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N-Chlorotaurine and ammonium chloride: An antiseptic preparation with strong bactericidal activity
Abstract
The bactericidal activity of the endogenous antiseptic N-chlorotaurine (NCT) is significantly enhanced in the presence of ammonium chloride which induces the formation of monochloramine (NH(2)Cl) whose strong bactericidal activity is well known. In this study the properties of NCT plus ammonium chloride have been investigated. The reaction of active chlorine compounds like chloramine-T (N-chlorotoluene-sulfonamide sodium), chloroisocyanuric acid derivatives, hypochlorites (NaOCl, CaOCl(2)) with ammonium chloride did not stop at the stage of monochloramine, and the pungent smelling by-products di- and trichloramine, NHCl(2) and NCl(3), were also formed. This was not the case with NCT where only monochloramine was generated. The equilibrium constant of the reaction of NCT with ammonium was found to be [Formula: see text] , which allows to estimate the equilibrium concentration of monochloramine in aqueous solutions of NCT and ammonium chloride. At concentrations each ranging between 0.01% and 1.0% it comes to [NH(2)Cl]=3.5-254 ppm. As an unexpected result the monochloramine containing formulation turned out to be most stable in plain water without buffer additives. Quantitative killing assays revealed complete inactivation of 10(6) to 10(7)CFU/mL of seven bacterial strains by 0.1% NCT plus 0.1% ammonium chloride within 5 min, while with plain 0.1% NCT an incubation time of 2-4h was needed to achieve the same effect. The highly significant increase of bactericidal activity (200-300-fold) could be assigned to the presence of monochloramine which could be isolated by vacuum distillation. Aqueous solutions of NCT and ammonium chloride provide a highly effective and well tolerable antiseptic preparation appropriate to a treatment cycle of at least 1 month if stored in the refrigerator.
... In samples of nasal secretion, killing by plain 1% NCT was significantly hastened (30 min compared to C4 h), which is explained by the formation of monochloramine by halogenation of ammonium, too, which was found at a concentration of 1 mM in these samples. Monochloramine is more lipophilic than NCT and penetrates microorganisms easily, which explains its rapid microbicidal activity [19,65]. ...
... Panhofer, M. Nagl). Due to the improved fungicidal activity (see above, [31,61,65]), in both cases 1% NCT plus 1% ammonium chloride was applied via soaked gauze two times daily. In both patients, the lesions could be cured within one week of treatment. ...
... Due to the outstanding tolerability, NCT can be applied to different body regions, including sensitive ones. In fungal infections with low exudation, e.g., eye and skin infections, the combination of NCT with ammonium chloride seems to be superior because of formation and rapid fungicidal activity of monochloramine (see above, [31,61,65]). If there is marked exudation, monochloramine is formed anyway at the site of application of NCT, and no addition of ammonium chloride is necessary. ...
N-Chlorotaurine (NCT) is a mild long-lived oxidant that can be applied to sensitive body regions as an endogenous antiseptic. Enhancement of its microbicidal activity in the presence of proteinaceous material because of transchlorination, a postantibiotic/postantifungal effect and antitoxic activity renders it interesting for treatment of fungal infections, too. This is confirmed by first case applications in skin and mucous membranes of different body sites. Recent findings of good tolerability of inhaled NCT suggest further investigations of this substance for treatment of bronchopulmonary diseases, where microorganisms play a role, particularly multi-resistant ones. The availability of a well-tolerated and effective inhaled antiseptic with anti-inflammatory properties could be a significant progress, in particular for chronic pulmonary diseases, such as chronic obstructive pulmonary disease or cystic fibrosis.
... Monochloramine (NH 2 Cl), the smallest N-chloro compound, has been in use for water disinfection since decades (Brodtmann and Russo 1979). Recently, it aroused interest in human medicine as it is formed from a combination of N-chlorotaurine (NCT) and ammonium chloride (eqn 1) (Gottardi et al. 2007), which seems to be useful for topical treatment of infections, for instance of the skin and the eye (Teuchner et al. 2008;Gottardi and Nagl 2010). ...
... On the other hand, usability of NH 2 Cl as antiseptic only became feasible by a very convenient in situ procedure, the reaction of NCT with ammonium chloride (eqn 1; Gottardi et al. 2007). The available sodium salt of NCT (Gottardi and Nagl 2002) combined with NH 4 Cl offers a very effective antiseptic formulation, which excels NCT alone and even CAT, however, without the irritating potential of the latter one (Romanowski et al. 2006;Teuchner et al. 2008). ...
... Monochloramine (NH 2 Cl) was prepared from NCT (Cl-HN-CH 2 -CH 2 -SO 3 Na, NCT) and ammonium chloride (NH 4 Cl) and isolated by vacuum distillation as previously described (Gottardi et al. 2007). Appropriate dilutions in 0Á1 mol l À1 phosphate-buffered saline (pH 7Á1) were made (Arnitz et al. 2009), which was also true for the iodine solution. ...
Unlabelled:
Recently, we showed that monochloramine (NH2 Cl) has a significantly stronger bactericidal and fungicidal activity than chloramine T despite its lower oxidizing power. This phenomenon was explained by increased penetration because of the higher lipophilicity and smaller bulk of NH2 Cl. As iodine (I2 ) has an even fivefold higher bulk than NH2 Cl, a comparison of both compounds regarding their microbicidal activity became the aim of this study. Aqueous solutions of I2 at a concentration of 10·7 μmol l(-1) killed 10(6) colony forming units per millilitre (CFU ml(-1) ) of Escherichia coli, Staphylococcus aureus or Pseudomonas aeruginosa to the detection limit of 10(2) CFU ml(-1) within 1 min at 20°C and pH 7·1, while a concentration of 36-355 μmol l(-1) of NH2 Cl was needed to achieve the same effect. Aspergillus fumigatus was inactivated within 5 min by 36 μmol l(-1) I2 and by 355 μmol l(-1) NH2 Cl, Candida albicans within 1 min by 10·7 μmol l(-1) I2 and by 355 μmol l(-1) NH2 Cl. The lipophilicity of I2 , determined with the octanol/water method, was three powers of 10 higher than that of NH2 Cl. The at least 10-fold stronger microbicidal activity of iodine suggests that the hindrance of penetration of the bulky molecule is outweighed by enhanced lipophilicity.
Significance and impact of the study:
The microbicidal activity of active halogen compounds increases not only with their reactivity, but also with higher lipophilicity and lower bulk, as shown recently. In this study, iodine showed a higher microbicidal activity than monochloramine and a 1000-fold higher lipophilicity. Therefore, the lipophilicity of a disinfectant may be more important than the bulk for bactericidal activity. These facts should be considered upon the design of new antiseptics and their clinical application.
... The remarkable enhancement of the killing of molds (and of bacteria and protozoa) by the addition of NH 4 Cl to NCT known from previous studies (21,23,36) was also confirmed to a similar extent against Scedosporium. Due to the more rapid killing of microorganisms in body fluids and exudates, and due to the successful therapeutic application of NCT in humans and animals (14,15,21,23,37,38), we are convinced that this effect plays a role in vivo. ...
... Due to the more rapid killing of microorganisms in body fluids and exudates, and due to the successful therapeutic application of NCT in humans and animals (14,15,21,23,37,38), we are convinced that this effect plays a role in vivo. It is explained by the formation of monochloramine (NH 2 Cl) in equilibrium with NCT (36,39). Because of its higher lipophilicity, NH 2 Cl penetrates and kills microorganisms more rapidly than NCT (11,36,40). ...
... It is explained by the formation of monochloramine (NH 2 Cl) in equilibrium with NCT (36,39). Because of its higher lipophilicity, NH 2 Cl penetrates and kills microorganisms more rapidly than NCT (11,36,40). ...
N-chlorotaurine (NCT), a well-tolerated endogenous long-lived oxidant that can be applied topically as antiseptic, was tested on its fungicidal activity against Scedosporium and Lomentospora, opportunistic fungi that cause severe infections with limited treatment options mainly in immunocompromised patients.In quantitative killing assays, both hyphae and conidia of Scedosporium apiospermum, Scedosporium boydii, and Lomentospora prolificans (former Scedosporium prolificans) were killed by 55 mM (1.0%) NCT at pH 7.1 and 37 °C with a log10 reduction in CFU of 1 - 4 after 4 h and of 4 to > 6 after 24 h. Addition of ammonium chloride to NCT markedly increased this activity. LIVE/DEAD staining of conidia treated with 1.0% NCT for 0.5 to 3 h disclosed increased permeability of the cell wall and membrane. Pre-incubation of the test fungi in 1.0% NCT for 10 - 60 min delayed the time to germination of conidia by 2 h - >12 h and reduced their germination rate by 10.0 - 100.0%. Larvae of Galleria mellonella infected with 1.0 × 10E7 conidia of S. apiospermum and S. boydii died at a rate of 90.0 - 100% after 8-12 days. The mortality rate was reduced to 20 - 50.0% if conidia were pre-incubated in 1.0% NCT for 0.5 h or if heat-inactivated conidia were used.Our study demonstrates fungicidal activity of NCT against different Scedosporium and Lomentospora species. A postantifungal effect connected with loss of virulence occurs after sublethal incubation times. The augmenting effect of ammonium chloride can be explained by formation of monochloramine.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
... N-chlorotaurine has been shown to react with ammonium chloride (NH 4 Cl), following which monochloramine (NH 2 Cl) is formed in equilibrium (Grisham et al. 1984;Thomas et al. 1986). The latter is more lipophilic and has a higher bactericidal and fungicidal activity than NCT because of increased penetration into tissue and bacteria and fungi (Gottardi et al. 2007;Gottardi & Nagl 2010). Recently, a combination of 0.1% NCT and 0.1% NH 4 Cl demonstrated activity superior to that of 1% NCT in the rabbit model of epidemic keratoconjunctivitis (Romanowski et al. 2006), and the tolerability of this combination has been proven in humans (Teuchner et al. 2008). ...
