approach, influencing the main receptorial systems involved in seizure initiation and propagation induced by OP poisoning. Moreover, it is anticipated that the inhibitory action of GABA receptors would attenuate some of the central anticholinergic adverse effects (e.g., disorientation, confusion, hallucinations), thus increasing current drugs' efficacy and safety. Based on our previously described prodrugs development such as the perphenazine-GABA ester for the treatment of schizophrenia 29,30 and the nortriptyline-GABA amide for the treatment of neuropathic pain 31 , we sought to synthesize a benactyzine-GABA mutual prodrug (labeled "gabactyzine"). It is expected to be able to cross the BBB due to the lipophilic character of the benactyzine, acting as the "carrier" and transporting GABA into the brain. Once the molecule crosses the BBB it should undergo hydrolysis releasing concomitantly benactyzine and GABA, which are expected to act synergistically. Methods Chemistry (general). 1 H and 13 C NMR spectra were obtained on Bruker Avance-200, Avance-DPX-300, Avance-400, Avance-DMX-600, and Avance-III-700 spectrometers. Chemical shifts are expressed in ppm downfield from Me 4 Si (TMS) used as internal standard. The values are given in δ scale. It should be noted that the compounds that have carbamates, frequently are seen in the 1 H NMR and 13 C NMR spectra as mixtures of pairs of rotamers. Whereby the signals for the protons of the CH 2 's, and the corresponding carbons appear in close proximity as pairs of signals. In these cases. the chemical shifts of the rotameric H's and C's are indicated while being linked by + signs. For some compounds, the NMR data assignment was aided by several 2-dimensional spectra including COSY, HMQC, and HMBC analyses. High-resolution mass spectra (HRMS) were obtained on a 6545 QTOF instrument (Agilent). The progress of the reactions was monitored by TLC on silica gel (Merck, Art. 5554). All the flash chromatographic procedures were carried out on silica gel (Merck, Art. 9385). The nomenclature of the compounds was assigned according to ChemDraw Ultra version 12.0.3.1216 (Cambridge Soft). General procedure 1: synthesis of esters 32. A mixture of an alkyl halide (1 mmol), an acid (1 mmol) (N-Boc-GABA or 2-(4-(tert-butoxycarbonylamino)butanoyloxy)-2,2-diphenylacetic acid, 7) and DBU (1 mmol) in ~ 2 mL of CH 3 CN (dried over molecular sieves) was stirred at room temperature overnight. The mixture was then quenched with distilled water. A white solid that precipitated was washed with ether, and the organic layer was washed with saturated KHSO 4. The organic layer was dried over Na 2 SO 4 , filtered, and evaporated. The residue was purified by silica gel chromatography, or by preparative HPLC. General procedure 2: N-Boc removal. To a solution of a Boc-protected amino compound in dry ether was added HCl(g). The solution was stirred for 1-2 h and the solvent was evaporated to give the hydrochloride salt of the free amino compound. α-Bromo-α,α-diphenylacetic acid (16). A suspension of benzilic acid 33 in HBr/AcOH was kept at 0 °C overnight. The solvent was evaporated, and the residue was dried under a high vacuum. 1
Israel Medical Association Journal, Apr 1, 2008
Advanced Healthcare Materials, 2012
In this study, we report on the design, synthesis, and full characterization of a covalently-link... more In this study, we report on the design, synthesis, and full characterization of a covalently-linked, triclosan silica-based nanoparticles (T-SNPs), coated with a polyaminated shell (NH 2-T-SNPs). Various techniques are used to elucidate and rationalize the potential biological mechanism of action of these novel nanoparticles. NH 2-T-SNPs are found to be potently bactericidal with no detectable lag time for the antimicrobial activity against E. coli and S. aureus. In this context, we also prove that triclosan is the chemical agent that mediated the bactericidal activity of these chemically-modifi ed NPs. The obtained experimental data allows us to pinpoint the actual minimal bactericidal concentrations (MBCs) of triclosan-bound NPs by quantifying intracellular triclosan concentrations. Furthermore, we conduct preliminary cytotoxicity studies, which show that triclosan bound NPs are less cytotoxic (2000 fold) in vitro compared to free-triclosan when tested with various human and mammalian cell lines. Taken together, our results further support the characterization and development