... Recently, a combination of 0.1% NCT and 0.1% NH 4 Cl demonstrated activity superior to that of 1% NCT in the rabbit model of epidemic keratoconjunctivitis (Romanowski et al. 2006), and the tolerability of this combination has been proven in humans (Teuchner et al. 2008). A specific advantage of NCT plus NH 4 Cl is the non-formation of irritating trichlor-amines, which is not the case with other active chlorine compounds in the presence of NH 4 Cl (Gottardi et al. 2007). ...
... Such penetration into the stroma could be enhanced by the addition of ammonium chloride (NH 4 Cl) to NCT, forming lipophilic monochloramine (NH 2 Cl) (Romanowski et al. 2006;Gottardi et al. 2007). Accordingly, the bactericidal activity of NCT in the pig corneas in the present study could be increased by NH 4 Cl. ...
Purpose:
N-chlorotaurine (NCT) and its analogues N-monochloro-2,2-dimethyltaurine (NVC-612) and N-dichloro-2,2-dimethyltaurine (NVC-422) are new anti-infectives for topical treatment for conjunctivitis. The aim of this study was to show that these compounds are safe in an EpiOcular model and effective in corneas infected ex vivo.
Methods:
Corneal buttons were excised from porcine eyes. In 183 of the 229 corneas, erosion and artificial superficial stromal incision were induced. They were bathed in suspensions of Pseudomonas aeruginosa or Staphylococcus aureus for 24 hr at 37°C and incubated in solutions of the test substances at 37°C and pH 7.1. Subsequently, they were subjected to histology (n = 20) or homogenized followed by quantitative bacterial cultures (n = 209). Ocular irritation was tested using the EpiOcular™ tissue system (MatTek Corporation).
Results:
Bacterial accumulations were detected histologically both on the corneal surface and also in the anterior third of the stroma of incised corneal buttons. All three test compounds at a concentration of 55 mm (equals 1% NCT) reduced the bacterial counts of P. aeruginosa and S. aureus by approximately 5 log10 after 60- and 120-min incubation, respectively. Significant killing was observed as early as after 5-min incubation. Also intrastromal bacteria were inactivated. In the EpiOcular™ tissue model, NCT, NVC-422 and NVC-612 had no or very low potential to irritate corneal tissue.
Conclusion:
N-chlorotaurine, NVC-422 and NVC-612 are non-irritating in cornea and kill P. aeruginosa and S. aureus, even following penetration into the deeper corneal stromal layers.
... 23 ) shows that the equilibrium of Equation (9) lies on the left side. 62 The specificity of this reaction is that at room temperature and without any buffer it yields only monochloramine. If strongly chlorinating agents such as CAT are used, also diand trichloramine, NHCl 2 and NCl 3 , very unpleasantly smelling by-products, are formed, which precludes application in practice. ...
... If strongly chlorinating agents such as CAT are used, also diand trichloramine, NHCl 2 and NCl 3 , very unpleasantly smelling by-products, are formed, which precludes application in practice. 62 The combination of NCT and ammonium chloride offers for the first time the chance to use NH 2 Cl as an antiseptic agent in human and veterinary medicine. Its enhanced bactericidal activity originates from its small bulk and the absence of charge (different to NCT), which both facilitate the penetration of cell walls. ...
... Tests with bacteria and fungi performed with NCT in the presence of ammonium chloride with both compounds in the range of 0.1% -1.0% disclosed a drastic reduction of killing times. 62 The most impressive results were obtained with both mycobacteria and moulds. Mycobacterium terrae was reduced below the detection limit within 20 min, 63 while hyphae and spores of moulds were killed within surprisingly short incubation times of a few minutes. ...
N-chlorotaurine, the N-chloro derivative of the amino acid taurine, is a long-lived oxidant produced by activated human granulocytes and monocytes. Supported by a high number of in vitro studies, it has mainly anti-inflammatory properties and seems to be involved in the termination of inflammation. The successful synthesis of the crystalline sodium salt (Cl-HN-CH(2)-CH(2)-SO(3)Na, NCT) facilitated its development as an endogenous antiseptic. NCT can be stored long-term at low temperatures, and it has killing activity against bacteria, fungi, viruses and parasites. Transfer of the active chlorine to amino groups of molecules of both the pathogens and the human body (transhalogenation) enhances rather than decreases its activity, mainly because of the formation of monochloramine. Furthermore, surface chlorination after sublethal incubation times in NCT leads to a post-antibiotic effect and loss of virulence of pathogens, as demonstrated for bacteria and yeasts. Being a mild oxidant, NCT proved to be very well tolerated by human tissue in Phase I and II clinical studies. A 1% aqueous solution can be applied to the eye, skin ulcerations, outer ear canal, nasal and paranasal sinuses, oral cavity and urinary bladder, and can probably be used for inhalation. Therapeutic efficacy in Phase II studies has been shown in external otitis, purulently coated crural ulcerations and keratoconjunctivitis, so far. Based upon all presently available data, NCT seems to be an antiseptic with a very good relation between tolerability and activity. Recently, C-methylated derivatives of NCT have been invented, which are of interest because of improved stability at room temperature.
... However, recently an important innovation was published e a formulation containing N-chlorotaurine (NCT) and ammonium chloride which produces NH 2 Cl without the unwanted by-products di-and trichloramine. 3 Since NH 2 Cl can be isolated easily by vacuum distillation, this offers a convenient means of making it available in high purity. 3 Not surprisingly, the microbicidal activity of active chlorine compounds largely correlates with the oxidising power. ...
... However, recently an important innovation was published e a formulation containing N-chlorotaurine (NCT) and ammonium chloride which produces NH 2 Cl without the unwanted by-products di-and trichloramine. 3 Since NH 2 Cl can be isolated easily by vacuum distillation, this offers a convenient means of making it available in high purity. 3 Not surprisingly, the microbicidal activity of active chlorine compounds largely correlates with the oxidising power. Thus, HOCl represents the strongest chlorine-based oxidant in aqueous solution, causing the highest killing rates. 1 The comparatively weak oxidant NH 2 Cl exhibits a bactericidal power which is nearly one hundred times lower. ...
... formation of chlorine covers on skin and bacterial surfaces by transchlorination 5,6 ) the sequence HOCl > chloroisocyanuric acids > CAT > NH 2 Cl > Nchlorotaurine (NCT) was established. 3 Tests show that the bactericidal activity of HOCl/OCl À > chloroisocyanuric acids > CAT > NCT. 1,3,4,7e9 The position of NH 2 Cl in this sequence has not been determined, but from these reports HOCl is presumptively more bactericidal than NH 2 Cl. ...
Chloramine T (CAT) and monochloramine (NH2Cl) are active chlorine compounds and well-known biocides. CAT has stronger oxidative activity than NH(2)Cl, which is a smaller, more lipophilic molecule. The question arises whether lower oxidative activity can be compensated by higher lipophilicity. To address this problem, we investigated the bactericidal and fungicidal activity of pure NH(2)Cl compared to CAT. Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Aspergillus fumigatus, A. flavus, and Candida albicans were subjected to quantitative killing assays at 20 degrees C and pH 7.1 in equimolar solutions of CAT or NH2Cl. NH2Cl was superior to CAT against all test strains at all test concentrations. At a concentration of 0.036 mM, NH2Cl reduced the count of E. coli (S. aureus) by 3log10 within 1 min (5 min), whereas CAT needed 120 min (30 min) for the same effect. At 0.107 mM NH2Cl, a 3log10 reduction of P. aeruginosa was achieved after 5 min compared to 20 min using CAT. NH2Cl (0.355 mM) caused a 2log10 reduction of C. albicans within 30 s, whereas 60 min were necessary for the same reduction with 0.355 mM CAT. The difference between the antiseptics was even more pronounced when tested on aspergilli. NH2Cl had a significantly stronger bactericidal and fungicidal activity than CAT despite its lower oxidative activity. This phenomenon can be attributed to its lipophilicity and smaller bulk, and it should be taken into account when developing and using chloramine antiseptics.
... At an inflammation site, NCT equilibrates with amino acids, peptides and proteins to form the corresponding N-chloramines (transchlorination, [31,32]). Upon reaction with ammonium ions, monochloramine (NH 2 Cl) is formed (NH 3 +NCT ! ...
... Upon reaction with ammonium ions, monochloramine (NH 2 Cl) is formed (NH 3 +NCT ! NH 2 Cl+taurine), which is more lipophilic, penetrates cells at a much higher rate than NCT and has a higher microbicidal activity [31,32]. Probably, the formation of monochloramine and also of some N-chloro-amino acids enhances the bactericidal activity of NCT at the site of its application in vivo, while chlorine transfer to proteins has rather the opposite effect [4,33]. ...
Purpose:
The antimicrobial activity of N-chlorotaurine (NCT), an endogenous long-lived oxidant applied topically, was tested against Chlamydiae in vitro.
Methodology:
Elementary bodies of Chlamydia pneumoniae strain CV-6 and Chlamydia trachomatis serovars A and D were incubated in 0.01, 0.1 and 1 % (w/v) NCT solution at pH 7.1 and 37 °C. After different incubation times, aliquots were removed and grown in cell culture. The number of inclusion forming units was quantified by immunofluorescence and real-time qPCR.Results/Key findings.Chlamydia pneumoniae and Chlamydia trachomatis were inactivated by 1 and 0.1 % NCT within 1 min. Moreover, 0.025-0.1 % NCT significantly reduced the number of intracellularly growing C. pneumoniae within 30 min.
Conclusions:
This is the first study demonstrating the antimicrobial activity of NCT against Chlamydiae. Clinical implications of these findings have to be investigated in further trials.
... N-chlorotaurine (NCT) was prepared as reported (Gottardi and Nagl, 2002), N-chloro-dimethyltaurine (DM-NCT) was kindly provided by D. Debabov and R. Najafi (NovaBay Pharmaceuticals, Inc., Emeryville, CA, USA) (Low et al., 2009;Wang et al., 2008). Monochloramine was prepared by vacuum distillation in a rotary evaporator from aqueous solutions of NCT plus ammonium chloride and quantified spectrophotometrically as published previously (Gottardi et al., 2007). Peptone (enzymatic digest from casein) was from Fluka (Buchs, Switzerland). ...
... Fig. 6 shows a rise of BA with factors of 27.4, 96.8, and 568 in the presence 0.01, 0.1, and 1.0% ammonium chloride, respectively. This effect can be attributed to the formation of monochloramine (NH 2 Cl) according to the equilibrium NCT + NH 4 + ↔ taurine + NH 2 Cl (Gottardi et al., 2007;Nagl et al., 2001). ...
The bactericidal activity (BA) of antimicrobial agents is generally derived from the results of killing assays. A reliable quantitative characterization and particularly a comparison of these substances, however, are impossible with this information. We here propose a new method that takes into account the course of the complete killing curve for assaying BA and that allows a clear-cut quantitative comparison of antimicrobial agents with only one number. The new Integral Method, based on the reciprocal area below the killing curve, reliably calculates an average BA [log10CFU/min] and, by implementation of the agent's concentration C, the average specific bactericidal activity SBA=BA/C [log10CFU/min/mM]. Based on experimental killing data, the pertaining BA and SBA values of exemplary active halogen compounds were established, allowing quantitative assertions. N-chlorotaurine (NCT), chloramine T (CAT), monochloramine (NH2Cl), and iodine (I2) showed extremely diverging SBA values of 0.0020±0.0005, 1.11±0.15, 3.49±0.22, and 291±137log10CFU/min/mM, respectively, against Staphylococcus aureus. This immediately demonstrates an approximately 550-fold stronger activity of CAT, 1730-fold of NH2Cl, and 150,000-fold of I2 compared to NCT. The inferred quantitative assertions and conclusions prove the new method suitable for characterizing bactericidal activity. Its application comprises the effect of defined agents on various bacteria, the consequence of temperature shifts, the influence of varying drug structure, dose-effect relationships, ranking of isosteric agents, comparison of competing commercial antimicrobial formulations, and the effect of additives.
Copyright © 2015. Published by Elsevier B.V.
... Coincidentally with superficial chlorination, penetration into intact pathogens and body cells also takes place, resulting in the initiation of the irreversible transformation (destruction) of vitally important constituents, mainly S-H functions (see below) (29)(30)(31). It is widely accepted knowledge that penetration is favored for noncharged agents with low bulk (32). But there also exist examples where this concept seems to be upset. ...
... While the oxidation of sulfur compounds (equation 7) is generally complete within seconds (35,37), the reaction of equation 6, standing for an aromatic substitution reaction, proceeds substantially slower. The equilibrium of transchlorination (equation 5), on the other hand, settles within minutes, e.g., in 10 to 15 min in the case of the reaction NH 4 Cl ϩ NCT ↔ NH 2 Cl ϩ taurine (32). These qualities can be attributed to differences in the susceptibilities of the particular functions for oxidation (chlorination). ...
Antibiotic resistance is a growing public health crisis. To address the development of bacterial resistance, the use of antibiotics has to be minimized for non-systemic applications in man, as well as in animals and plants.Possible substitutes with low potential for developing resistance are active chlorine compounds that have been in clinical use for over 180 years. These agents are characterized by pronounced differences in their chlorinating and/or oxidizing activity, with hypochlorous acid (HOCl) as the strongest and organic chloramines as the weakest members.Bacterial killing in clinical practice is often associated with unwanted side effects like chlorine consumption, tissue irritation and pain, increasing proportionally with the chlorinating/oxidizing potency. Since the chloramines are able to effectively kill pathogens (bacteria, fungi, viruses, protozoa), their application as antiinfectives is advisable, all the more they exhibit additional beneficial properties like destruction of toxins, degradation of biofilms, anticoagulative and antiinflammatory activities.Within the ample field of chloramines, the stable N-chloro derivatives of β-aminosulfonic acids are most therapeutically advanced. Being available as sodium salts, they distinguish themselves by good solubility and absence of smell. Important representatives are N-chlorotaurine, a natural compound occurring in the human immune system and novel mono- and dichloro derivatives of dimethyltaurine, which feature improved stability.
... Fürnkranz, M. Nagl, W. Gottardi, M. Duchêne, H. Aspöck and J. Walochnik, unpublished results). An enhancing effect of NH 4 Cl on the efficacy of NCT, explained by the formation of the lipophilic and highly microbicidal monochloramine (NH 2 Cl) in equilibrium (NCT+NH 4 Cl«taurine+ NH 2 Cl+H + +Cl 2 ), has been outlined previously (Gottardi et al., 2007;Nagl & Gottardi, 1996). Respective tests were included in this study. ...
... The highest level of effectiveness was achieved by co-treatment with 5.5 mM NCT plus 19 mM NH 4 Cl (molar ratio 1 : 3.4) in PBS, which led to complete killing of promastigotes of both strains within 15 min (Fig. 1). These findings are in good accordance with previous studies, where the addition of NH 4 Cl decreased the killing times of NCT markedly against bacteria and particularly fungi (Gottardi et al., 2007;Nagl & Gottardi, 1996;. The enhancing effects are explained by the transfer of active chlorine from NCT to NH 4 Cl, whereby NH 2 Cl is formed in equilibrium, which penetrates and kills pathogens more rapidly. ...
Protozoan parasites of the genus Leishmania are the causative agents of life-threatening visceral as well as cutaneous and mucocutaneous leishmaniasis. First-line drugs are antimonials, but toxicity and resistance in some endemic areas cause serious problems. In the current study, the antileishmanial activity of the weak oxidant N-chlorotaurine (NCT) was investigated. NCT is a derivative of the amino acid taurine produced by granulocytes and monocytes during oxidative burst, but can also be synthesized chemically and used topically as an antiseptic at a concentration of 1 % (55 mM) in vivo. NCT susceptibility tests were performed in vitro with promastigotes and amastigotes of Leishmania infantum and Leishmania donovani. As NH(4)Cl is known to increase the activity of NCT by the formation of monochloramine (NH(2)Cl), co-treatment assays were included in the study. Mean EC(50) values after 1 h of treatment were 5.94 mM for L. infantum and 9.8 mM for L. donovani promastigotes. Co-treatment with 5.5 mM NCT plus 19 mM NH(4)Cl led to complete killing of promastigotes of both strains within 15 min. Amastigotes were inactivated by treatment with 2 mM NCT alone. The results of this study indicate a high potential of NCT against Leishmania species.
... 1−5 Moreover, ammonia has become a new clean energy source with a highenergy density of 4.3 kW h kg −1 . 6−9 Therefore, researchers have been continuously investigating how to increase the yield rate and Faradaic efficiency (FE) of NH 3 in order to provide feedstock support for its large-scale use. For various applications, ammonia is currently prepared by the industrial technology of Haber-Bosch, which generates ammonia directly from nitrogen and hydrogen (usually produced by the decomposition of CH 4 ) at high temperatures and pressures (300−500°C, 150−300 atm), 10,11 and which consumes vast energy and emits a large amount of CO 2 during the whole process. ...
Electrocatalytic nitrate reduction for ammonia (eNIRR) is an ammonia production process that simultaneously removes nitrate contaminants from water. However, the lack of activity of cathode catalysts used as eNIRR catalysts is the main limiting factor for its development. Motivated by this fact, born-doped copper (BDCu) was obtained by using ZnO, which was easily removed at high temperature, as a dispersant, combined with weakly reducing boron clusters (closo-[B 12 H 12 ] 2−) as a reducing agent and B source during high-temperature pyrolysis. Impressively, BDCu demonstrated a Faradaic efficiency of 96.58% and a yield rate of 25741.51 μg h −1 mg cat −1 toward ammonia production at −1.8 V (vs saturated calomel electrode). The ammonia yield rate of BDCu was twice as high as in the case of undoped B. Evolutionary behavior of NO 3 − to NH 3 conversion detected by in situ Fourier-transform infrared (in situ FT-IR) and electrochemical in situ mass spectrometry (in situ DEMS). Experimental and density functional theory (DFT) calculations explained that the activation of water was enhanced by B-doped Cu, and the adsorption of proton *H was weakened, which made it easy for *H to migrate away from the catalyst to NO 3 − as a proton required for NO 3 − reduction. In addition, the electron-deficient of B provides conditions for electron transfer between B and Cu. The electron transfer from Cu to B in BDCu led to a decrease in the center of the d-band of Cu, which modulated the electronic properties of Cu and altered the behavior of the NO 3 − to NH 3 transition on the Cu surface. Compared with Cu undoped B as well as unreduced CuO, BDCu lowered the energy barrier of the rate-determining step (*NO → *N), allowing for a smoother conversion of NO 3 − to NH 3. This study provides a strategy to change the electronic structure of transition metals by B-modification and thus improve the performance of ammonia synthesis.
... However, it can be explained by an overcompensation of this consumption by chlorine transfer from NCT to amino compounds in the milk with the formation of corresponding chloramines in equilibrium (transchlorination, transhalogenation) [34,35]. Particularly, the formation of monochloramine (NH 2 Cl) from NCT and ammonium is important, since this compound is more lipophilic and penetrates pathogens better than NCT with clear enhancement of killing activity against bacteria and, particularly, fungi [36,37]. ...