of these new nanoscale materials for various biomedical applications. There are numerous routes for preparing silica nanoparticles in a variety of sizes and morphologies, and one of the fi rst systematic studies on the subject was published by Stöber, [ 1 ] on the sol-gel process. The method allows for monodispersed silica NPs to be formed, as well as enabling the incorporation of various functionalities during the synthesis process. As stated in our previous study, [ 2 ] there are two main routes that can enable the introduction of a functional group or a guest molecule into the forming inorganic network, i.e., building on a non-covalent physical or a covalent linkage between both components. In our study we chose to covalently incorporate the known biocide, triclosan, into the silica network of SiO 2 NPs to afford the corresponding hybrid triclosan-bound NPs. Triclosan (Irgasan) is a well-known commercial and Food and Drug Administration (FDA)-approved, synthetic, non-ionic, broad-spectrum antimicrobial agent, possessing mostly antibacterial, but also some antifungal and antiviral properties. [ 3 ] Numerous studies conducted on different bacteria strains showed that triclosan acts on a defi ned bacterial target in the bacterial fatty acid biosynthetic pathway, the NADH-dependent enoyl-[acyl carrier protein] reductase (ENR). [ 4-7 ] In our previous work, we have developed a linker molecule that enables covalent binding between the inorganic matrix of hybrid silica NPs and triclosan using a carbamate linkage. [ 2 ] This covalent carbamate bond within the silicate linker (blue part of TTESPC species, Figure 1) and its biologically-active component (red part of TTESPC species, Figure 1) have been specifi cally designed to be readily hydrolyzed by esterases on one hand but to withstand spontaneous hydrolysis (contacting medium) on the other hand (Figure 1 and Scheme 1). Subsequently, the locally released active triclosan molecules act upon their ENR target within the bacteria cell itself. Accordingly, esterases produced by the bacteria themselves are responsible for the release of the antimicrobial agent, resulting in pathogen cell death. Herein, we report on the design, preparation, and full characterization of nanosized hybrid silica-based particles, namely NH 2-T-SNPs that possess an outer polyamine (polyNH 2) shell. We have discovered that the one-step introduction of the polyamines that created a polycationic shell had a www.MaterialsViews.com
Toxicology, 2014
Poisoning with organophosphates (OPs) may induce status epilepticus (SE), leading to severe brain... more Poisoning with organophosphates (OPs) may induce status epilepticus (SE), leading to severe brain damage. Our objectives were to investigate whether OP-induced SE leads to the emergence of spontaneous recurrent seizures (SRSs), the hallmark of chronic epilepsy, and if so, to assess the efficacy of benzodiazepine therapy following SE onset in preventing the epileptogenesis. We also explored early changes in hippocampal pyramidal cells excitability in this model. Adult rats were poisoned with the paraoxon (450μg/kg) and immediately treated with atropine (3mg/kg) and obidoxime (20mg/kg) to reduce acute mortality due to peripheral acetylcholinesterase inhibition. Electrical brain activity was assessed for two weeks during weeks 4-6 after poisoning using telemetric electrocorticographic intracranial recordings. All OP-poisoned animals developed SE, which could be suppressed by midazolam. Most (88%) rats which were not treated with midazolam developed SRSs, indicating that they have become chronically epileptic. Application of midazolam 1min following SE onset had a significant antiepileptogenic effect (only 11% of the rats became epileptic; p=0.001 compared to non-midazolam-treated rats). Applying midazolam 30min after SE onset did not significantly prevent chronic epilepsy. The electrophysiological properties of CA1 pyramidal cells, assessed electrophysiologically in hippocampal slices, were not altered by OP-induced SE. Thus we show for the first time that a single episode of OP-induced SE in rats leads to the acquisition of chronic epilepsy, and that this epileptogenic outcome can be largely prevented by immediate, but not delayed, administration of midazolam. Extrapolating these results to humans would suggest that midazolam should be provided together with atropine and an oxime in the immediate pharmacological treatment of OP poisoning.
Magnetic Resonance in Medicine, 2012
Organophosphates are highly toxic substances, which cause severe brain damage. The hallmark of th... more Organophosphates are highly toxic substances, which cause severe brain damage. The hallmark of the brain injury is major convulsions. The goal of this study was to assess the spatial and temporal MR changes in the brain of paraoxon intoxicated rats. T2-weighted MRI and 1 H-MR-spectroscopy were conducted before intoxication, 3 h, 24 h, and 8 days postintoxication. T2 prolongation mainly in the thalami and cortex was evident as early as 3 h after intoxication (4-6% increase in T2 values, P < 0.05). On spectroscopy, N-acetyl aspartate (NAA)/creatine and NAA/choline levels significantly decreased 3 h postintoxication (>20% decrease, P < 0.005), and 3 h lactate peak was evident in all intoxicated animals. On the 8th day, although very little T2 changes were evident, NAA/creatine and choline/creatine were significantly decreased (>15%, P < 0.05). Animals who succumbed had extensive cortical edema, significant higher lactate levels and a significant decrease in NAA/creatine and NAA/choline levels compared to animals which survived the experiment. Organophosphates-induced brain damage is obvious on MR data already 3 h postintoxication. In vivo spectroscopic changes are more sensitive for assessing long-term injury than T2-weighted MR imaging. Early spectroscopic findings might be used as biomarkers for the severity of the intoxication and might predict early survival.
The American Journal of Emergency Medicine, 2009
Advanced Functional Materials, 2011
... 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 1 www.MaterialsViews.com wileyonlinelibra... more ... 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 1 www.MaterialsViews.com wileyonlinelibrary.com Adv. Funct. Mater. 2011, XX, 1–10 Igor Makarovsky , Yonit Boguslavsky , Maria Alesker , Jonathan Lellouche , Ehud Banin , and Jean-Paul Lellouche * 1. Introduction ...
Journal of Materials Chemistry, 2011
ABSTRACT The novel reporters, unimodal FT-IR-traceable, bimodal fluorescent and FT-IR-traceable h... more ABSTRACT The novel reporters, unimodal FT-IR-traceable, bimodal fluorescent and FT-IR-traceable hybrid silica (SiO2) nanoparticles (NPs), were prepared using the Stöber methodology. Initially, the basic Stöber co-hydrolysis of tetraethoxysilane (TEOS) and of the iron-complexed alkyl-triethoxysilane (EtO)3Si-L-(η4-2E,4E-dienyl)-Fe(CO)3(0) (L = alkyl linker, DIT-tag reagent 3) afforded unimodal 13.7 ± 2 nm-sized SiO2@DIT-tag60 NPs. These NPs can incorporate an organometallic FT-IR sensitive (η4-2E,4E-dienyl)-tricarbonyliron(0) complex moiety which acts as a sensitive FT-IR traceable species due to the strong iron complex νFeCO vibrational bands that appear in the 1996–2063 cm−1 region, a region free of any parasitic band. The sensitivity of the FT-IR-based detection ofSiO2@DIT-tag60 NPs has been determined using incremental mixtures of B16 melanoma cell lysates as a biological medium model. The detection limit was found to be 0.190 μg of Fe per mg of B16cell lysate. In the second step, bimodal hybrid fluorescent and FT-IR-traceable 35.7 ± 5 nm sized SiO2@DIT-tag20@FITC NPs were similarly fabricated, in order to enable both fluorescence and FT-IR spectroscopy detection. This has been readily obtained through the straightforward co-incorporation of an additional fluorescein-containing alkyl-triethoxysilane conjugate FITC–APTES (FITC: fluorescein isothiocyanate, APTES: (3-aminopropyl)triethoxysilane). Subsequent surface modification with APTES of the resulting SiO2@DIT-tag20@FITC NPs afforded amine functionalized 34.4 ± 6 nm-sized SiO2@DIT-tag20@FITC@NH2 NPs that were readily endocytosed by B16 melanoma cells. All these novel hybrid silica NPs have been fully characterized by FT-IR spectroscopy, high resolution TEM/SEM (HR-TEM/SEM) with elemental energy-dispersive X-ray spectroscopy (compositional EDAX analysis), dynamic light scattering (DLS), ζ potential measurements, and inductively coupled plasma-optical emission spectroscopy (ICP-OES). Preliminary biological studies demonstrated the non-toxicity of the NPs. No observable modification in the B16cells&#39; morphology or mortality was seen after the internalization of SiO2@DIT-tag20@FITC@NH2 NPs.