N-chlorotaurine (NCT), the N-chloro derivative of the amino acid taurine, is a long-lived oxidant produced by stimulated human leucocytes. NCT has antimicrobial activities which are generally enhanced in the presence of organic material. The aim of this study was to investigate fungicidal effects of NCT and conventional antiseptics against Candida isolated from vulvovaginal candidiasis (VVC). Chlorhexidine (CHX, 1.6%), octenidine dihydrochloride (OCT, 0.08%), povidone iodine (PVP-I, 8%), boric acid (8%), and NCT (0.1% (5.5 mM)) were evaluated against forty-four Candida isolates, according to European Standard methods, at 30, 60, 90, and 120 min and 24 h in the presence of skim milk as an organic material. CHX, OCT, and PVP-I showed rapid fungicidal activity against all Candida isolates with 5–6 log10 reduction of viable counts after 30 min, whereas boric acid and NCT needed 1 h against Candida albicans and 2 h against non-albicans Candida for a significant 3 log10 reduction. NCT showed fungicidal activity (defined as ≥4 log10 reduction) against C. albicans within 90 min and C. non–albicans within 24 h. Based upon all presently available data, including our results, NCT could be used as a new agent for treatment of local fungal infections such as VVC.
... This is based on chlorine transfer from NCT to amino groups present in these fluids and formation of the corresponding chloramines in equilibrium (transhalogenation, transchlorination [1,29]). Particularly, formation of monochloramine (NH 2 Cl), which penetrates microorganisms better than NCT because of its higher lipophilicity, plays a role, above all against fungi [25,27,28,30]. In addition, a postantifungal effect (lag of regrowth) after contact with NCT for a sublethal time caused by a chlorine cover may play a role in attenuation of the infection [28,31]. ...
N-chlorotaurine (NCT) can be used topically as a well-tolerated anti-infective at different body sites. The aim of this study was to investigate the efficacy of inhaled NCT in a mouse model of fungal pneumonia. Specific pathogen-free female C57BL/6JRj seven-week-old mice were immune-suppressed with cyclophosphamide. After 4 days, the mice were inoculated intranasally with 1.5 × 10E7 spores of Lichtheimia corymbifera or 1.0 × 10E7 spores of Aspergillus fumigatus. They were randomized and treated three times daily for 10 min with aerosolized 1% NCT or 0.9% sodium chloride starting 1 h after the inoculation. The mice were observed for survival for two weeks, and fungal load, blood inflammation parameters, bronchoalveolar lavage, and histology of organs were evaluated upon their death or at the end of this period. Inhalations were well-tolerated. After challenge with L. corymbifera, seven out of the nine mice (77.8%) survived for 15 days in the test group, which was in strong contrast to one out of the nine mice (11.1%) in the control group (p = 0.0049). The count of colony-forming units in the homogenized lung tissues came to 1.60 (1.30; 1.99; median, quartiles) log10 in the test group and to 4.26 (2.17; 4.53) log10 in the control group (p = 0.0032). Body weight and temperature, white blood count, and haptoglobin significantly improved with NCT treatment. With A. fumigatus, all the mice except for one in the test group died within 4 days without a significant difference from the control group. Inhaled NCT applied early demonstrated a highly significant curative effect in L. corymbifera pneumonia, while this could not be shown in A. fumigatus pneumonia, probably due to a too high inoculum. Nevertheless, this study for the first time disclosed efficacy of NCT in pneumonia in vivo.
... Cl-HN-CH 2 -CH 2 -SO − 3 + NH 4 Cl ↔ H 2 N-CH 2 -CH 2 -SO − 3 + NH 2 Cl + H + + Cl − NCT + ammonium chloride ↔ taurine + monochloramine Monochloramine is more lipophilic than NCT and penetrates microorganisms more easily, which leads to enhanced inactivation by the reaction just mentioned [17,56]. The stronger activity of NCT in the presence of fluids containing proteinaceous material is a general principle observed in different compositions, such as artificial sputum medium, different body fluids, peptone, and plasma for bacteria and fungi (for review see [14,24,57]). ...
AbstractN-chlorotaurine (NCT) a long-lived oxidant generated by leukocytes, can be synthesized chemically and applied topically as an anti-infective to different body sites, including the lung via inhalation. Here, we demonstrate the activity of NCT against viruses causing acute respiratory tract infections, namely severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza viruses, and respiratory syncytial virus (RSV).Virucidal activity of NCT was tested in plaque assays, confirmed by RT-qPCR assays. Attack on virus proteins was investigated by mass spectrometry.NCT revealed broad virucidal activity against all viruses tested at 37°C and pH 7. A significant reduction in infectious particles of SARS-CoV-2 isolates from early 2020 by 1 log10 was detected after 15 min of incubation in 1% NCT. Proteinaceous material simulating body fluids enhanced this activity by transchlorination mechanisms (1 -2 log10 reduction within 1-10 minutes). Tested SARS-CoV-2 variants B.1.1.7 (Alpha) und B.1.351 (Beta) showed a similar susceptibility. Influenza virus infectious particles were reduced by 3 log10 (H3N2) to 5 log10 (H1N1pdm), RSV by 4 log10. Mass spectrometry of NCT-treated SARS-CoV-2 spike protein and 3C-like protease, influenza virus hemagglutinin and neuraminidase, and RSV fusion glycoprotein disclosed multiple sites of chlorination and oxidation as the molecular mechanism of action.Application of 1.0% NCT as a prophylactic and therapeutic strategy against acute viral respiratory tract infections deserves comprehensive clinical investigation.
... The latter can be explained by transchlorination from NCT to amino groups of peptone, whereby among others low molecular weight chloramines are formed in equilibrium, which have stronger microbicidal activity (Gottardi et al. 2014). This is particularly true for monochloramine (NH 2 Cl) because of its higher lipophilicity (Gottardi et al. 2007). The enhancement of activity under protein load renders NCT a particularly interesting antiseptic for treatment of infections with high amounts of exudate (Gottardi et al. 2014;. ...
N-chlorotaurine (NCT) and hydrogen peroxide are powerful endogenous antiseptics. In vivo, the reaction between hydrogen peroxide and metal ions leads to the formation of free hydroxyl radicals, which have an increased bactericidal activity. This study examined whether there is an additive antimicrobial effect of NCT combined with hydrogen peroxide. Additionally, it was tested if the additive effect is based on the formation of free radicals. We found by luminometry that, in the presence of H2O2, NCT caused a slow and long-lasting production of singlet oxygen in contrast to HOCl, where this burst occurred instantaneously. Both NCT and hydrogen peroxide (1.0 and 0.1%) demonstrated bactericidal and fungicidal activity. At pH 7.1 and 37 °C, hydrogen peroxide (1%, 294 mM) showed a stronger bactericidal and particularly fungicidal activity than NCT (1%, 55 mM), whereas at pH 4.0 and also in the presence of 5.0% peptone NCT revealed a stronger bactericidal activity. A combination of NCT and hydrogen peroxide led to an increased bactericidal but no increased fungicidal activity compared to both substances alone. The additive effect against bacteria was not removed in the presence of the radical scavengers NaN3, DMSO, or peptone. As a conclusion, NCT and hydrogen peroxide used concurrently interact additive against a range of microorganisms. However, the results of this study suggest that the additive effect of NCT combined with hydrogen peroxide is rather not based on the formation of free radicals.
... The active chlorine atom of NCT is not only reduced and inactivated in the presence of organic material, it is partly also transferred to amino groups of the organic material, thereby forming the corresponding chloramines in equilibrium (20,26,44,49). Particularly the transhalogenation from NCT to ammonium, which forms the more lipophilic, better penetrating and stronger microbicidal monochloramine (NH 2 Cl), has been considered as causative (22,50). As a first consequence, this remarkable increase of microbicidal activity of NCT in human body fluids and exudates enables the clinical application of a mildly oxidizing compound, avoiding the irritative adverse effects of stronger reactive antiseptics (23,30,37). ...
Lung infections with multiresistant pathogens are a major problem of patients suffering from cystic fibrosis (CF). N-chlorotaurine (NCT), a microbicidal active chlorine compound with no resistance development, is well tolerated upon inhalation. The aim of this study was to investigate NCT on its bactericidal and fungicidal activity in vitro in artificial sputum medium (ASM) mimicking the composition of cystic fibrosis mucus.
The medium was inoculated with bacteria ( Staphylococcus aureus including some MRSA strains, Pseudomonas aeruginosa , Escherichia coli ) or spores of fungi ( Aspergillus fumigatus , Aspergillus terreus , Candida albicans , Scedosporium apiospermum , Scedosporium boydii , Lomentospora prolificans , Scedosporium aurantiacum , Scedosporium minutisporum , Exophiala dermatitidis , Geotrichum sp. ) to final concentrations of 10 ⁷ -10 ⁸ CFU/ml. NCT was added at 37°C, and time-kill assays were performed.
At a concentration of 1% (10 mg/ml, 55 mM) NCT, bacteria and spores were killed within 10 min and 15 min to the detection limit of 10 ² CFU/ml (reduction by 5-6 log 10 ). A reduction by 2 log 10 was still achieved by 0.1% (bacteria) and 0.3% NCT (fungi), largely within 10-30 min. Measurements by means of iodometric titration showed oxidizing activity over 1, 30, 60, and >60 min at a concentration of 0.1%, 0.3 %, 0.5%, and 1.0 % NCT, respectively, which matches the killing tests.
NCT demonstrated broad-spectrum microbicidal activity in the milieu of CF mucus at concentrations ideal for clinical use. Microbicidal activity of NCT in ASM was even stronger than in buffer solution, particularly pronounced with fungi. This can be explained largely by formation of monochloramine by transhalogenation, which rapidly penetrates pathogens.
... As a more potent chloramine formulation and as a positive control, we chose a 1% combination of NCT and ammonium chloride (NH 4 Cl). This leads to formation of about 0.025% (4.9 mM) monochloramine (NH 2 Cl) which is only little more reactive but significantly more lipophilic than the hydrophilic NCT [46] . The consequence is increased penetration of pathogens but also body cells and tissue, which may be wanted in some indications , e.g. in the eye for treatment of viral conjunctivitis [11,43]. ...
N-chlorotaurine, a long-lived oxidant produced by human leukocytes, can be applied in human medicine as an endogenous antiseptic. Its antimicrobial activity can be enhanced by ammonium chloride. This study was designed to evaluate the tolerability of inhaled N-chlorotaurine (NCT) in the pig model.
Anesthetized pigs inhaled test solutions of 1% (55 mM) NCT (n = 7), 5% NCT (n = 6), or 1% NCT plus 1% ammonium chloride (NH4Cl) (n = 6), and 0.9% saline solution as a control (n = 7), respectively. Applications with 5 ml each were performed hourly within four hours. Lung function, haemodynamics, and pharmacokinetics were monitored. Bronchial lavage samples for captive bubble surfactometry and lung samples for histology and electron microscopy were removed.
Arterial pressure of oxygen (PaO2) decreased significantly over the observation period of 4 hours in all animals. Compared to saline, 1% NCT + 1% NH4Cl led to significantly lower PaO2 values at the endpoint after 4 hours (62 +/- 9.6 mmHg vs. 76 +/- 9.2 mmHg, p = 0.014) with a corresponding increase in alveolo-arterial difference of oxygen partial pressure (AaDO2) (p = 0.004). Interestingly, AaDO2 was lowest with 1% NCT, even lower than with saline (p = 0.016). The increase of pulmonary artery pressure (PAP) over the observation period was smallest with 1% NCT without difference to controls (p = 0.91), and higher with 5% NCT (p = 0.02), and NCT + NH4Cl (p = 0.05).Histological and ultrastructural investigations revealed no differences between the test and control groups. The surfactant function remained intact. There was no systemic resorption of NCT detectable, and its local inactivation took place within 30 min. The concentration of NCT tolerated by A549 lung epithelial cells in vitro was similar to that known from other body cells (0.25-0.5 mM).
The endogenous antiseptic NCT was well tolerated at a concentration of 1% upon inhalation in the pig model. Addition of ammonium chloride in high concentration provokes a statistically significant impact on blood oxygenation.
... Second, it has oxidative activity in the eye for 4 to 5 min, so that longterm adverse effects are very improbable and have actually not been observed. Third, it has excellent activity in vitro against pathogens [1], and in vivo it was as effective as are higher concentrations in the viral conjunctivitis rabbit model [23]. Fourth, it is as well-tolerated in the healthy eye as is 1% NCT alone [14]. ...
N-chlorotaurine (NCT), an endogenous mild antiseptic, is well-tolerated by application to the human conjunctiva and has been shown to offer beneficial effects in infectious conjunctivitis. Animal tests revealed improved efficacy of a combination of NCT with ammonium chloride in adenoviral conjunctivitis. The aim of this study was to evaluate the tolerability of NCT plus ammonium chloride in the healthy rabbit and human eye.
First, a tolerability study was performed in rabbits. In a blinded and randomized fashion, one eye was treated with the test medication, the other one with 0.9% saline. Twenty-one animals (three per concentration) were treated with one drop every 2 hours for 6 days. Second, in two volunteers one drop of a defined concentration was applied to one eye every 15 min for 1 hour, saline to the control eye. Four different concentrations were tested on different days. Third, a double-blind, randomized phase 1 study in 13 healthy volunteers was performed. One drop of 0.1% NCT plus 0.1% NH(4)Cl versus saline was applied every 15 min within the first hour, followed by four drops every 2 hours. This regimen was done daily for 5 days.
In rabbits, no side effects were seen with 0.1% NCT plus 0.1% NH(4)Cl, while higher concentrations sometimes caused short-time and minimal conjunctival injection and secretion after dosing. By 1% NCT plus 1% NH(4)Cl, these effects were moderate, but disappeared again without any detectable residues. In the pilot study with two volunteers, treatment with 0.5% NCT plus 0.1% NH(4)Cl caused medium-scale eye burning for 30 seconds, while 0.1% NCT plus 0.1% NH(4)Cl was very well-tolerated, with no or minimal burning for a few seconds. In the subsequent phase 1 study, 0.1% NCT plus 0.1% NH(4)Cl was well-tolerated by all subjects except for minimal eye burning for a few seconds after dropping. No objective signs of eye changes could be detected in the human beings.
The results of this study clearly demonstrate the good tolerability of a promising NCT formulation with improved activity.
Aims:
N-chlorotaurine is a body-own mild oxidizing antiseptic that can be applied topically as a well-tolerated anti-infective at many body sites. The objective of this study was to demonstrate its activity against representative nosocomial multidrug-resistant bacteria.
Methods and results:
The bactericidal activity of N-chlorotaurine was tested in quantitative killing assays against a panel of multiresistant Gram-positive and Gram-negative clinical isolates. N-chlorotaurine (1%, 55 mmol l-1 ) reduced the number of CFU of strains of methicillin-resistant Staphylococcus aureus, linezolid-resistant Staphylococcus epidermidis, vancomycin-resistant, and linezolid- and vancomycin-resistant Enterococcus faecium, 3MRGN and 4MRGN Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae by at least 2 log10 steps after 15 min and completely or nearly to the detection limit after 30 min at pH 7.1 and 37°C.
Conclusion:
The activity of N-chlorotaurine against these clinical isolates is similar to that against non-resistant ATCC strains and therefore not influenced by antibiotic resistance. This can be explained by the oxidizing and chlorinating mechanism of action of N-chlorotaurine, which leads to an attack of multiple targets in the microorganisms.
Significance and impact of study:
The bactericidal spectrum of N-chlorotaurine is not restricted by resistance against antibiotics. Therefore, it can be used against resistant strains, too.
N-chlorotaurine (NCT) is a long-lived oxidant generated in activated cells of the innate immune system, namely neutrophilic and eosinophilic granulocytes and monocytes. NCT acts as an antiseptic agent that can be synthesized chemically and applied topically on different infected body sites. Even treatment of the lower respiratory tract via inhalation, which has been in development in the last years, was well tolerated in a recent phase I clinical trial. In this study, we demonstrate the activity of NCT against viruses causing acute respiratory tract infections, in fact severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza viruses, and respiratory syncytial virus.
NCT revealed broad virucidal activity against all viruses tested. In the presence of organic proteinaceous material simulating body fluids, this activity was enhanced by transchlorination mechanisms so that significant inactivation of viruses could be achieved within 1 – 10 minutes.
Inhalation of 1.0% NCT as a prophylactic and therapeutic strategy against acute viral respiratory tract infections deserves comprehensive clinical investigation.
Background
N-chlorotaurine (NCT) is an endogenous active chlorine compound that can be used as an antiseptic and anti-infective in different body regions. Recently, tolerability of inhaled NCT has been demonstrated in humans so that it is of interest for future treatment of cystic fibrosis. In the present study, we tested the bactericidal and fungicidal activity of NCT in different lung cell culture models.
Methods
Bacteria (Staphylococcus aureus, Pseudomonas aeruginosa) and fungi (Candida albicans, Exophiala dermatitidis) were co-incubated with lung epithelial cell cultures, and after 4 h NCT was added. After different incubation times, aliquots were removed and quantitative cultures were performed.
Results
NCT at the therapeutically applied concentration of 1% (55 mM) completely killed the test pathogens within 15 - 30 min at 20 °C and at 37 °C. Killing by 0.3% NCT lasted up to 4 h dependent on the pathogen at 20 °C and up to 1 h at 37 °C. 0.1% NCT was the threshold concentration for killing since this amount of oxidation capacity was consumed by reactions with the organic compounds of the medium within 3 h (20 °C) and 0.5 h (37 °C).
Conclusions
NCT in therapeutic concentration demonstrated its microbicidal activity in the presence of lung epithelial cells. Remarkably, particularly the fungicidal activity was higher under these conditions than in phosphate buffer. This can be explained by formation of the stronger microbicidal monochloramine in equilibrium by transchlorination. The results suggest the suitability of NCT as inhalation medication in the lung.
Purpose:
N-chlorotaurine (NCT) is an anti-infective belonging to the class of chloramines and an investigative drug for the topical treatment of keratoconjunctivitis. The aim of the present study was to demonstrate its efficacy against Acanthamoeba and Candida in corneas infected ex vivo.
Methods:
Corneal buttons from porcine eyes were contaminated with Acanthamoeba castellanii trophozoites or Candida albicans Centraalbureau voor Schimmelcultures 5982 and incubated for 7 and 3 days, respectively. Subsequently, they were treated with 1% NCT for 5 to 120 minutes. After further incubation for 2 days in the absence of NCT in tests with A. castellanii, the buttons were homogenized, and the amoebae grown for a further 5 days before they were counted in a light microscope. For C. albicans, quantitative cultures were performed from corneal homogenates.
Results:
Incubation of 120 minutes in NCT completely inhibited the regrowth of A. castellanii and reduced the number of C. albicans colony-forming unit counts by 4 log10. In addition, at 60 minutes, significant reductions of both pathogens could be observed. Histology showed penetration of pathogens into the stroma of the corneal buttons.
Conclusions:
NCT inactivates A. castellanii and C. albicans in corneal tissue.