HF is a corrosive mineral acid. It has extremely harmful systemic effects through any route of ex... more HF is a corrosive mineral acid. It has extremely harmful systemic effects through any route of exposure. In dilute solutions the onset of symptoms is latent. It is important for caregivers to remember that HF has distinct clinical signs and a specific antidote, namely calcium gluconate. The industrial use of HF heightens the importance of being prepared for possible exposures. The emergency medical teams should be familiar with its symptoms, should possess the proper protective means and should be ready to respond properly in case of emergency.
Ammonia is a gas with a urine-like odor widely used for industrial purposes. Its odor threshold i... more Ammonia is a gas with a urine-like odor widely used for industrial purposes. Its odor threshold is sufficiently low to acutely provide adequate warning of its presence.
The Israel Medical Association journal : IMAJ, 2008
Ammonia is a common household and industrial chemical. In the medical literature and the electron... more Ammonia is a common household and industrial chemical. In the medical literature and the electronic press there are many descriptions of accidental spills of anhydrous ammonia, but apart from the Chechen war, there is no evidence of its intentional use by a terrorist to date. When considering its characteristics, ammonia tankers may pose an imminent threat for a civilian population nearby. This short review attempts to highlight the main health issues and basic principles of medical management after exposure to ammonia. Ammonia can directly cause damage due to its irritating as well as alkaline properties. The management of toxic exposure to ammonia is largely supportive and there is no specific antidote. Emergency medical response on site includes rapid evacuation, life-saving procedures and decontamination if necessary and if possible. Major clinical manifestations include respiratory symptoms, such as hypoxia, bronchospasm and pulmonary edema, as well as hypovolemia and burns to ...
The Israel Medical Association journal : IMAJ, 2007
OsO4 is a powerful oxidizer. It affects mainly the skin and mucous membranes. Although unsuitable... more OsO4 is a powerful oxidizer. It affects mainly the skin and mucous membranes. Although unsuitable for a large-scale terrorist attack, mainly due to its scarcity, it could be used in small-scale attacks. The small quantity contained in a vial would cause irritation to the eyes, nose, throat and skin. Combining the agent with an explosive material will probably destroy most of it, chemically. Thus, releasing the chemical without using explosives may be considerably more dangerous. Medical management is mainly symptomatic. As soon as the chemical enters the body, it rapidly reacts with the tissues in contact. Medical personnel should be aware of its poisonous effects and be equally familiar with the necessary self-protection measures and the treatment protocols.