Background: Polymorphonuclear neutrophil granulocytes (PMN) destroy fungi, bacteria, parasites, or micro-thrombi. Main PMN weapons are the reactive oxygen species (ROS) that are generated by assembly of NADPH oxidase at the cell membrane and release of myeloperoxidase. Mother ROS is H2O2 (HO-OH), daughter ROS are hydroxyl-radical (OH) and non-radicalic singlet oxygen (1ΔO2*). PMN are strongly activated by triggers and prepared for activation by primers. Zymosan A (ZyA) is a typical trigger, 1ΔO2* with its about 300-400 nm photon (out of R-C=O*) is a typical primer. Material and Methods: 20 μl citrated normal blood samples (n=4) were incubated for 5 min (37°C) with 2 μl chloramine T ® (CT; 0-1 mM blood conc.), or two citrated blood samples were incubated with 2 μl zymosan A (ZyA; 0-6 μg/ml plasma conc.). 2.5 M arginine, 1 % Triton X 100®, pH 8.7 (cell lysing reagent) was added in 1+1 relation and incubated for 90 min. 250 μl 2.5 M arginine were added. After freezing/thawing the blood samples were subjected for analysis of ultraviolet (UV) wavelength opsin (OPN5) or rhodopsin (RHO) concentration by enzyme immuno assay (EIA). The EIA was also applied for pooled normal EDTA-plasma, stabilized by 1.25 M arginine, pH 8.7. Results: Both primer and trigger increased the expression of RHO and OPN5 in blood. The approx. SC200 on RHO expression was about 0.1 mM chloramine, two of four samples had an approx. SC150 on OPN5 expression of about 0.1 mM chloramine but there appeared also an approx. IC75 of 0.3 mM chloramine in two of them. The approx. SC200 was about 0.3-0.9 μg/ml ZyA for RHO or OPN5 expression with an up to 3fold increase of RHO and 1.5fold increase of OPN5. Discussion: Singlet oxygen stimulated RHO expression more than OPN5 expression. Rhodopsin often seems to be the opsin for initial priming, blue(violet)-opsin for advanced priming, and UV-opsin the reserve receptor for ultimate priming. Rhodopsin and violet-opsin seem to be the most important opsins for normal PMN function. Upon light exposure the neutrophils improve their vision, at too much light the light receptors are downregulated. The neutrophils primer singlet oxygen generated by about 0.1 mM chloramine could be of great pharmacological interest to improve the physiologic bright or violet vision of neutrophils.
Acanthamoeba spp. are the causative agents of Acanthamoeba keratitis (AK), which mainly occurs in contact lens wearers, and of skin lesions, granulomatous amoebic encephalitis (GAE),
and disseminating diseases in the immunocompromised host. AK therapy is complex and irritating for the eye, skin lesions are
difficult to treat, and there is no effective treatment for GAE. Therefore, new anti-Acanthamoeba drugs are needed. We investigated the anti-Acanthamoeba activity of N-chlorotaurine (NCT), an endogenous mild antiseptic. It was shown that NCT has amoebicidal qualities, both in phosphate-buffered
saline (PBS) and in amoebic culture medium. After 6 h of treatment with 10 mM NCT in PBS, the levels of trophozoites of all
strains investigated already showed at least a 2-log reduction. When the trophozoites were treated with 20 mM NCT in culture
medium, they showed a 2-log reduction after 24 h. The addition of NH4Cl to NCT led to a faster decrease in the numbers of living cells, if tests were carried out in PBS. A delay of excystation
was observed when cysts were treated with 55 mM (1%) NCT in culture medium. A complete failure of excystment was the result
of treatment with 1% NCT plus 1% NH4Cl in PBS. Altogether, NCT clearly demonstrated amoebicidal activity at concentrations well tolerated by human tissues and
might be useful as a topical drug for the treatment of Acanthamoeba infections. The addition of ammonium chloride can be considered to enhance the activity.
The influence of organic matter on the antibacterial activity of the endogenous substance N-chlorotaurine was examined. In contrast to other active N-chlorine compounds (e.g. hypochlorite, chloramine T) the efficacy of N-chlorotaurine was enhanced in the presence of the amine compounds α- and β-alanine, glycine and especially ammonium chloride. This remarkable effect was found to result from an equilibration between N-chlorotaurine and the amino acids, resp. ammonium, and formation of the corresponding N-chlorine derivatives by transhalogenation. In human exudates, too, the efficacy of N-chlorotaurine increased, which can be explained by an over-compensation of consumption effects by generation of these highly bactericidal N-chlorine derivatives. Moreover, repeated treatment at sublethal doses did not cause a decrease in efficacy of N-chlorotaurine. This suggests that application of N-chlorotaurine for local treatment of topical infections will be successful.
We have studied the activity of the weak endogenous oxidant N-chlorotaurine against Mycobacterium terrae.
The study revealed slow killing of more than 2 h duration by 1% (55 mM) N-chlorotaurine. In the presence of ammonium chloride, however, killing times decreased to a few minutes, even by 0.1% N-chlorotaurine.
This phenomenon is explained by formation of the lipophilic and therefore more bactericidal monochloramine as a result of transhalogenation of ammonia by N-chlorotaurine.
This review is an attempt to summarize our knowledge about taurine bromamine (TauBr) properties, its role in innate immunity and its therapeutic potential.
TauBr and taurine chloramine (TauCl) are major haloamines generated by eosinophils and neutrophils at a site of inflammation. Both haloamines share anti-inflammatory and anti-oxidant properties. TauBr, similarly to TauCl, decreases the production of proinflammatory mediators. Their anti-inflammatory and anti-oxidant activities are enhanced by their ability to induce the expression of heme oxygenase-1 (HO-1). TauCl is more stable than TauBr. On the other hand, only TauBr was found to be highly membrane-permeable showing stronger microbicidal activity than TauCl.
In the light of the anti-inflammatory and antimicrobial properties of TauBr we discuss its therapeutic potential in local treatment of inflammation, especially acne vulgaris, the most common inflammatory skin disorder. TauBr, at non-cytotoxic concentrations, is able to kill Propionibacterium acnes, the skin bacteria involved in pathogenesis of acne vulgaris.
As topical antibiotics used in the therapy of acne are associated with the emergence of resistant bacteria, topical TauBr seems to be a good candidate for an alternative therapy.
Recently, in a double blind trial, the efficacy of TauBr was compared with the efficacy of clindamycin, one of the most common topical antibiotics used in acne therapy. Comparable reduction of acne lesions was observed in the TauBr and clindamycin groups of patients with mild and moderate inflammatory facial acne vulgaris. We conclude that this pilot study supports our concept that TauBr can be used as a topical agent in the treatment of acne vulgaris, especially in patients who have already developed antibiotic resistance. Further studies are necessary to substantiate the more extended use of TauBr as an anti-inflammatory and anti-oxidant agent in human medicine.
The antifungal activity of N -chlorotaurine (NCT), a long-lived oxidant produced by stimulated human leucocytes, was investigated. Incubation of Aspergillus spp., Candida spp., Fusarium spp., Penicillium spp. and Alternaria spp. in 1% NCT (55 mM) for 1–4 h produced a log10 reduction in cfu of between 1 and 4. In samples of nasal secretion, killing was significantly hastened (30 min), which may be explained by the formation of monochloramine by halogenation of ammonium, which was found at a concentration of 1 mM in these samples. For these reasons, NCT is of interest as a new agent for treatment of local inflammatory mycosis, e.g. eosinophilic fungal rhinosinusitis.
Isolated human neutrophilic leukocytes were stimulated to produce hydrogen peroxide (H2O2) and to secrete cytoplasmic granule components including myeloperoxidase into the medium. Myeloperoxidase catalyzed the oxidation of chloride (Cl-) by H2O2 to yield hypochlorous acid (HOCl), which reacted with endogenous nitrogen compounds to yield derivatives containing nitrogen-chlorine (N-Cl) bonds. Compounds available for reaction with HOCl were ammonia (NH+4), taurine, alpha-amino acids, and granule proteins and peptides that were released into the medium. A portion of the N-Cl derivatives formed under these conditions accumulated in the extracellular medium. These long lived oxidizing agents were characterized as hydrophilic, low molecular weight, mono-N-chloramine (RNHCl) derivatives based on their absorption spectrum, ability to oxidize 5-thio-2-nitrobenzoic acid and to chlorinate ammonia (NH+4), and behavior upon ultrafiltration, gel chromatography, and extraction with organic solvents. The RNHCl derivatives were of low toxicity, but reacted with NH+4 to yield the lipophilic oxidizing agent monochloramine (NH2Cl). Therefore, the addition of NH+4 conferred bactericidal, cytotoxic, and cytolytic activities on the RNHCl derivatives. The results indicate that taurine and other neutrophil amines protect neutrophils and other cells against oxidative attack by acting as a trap for HOCl and by competing with endogenous NH+4 for reaction with HOCl. However, the RNHCl derivatives act as a reserve of oxidizing equivalents that is converted to a toxic form when an increase in NH+4 concentration favors formation of NH2Cl.
N-chlorotaurine (NCT), an essential weak oxidative N-chloro compound produced by stimulated human leukocytes, shows bactericidal, fungicidal, virucidal and vermicidal efficacy. A double-blind, randomized and placebo controlled study was done to evaluate the tolerance of the aqueous NCT solution by application to rabbit and human conjunctiva. In six rabbits treated with 1% and 3% NCT regimen for nine days no ocular and behaviour changes could be observed. In a pilot study with two volunteers, treatment with 2.8% NCT for five days caused a self-limited conjunctival injection of one subject, while 1% NCT was well tolerated. Subsequently, eight healthy volunteers participated in a phase I clinical study. One percent NCT was applied for five days and was well tolerated by all subjects except for minimal eye burning after the application. Because of these positive results, usage of the antimicrobial agent NCT in ophthalmology is suggested.
N-chlorotaurine, a weak antimicrobial oxidant produced by stimulated human leukocytes, was used to treat cystitis caused by an omniresistant Pseudomonas aeruginosa. A 21-year-old male patient was treated by repeated daily lavages of the urinary bladder with an aqueous solution of 1% N-chlorotaurine for one month. N-chlorotaurine was well tolerated; no local or systemic side effects could be detected. Despite killing of > 10(6) cfu/ml of bacteria within ten minutes in vitro and in vivo, it was not possible to eradicate the Pseudomonas infection obviously caused by inflammation of the upper urinary tract and perpetuated by intravesical concrements. Nevertheless, in actually localized infection, treatment with N-chlorotaurine might be successful because of its sufficient bactericidal action.
We have studied the activity of the weak endogenous oxidant N-chlorotaurine against Mycobacterium terrae. The study revealed slow killing of more than 2h duration by 1% (55 mM) N-chlorotaurine. In the presence of ammonium chloride, however, killing times decreased to a few minutes, even by 0.1% N-chlorotaurine. This phenomenon is explained by formation of the lipophilic and therefore more bactericidal monochloramine as a result of transhalogenation of ammonia by N-chlorotaurine.
N-Chlorotaurine (NCT) is an endogenous microbicidal oxidant. This open pilot study (phase IIa) with 9 patients was done to gain first knowledge on the tolerance of NCT in infectious conjunctivitis. By application of 1% NCT 5 times a day, no adverse effects could be observed. All 6 subjects with bacterial conjunctivitis were cured within 3-5 days. Two subjects with epidemic keratoconjunctivitis were treated for 7-10 days and 1 subject with herpes simplex blepharitis for 3 days with no rapid improvement but probable mitigation of inflammation. Therefore, NCT seems to be useful in the treatment of infectious conjunctivitis, and further investigation on its therapeutic efficacy is suggested.
N-chlorotaurine (NCT) is known to play an important role in the human defence system. The already proved utility of the sodium salt as a disinfectant in human medicine suggested a thorough investigation of its chemical properties. Chlorine transfer to N-H groups (transhalogenation) and oxidation of thio and aromatic compounds represent its main reactions. Auto-chlorination causes disproportionation forming N, N-dichlorotaurine (NDCT) with K(d) = [NDCT][taurine]/f(a)[NCT]2aH+ = (4.5 +/- 0.8) x 10(6), while the reaction with ammonium releasing NH2Cl is characterised by K(NHCl2) = [NH2Cl][taurine]/[NCT][NH4+]f(a)2 = 0.02 +/- 0.004. The verified unique stability and low level reactivity of NCT are considered essential for its function in the mammalian defence system and its practical applicability, which manifests itself in an optimal compromise between microbicidal activity and toxicity.
The well-known active chlorine compound chloramine T (CAT) with broad-spectrum antimicrobial activity is in common therapeutic use for leg ulcers with purulent coatings; however, this treatment is painful. The tolerability of the less aggressive N-chlorotaurine (NCT), an endogenous compound also produced in vivo by stimulated human granulocytes, could be superior.
To assess the tolerability and efficacy of NCT in the cleaning of purulent coatings in chronic leg ulcers in comparison with CAT.
In a double-blind, randomized phase IIb clinical study 40 patients were treated for a median of 7 days (range 3-14) with a 1% aqueous solution of either NCT (20 subjects) or CAT (20 subjects) by twice-daily application of dressings soaked in the test solutions. Criteria for evaluation of tolerability were intensity and duration of pain caused by the ulcer therapy and scores of tissue toxicity (necrosis, granulation tissue and re-epithelialization). Therapeutic efficacy was graded as scores of intensity of purulent coating of the ulcers.
The concentration tolerated in vitro by human epidermoid carcinoma cells was at least 10-fold higher for NCT (0.01%) compared with CAT (0.0001-0.001%). There was significantly less pain caused by NCT compared with CAT (P < 0.05) on days 1 and 4 and a trend for a shorter duration of pain (P = 0.093). The scores of intensity of coating improved without difference in both treatment groups, whereas granulation and re-epithelialization appeared earlier in the NCT group (P < 0.05). Non-quantitative microbiological cultures from ulcer smears revealed persistence of colonization by bacterial species in approximately half of both treatment groups.
Both active chlorine compounds were helpful in reducing purulent coatings. Because of its lower toxicity and better tolerability, NCT is of advantage in the treatment of leg ulcers.
The aim of this study was to assess the tolerability and efficacy of N-chlorotaurine (NCT), an endogenous antimicrobial agent, in epidemic keratoconjunctivitis. In a prospective double-blind, randomized phase 2b study, the infected eyes were treated for 7 days with eye drops containing 1% aqueous solution of N-chlorotaurine (33 subjects) or gentamicin (27 subjects, control group). Adenovirus types 3, 4, 8, 19, and 37 were detected in 39 subjects (65%), enteroviruses in 8 (13.3%), and staphylococci in 5 (8.3%). Subjective and objective symptoms were scaled and added to a subjective and objective score, respectively, on day 1 (baseline), day 4, and day 8. Analyzing the whole study population, the subjective score on day 8 was lower in the NCT group (P = 0.016), whereas there were no differences in the objective score. However, in severe infections caused by adenovirus type 8 (n = 20) both the subjective and objective score were lower in the NCT group on day 4 (P = 0.003 and 0.015, respectively), which was also true for the subjective score on day 8 (P = 0.004) in this subgroup. The frequency of subepithelial infiltrates was similar in both groups. N-chlorotaurine was well-tolerated, shortened the duration of illness, and seems to be a useful causative therapeutic approach in severe epidemic keratoconjunctivitis.
The biogenous antimicrobial agent N-chlorotaurine (NCT) converts by disproportionation to N,N-dichlorotaurine (NDCT) at a rate proportional to acidity. This occurs at appreciable amounts already in weakly acidic biological systems. To understand the consequences of NDCT formation, a thorough investigation of this undescribed compound was mandatory, which needed its synthesis. Differently from NCT, this was possible in the aqueous system using trichloroisocyanuric acid. While the free acid, Cl(2)HNCH(2)CH(2)SO(3)H, was not available in pure form, its sodium and potassium salts were analytically pure and showed melting points (decomposition) of 125-128 degrees C (potassium) and 162-164 degrees C (sodium). The sodium salt demonstrated unexpected long-term stability even at room temperature (8.4 % loss of activity within 4 months). The aqueous solutions of both salts exhibited a weak acid reaction, and they were less stable than NCT. With regard to chlorination of amines (transhalogenation), NDCT was, surprisingly, less efficacious than NCT, which manifested itself by a lack of reactivity at pH < 7, for which a mechanistic explanation is given. Compared on a molar scale, NDCT was more bactericidal than NCT against the gram-negative bacteria E. coli, P. aeruginosa and P. mirabilis, while there was no difference concerning the gram-positive ones, S. aureus and S. epidermidis. The increase of bactericidal activity at acidic pH was the same as observed with NCT and is attributed to a higher susceptibility of bacteria in this environment. Taken together, NDCT seems not to be suited to substitute NCT as a preparation fit for medical practice.
To determine whether N-chlorotaurine (NCT) demonstrates antiviral activity against adenovirus (Ad) in vitro and in the Ad5/NZW rabbit ocular model.
The in vitro activity of NCT was evaluated by incubating different Ad serotypes with several concentrations of NCT for 1 hour and determining the reduction in Ad titers. In rabbit study 1, Ad5-infected eyes were treated with 2.5%, 2.0%, and 1.0% NCT; 0.5% cidofovir; or saline. NCT and saline groups were treated 10 times for 1 day and then 5 times daily for 6 days. In rabbit study 2, Ad5-infected eyes were treated with 1.0% NCT/0.1% ammonium chloride (NH4Cl), 0.1% NCT/1.0% NH4Cl, 0.1% NCT/0.1% NH4Cl, and 0.5% cidofovir or saline. The NCT and saline groups were treated five times daily for 10 days. Cidofovir-treated eyes received the authors' standard cidofovir dose regimen: twice daily for 7 days.
In vitro, NCT demonstrated concentration-dependent direct inactivation of all ocular Ad serotypes tested. Rabbit study 1: 2.5%, 2.0%, 1.0% NCT, and cidofovir demonstrated significantly fewer positive cultures per total cultures during days 1 to 14, compared with saline. Rabbit study 2: 1.0% NCT/0.1% NH4Cl, 0.1% NCT/1.0% NH4Cl, 0.1% NCT/0.1% NH4Cl, and cidofovir demonstrated significantly fewer positive cultures per total cultures, during days 1 to 14; shorter durations of shedding; and lower mean combined titers, during days 7 to 14, compared with saline. Cidofovir was significantly more effective than NCT in several outcome measures in both rabbit studies.
NCT demonstrated antiviral activity against adenovirus in vitro and in vivo. Further development of NCT as a topical antimicrobial is indicated.
In recent years taurine chloramine raised considerable interest as a part of the immune system. Regarded at first as a simple end-product of HOCl metabolism, during further studies it revealed oxidative, bactericidal and immunomodulatory properties. Today there is little doubt as to its complex role in mechanisms of both innate and acquired immunity. This review is an attempt to summarize our knowledge about its properties and role in the immune system.
An existing model describing the slow decomposition of chloramines in the presence of excess ammonia was modified to incorporate general acid catalysis of monochloramine disproportionation, a key reaction in determining the rate of chloramine loss. Experiments were conducted at various reaction conditions in the presence of varying concentrations of phosphate which was used as an analog for other naturally occurring proton donors. Results were used to obtain an estimate of the specific rate constant characterizing the effect of H2PO4− and to demonstrate the validity of the overall model formulation. Measured chloramine concentrations compared favorably with predicted values indicating that inclusion of the catalytic effect on monochloramine disproportionation alone appears justified in assessing the effect of phosphate. By analogy, it is expected that similar inorganic proton donors such as those of carbonate and silicate would also potentially affect only monochloramine disproportionation and that the modified model should be better capable of assessing chloramine decay in natural waters.
The model hydrogen peroxide-myeloperoxidase-chloride system is capable of generating the powerful oxidant hypochlorous acid, which can be quantitated by trapping the generated species with the β-amino acid, taurine. The resultant stable product, taurine chloramine, can be quantitated by its ability to oxidize the sulfhydryl compound, 5-thio-2-nitro-benzoic acid to the disulfide, 5,5′-dithiobis(2-nitroben-zoic acid) or to oxidize iodide to iodine. Using this system, purified myeloperoxidase in the presence of chloride and taurine converted stoichiometric quantities of hydrogen peroxide to taurine chloramine. Chloramine generation was absolutely dependent on hydrogen peroxide, myeloperoxidase, and chloride and could be inhibited by catalase, myeloperoxidase inhibitors, or chloride-free conditions. In the presence of taurine, intact human neutrophils stimulated with either phorbol myristate acetate or opsonized zymosan particles generated a stable species capable of oxidizing 5-thio-2-nitrobenzoic acid or iodide. Resting cells did not form this species. The oxidant formed by the stimulated neutrophils was identified as taurine chloramine by both ultraviolet spectrophotometry and electrophoresis. Taurine chloramine formation by the neutrophil was dependent on the taurine concentration, time, and cell number. Neutrophil-dependent chloramine generation was inhibited by catalase, the myeloperoxidase inhibitors, azide, cyanide, or aminotriazole and by chloride-free conditions, but not by superoxide dismutase or hydroxyl radical scavengers. Thus, it appears that stimulated human neutrophils can utilize the hydrogen peroxide-myeloperoxidase-chloride system to generate taurine chloramine. Based on the demonstrated ability of the myeloperoxidase system to generate free hypochlorous acid we conclude that neutrophils chlorinate taurine by producing this powerful oxidant. The biologic reactivity and cytotoxic potential of hypochlorous acid and its chloramine derivatives suggest that these oxidants play an important role in the inflammatory response and host defense.