Journal of Medicinal Chemistry, 2008
New and more potent prodrugs of the 5-fluorouracyl family derived by hydroxymethylation or acylox... more New and more potent prodrugs of the 5-fluorouracyl family derived by hydroxymethylation or acyloxymethylation of 5-fluoro-1-(tetrahydro-2-furanyl)-2,4(1H,3H)-pyrimidinedione (tegafur, 1) are described. The anticancer activity of the butyroyloxymethyl-tegafur derivative 3 and not that of tegafur was attenuated by the antioxidant N-acetylcysteine, suggesting that the increased activity of the prodrug is in part mediated by an increase of reactive oxygen species. Compound 3 in an in vitro matrigel assay was found to be a more potent antiangiogenic agent than tegafur. In vivo 3 was significantly more potent than tegafur in inhibiting 4T1 breast carcinoma lung metastases and growth of HT-29 human colon carcinoma tumors in a mouse xenograft. In summary, the multifunctional prodrugs of tegafur display selectivity toward cancer cells, antiangiogenic activity, and anticancer activities in vitro and in vivo, superior to those of tegafur. 5-Fluoro-1-(tetrahydro-2-furanyl)-2,4(1H,3H)-pyrimidinedione (tegafur, 1), the oral prodrug of 5-FU, has been widely used for treatment of gastrointestinal malignancies with modest efficacy. The aim of this study was to develop and characterize new and more potent prodrugs of the 5-FU family derived by hydroxymethylation or acyloxymethylation of tegafur. Comparison between the effect of tegafur and the new prodrugs on the viability of a variety of cancer cell lines showed that the IC 50 and IC 90 values of the novel prodrugs were 5-10-fold lower than those of tegafur. While significant differences between the IC 50 values of tegafur were observed between the sensitive HT-29 and the resistant LS-1034 colon cancer cell lines, the prodrugs affected them to a similar degree, suggesting that they overcame drug resistance. The increased potency of the prodrugs could be attributed to the antiproliferative contribution imparted by formaldehyde and butyric acid, released upon metabolic degradation. The anticancer activity of the butyroyloxymethyl-tegafur derivative 3 and not that of tegafur was attenuated by the antioxidant N-acetylcysteine, suggesting that the increased activity of the prodrug is in part mediated by an increase of reactive oxygen species. Compound 3 in an in vitro matrigel assay was found to be a more potent antiangiogenic agent than tegafur. In vivo 3 was significantly more potent than tegafur in inhibiting 4T1 breast carcinoma lung metastases and growth of HT-29 human colon carcinoma tumors in a mouse xenograft. In summary, the multifunctional prodrugs of tegafur display selectivity toward cancer cells, antiangiogenic activity and anticancer activities in vitro and in vivo, superior to those of tegafur.
The Israel Medical Association Journal Imaj, May 1, 2008
Hydrazine is considered a dangerous toxic compound. It is flammable, easily ignitable and may exp... more Hydrazine is considered a dangerous toxic compound. It is flammable, easily ignitable and may explode upon contact with different materials, including clothing. As a volatile liquid, it affects mainly the upper respiratory tract, mucous membranes and skin. The characteristics and availability of this agent warrant our attention. Medical personnel should be familiar with its properties, major health effects and the treatment needed. The key principles in treating hydrazine victims include protection from further exposure and aggressive antidotal treatment with pyridoxine (vitamin B6), as well as supportive treatment as required. Finally, medical teams should also be equipped with the proper protection measures (appropriate suits, gloves and breathing apparatuses) in order to avoid secondary exposure of themselves and others.
The Israel Medical Association Journal Imaj, Oct 1, 2007
Bromine is a strong and prevalent irritating agent that can spread both as liquid and as fumes. I... more Bromine is a strong and prevalent irritating agent that can spread both as liquid and as fumes. It has a characteristic reddish-brown color. The mainstay of the medical management is supportive and symptomatic therapy that should be given as soon as possible to prevent further damage. Medical personnel, especially the emergency department staff, should be familiar with its health effects, including the safety precautions needed when caring for casualties following such an exposure.
The Israel Medical Association journal : IMAJ, 2008
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Papers by Igor Makarovsky