The ultraviolet spectra of six alkylchloramines are determined between 220 and 320 nm. The wavelengths of maximum absorption are 244 nm (ϵ = 458 l mol−1 cm−1) for monochloramine, 252 nm (ϵ = 372 l mol−1 cm−1) for methylchloramine, 251 nm (ϵ = 378 l mol−1 cm−1) for ethylchloramine, 250 nm (ϵ = 368 l mol−1 cm−1) for isopropylchloramine, 264 nm (ϵ = 354 l mol−1 cm−1) for dimethylchloramine and 262 nm (ϵ = 315 l mol−1 cm−1) for diethylchloramine.
This paper reports on a study of the formation of an unidentified product(s) of the slow decomposition of monochloramine in organic free aqueous solutions at pH values and Cl/N ratios of importance in the chloramination disinfection of drinking water. Chloramine and total oxidant concentrations determined spectrophotometrically in these solutions became significantly greater with time than those determined by a titrimetric method due to the absorbance of the unidentified product(s). The u.v. spectra of the product(s) was calculated from the difference between measured and predicted spectra and was similar to that obtained in a chloramine free solution resulting from the rapid decomposition of dichloramine at high pH. No spectrophotometric evidence could be found for the formation of significant concentrations of nitrite and/or nitrate.Relative concentration changes of the unidentified product(s) as measured by its calculated absorbance at 243 nm showed that the product(s) accumulates with time and therefore is not likely to be an intermediate in the formation of nitrogen gas. Both increased pH and phosphate buffer increased its formation rate. A formation mechanism involving the decomposition of dichloramine is suggested. Findings suggest that the age/history of chloramine solutions could be an important variable in toxicological studies of chloramines and their reaction products depending on the health effects of the unidentified product(s).
Exogenous ammonium ions (NH(4) (+)) and amine compounds had a profound influence on the antibacterial activity of the myeloperoxidase-hydrogen peroxide-chloride system against Escherichia coli. The rate of killing increased in the presence of NH(4) (+) and certain guanidino compounds and decreased in the presence of alpha-amino acids, polylysine, taurine, or tris (hydroxymethyl) aminomethane. Myeloperoxidase catalyzed the oxidation of chloride to hypochlorous acid, which reacted either with bacterial amine or amide components or both or with the exogenous compounds to yield chloramine or chloramide derivatives or both. These nitrogen-chlorine derivatives could oxidize bacterial components. Killing was correlated with oxidation of bacterial components. The rate of oxidation of bacterial sulfhydryls increased in the presence of the compounds that increased the rate of killing and decreased in the presence of the other compounds. The reaction of HOCl with NH(4) (+) yielded monochloramine (NH(2)Cl), which could be extracted into organic solvents. The N-Cl derivatives of bacterial components or of polylysine, taurine, or tris(hydroxymethyl)aminomethane could not be extracted. The effect of NH(4) (+) on killing is attributed to the ability of NH(2)Cl to penetrate the hydrophobic cell membrane and thus to oxidize intracellular components. Polylysine, taurine, and tris(hydroxymethyl)aminomethane formed high-molecular-weight, charged, or polar N-Cl derivatives that would be unable to penetrate the cell membrane. These results suggest an important role for leukocyte amine components in myeloperoxidase-catalyzed antimicrobial activity in vivo.
The model hydrogen peroxide-myeloperoxidase-chloride system is capable of generating the powerful oxidant hypochlorous acid, which can be quantitated by trapping the generated species with the beta-amino acid, taurine. The resultant stable product, taurine chloramine, can be quantitated by its ability to oxidize the sulfhydryl compound, 5-thio-2-nitro-benzoic acid to the disulfide, 5,5'-dithiobis(2-nitroben-zoic acid) or to oxidize iodide to iodine. Using this system, purified myeloperoxidase in the presence of chloride and taurine converted stoichiometric quantities of hydrogen peroxide to taurine chloramine. Chloramine generation was absolutely dependent on hydrogen peroxide, myeloperoxidase, and chloride and could be inhibited by catalase, myeloperoxidase inhibitors, or chloride-free conditions. In the presence of taurine, intact human neutrophils stimulated with either phorbol myristate acetate or opsonized zymosan particles generated a stable species capable of oxidizing 5-thio-2-nitrobenzoic acid or iodide. Resting cells did not form this species. The oxidant formed by the stimulated neutrophils was identified as taurine chloramine by both ultraviolet spectrophotometry and electrophoresis. Taurine chloramine formation by the neutrophil was dependent on the taurine concentration, time, and cell number. Neutrophil-dependent chloramine generation was inhibited by catalase, the myeloperoxidase inhibitors, azide, cyanide, or aminotriazole and by chloride-free conditions, but not by superoxide dismutase or hydroxyl radical scavengers. Thus, it appears that stimulated human neutrophils can utilize the hydrogen peroxide-myeloperoxidase-chloride system to generate taurine chloramine. Based on the demonstrated ability of the myeloperoxidase system to generate free hypochlorous acid we conclude that neutrophils chlorinate taurine by producing this powerful oxidant. The biologic reactivity and cytotoxic potential of hypochlorous acid and its chloramine derivatives suggest that these oxidants play an important role in the inflammatory response and host defense.
Chloramines have long been used to provide a disinfecting residual in distribution systems where it is difficult to maintain a free chlorine residual or where disinfection by-product (DBP) formation is of concern. While chloramines are generally considered less reactive than free chlorine, they are inherently unstable even in the absence of reactive substances. These reactions, often referred to as "auto-decomposition", always occur and hence define the maximum stability of monochloramine in water. The effect of additional reactive material must be measured relative to this basic loss process. A thorough understanding of the auto-decomposition reactions is fundamental to the development of mechanisms that account for reactions with additional substances and to the ultimate formation of DBPs. A kinetic model describing auto-decomposition was recently developed. This model is based on studies of isolated individual reactions and on observations of the reactive ammonia-chlorine system as a whole. The work presented here validates and extends this model for use in waters typical of those encountered in distribution systems and under realistic chloramination conditions. The effect of carbonate and temperature on auto-decomposition is discussed. The influence of bromide and nitrite at representative monochloramine concentrations is also examined, and additional reactions to account for their influence on monochloramine decay are presented to demonstrate the ability of the model to incorporate inorganic demand pathways that occur parallel to auto-decomposition.
The study's objective was to test the tolerability and efficacy of the endogenous antiseptic N-chlorotaurine (NCT) in comparison with a standard clinical treatment according to a phase IIb clinical trial protocol.
The antimicrobial agent NCT was compared with the antibiotic component drops Otosporin (containing neomycin, polymyxin B, and hydrocortisone) for topical treatment of acute otitis externa in a randomized and rater-blinded clinical study.
Fifty patients suffering from acute otitis externa were divided into two groups according to a randomized list. The test group was treated with 1 mL of 1% aqueous NCT solution, the reference group with 1 mL of Otosporin. The substances were applied to the external ear canal at one daily session until the signs of infection disappeared. Efficacy and tolerability were evaluated daily by visual analogue scale and a six-step infection score. In addition, smears were analyzed to identify the causative pathogens.
Both medications were equally well tolerated by the patients. The treatment was successful for all patients of the NCT group, whereas in one patient from the reference group, the infection did not disappear. The inflammation score improved more rapidly in the NCT group, which resulted in an earlier termination of the therapy. This difference became highly significant on days 4 to 7 (P <.01 each). Time needed for disappearance of inflammation (score 0) was 5.6 +/- 1.6 (mean +/- SD, range 3-9) days in the NCT group and 7.4 +/- 1.6 (range 4-10) days in the Otosporin group (P <.001). As expected, microbiologic cultures from ear swabs revealed Pseudomonas aeruginosa (58%) followed by Staphylococcus aureus (18%) as the main causative pathogens.
NCT appears to be well tolerated and more effective than the therapy using antibiotic component drops. Because of its endogenous nature and its higher efficacy, NCT appears to be a good choice for topical treatment of acute otitis externa.
A rational approach in the treatment of chronic rhinosinusitis (CRS) is the intranasal application of antiseptic agents, due to the pathogenetic role of bacteria and fungi. N-Chlorotaurine (NCT), a mild endogenous oxidant with broad-spectrum antimicrobial activity, has been tested for the first time in CRS.
This one-arm phase IIa clinical study is the first step in the clinical development of this promising substance for local therapy of CRS. The nasal and paranasal cavities of 12 patients were rinsed with 10-20 ml of 1% aqueous NCT solution, applied via a novel catheter system (YAMIK). Treatment consisted of three lavages per week for 4 weeks.
NCT caused neither alterations of the mucosa nor burning pain during application. Nevertheless, the insertion of the catheter, the insufflation of the posterior cuff and the overpressure inside the sinuses after infiltration led to moderate pain in some patients. Mucosal swelling decreased in all subjects, nasal breathing could be improved in nine patients and impaired olfaction in seven. Polyps did not disappear within the 1-month period of the study.
The good tolerability and possible beneficial effects of NCT encourage its further investigation in CRS. Despite some limitations the YAMIK catheter proved to be a convenient and safe device for rinsing the nasal and paranasal sinuses.
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