N-chlorotaurine Research Articles

Tolerability of N-chlorotaurine in chronic rhinosinusitis applied via yamik catheter

Objectives: 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. Methods: 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. Results: 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. Conclusions: 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.

Chlorine covers on living bacteria: the initial step in antimicrobial action of active chlorine compounds

Although active chlorine compounds are well-known antimicrobial agents in human medicine, their initial steps of action have not been completely clarified. Using N-chlorotaurine (NCT), an endogenous mild representative, we observed persisting oxidation capacity affixed to bacteria. It was the aim of this study to investigate this 'chlorine cover'. Pathogens were incubated in NCT, which was subsequently washed off. The oxidation capacity on the bacterial surface was measured photometrically. Superficial chlorination in the form of covalent N-Cl bonds to Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa and Candida albicans could be attached before killing took place. For S. aureus, 3 min incubation with NCT produced a cover of 3.3 x 10(-16) mol Cl(+)/cfu, while the cfu count was reduced by only 26%. The kind of microorganism, coating time, pH, buffer system and, basically, the chlorine compound, influenced the cover strength. The relative cover strength on S. aureus by NCT, chloramine T, sodium dichloro-isocyanurate or N,N-dichlorotaurine was 1:15.7:38.7:0.24. Chlorine covers were surprisingly stable and could be detected for 3 h at 20 degrees C (>8 h at 1 degrees C), even without a reduction of cfu. However, addition of 5% ammonium chloride caused a rapid loss of viability, explained by formation of highly bactericidal NH(2)Cl, an effect that resembles the ignition of a time-bomb. The chlorine cover can be regarded as the first sign of interaction between chlorinating agent and microorganism, and may explain the non-lethal features of postantibiotic effect and attenuation of bacterial virulence. Furthermore, it may be a decisive step in bacterial inactivation by the myeloperoxidase-hypochlorite system in innate immunity.

Tolerability and Efficacy of N-Chlorotaurine in Epidemic Keratoconjunctivitis—a Double-Blind, Randomized, Phase-2 Clinical Trial

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.

Down-regulatory effect of N-chlorotaurine on tryptophan degradation and neopterin production in human PBMC

N-Chlorotaurine (NCT) plays an important role in the human defense system as a main component of long-lived oxidants, and shows bactericidal, fungicidal, and virucidal activity. Besides this role, NCT seems to act regulatory on immunocompetent cells by altering cytokine production. NCT inhibited nitric oxide, TNF-α, and prostaglandin E 2 (PGE 2) production in activated rodent macrophages, and suppressed superoxide anion, IL-6, and IL-8 formation in human polymorphonuclear leukocytes. In this study, the influence of NCT on the production of neopterin and the activation of the enzyme indoleamine-2,3 dioxygenase (IDO) was investigated in human peripheral blood mononuclear cells (PBMC). Both events are well established to be triggered by IFN-γ and therefore related to Th1-type immune activation. Mitogen-induced neopterin production as well as tryptophan degradation were drastically reduced upon addition of NCT. Results fit in the concept of a reduction of pro-inflammatory cytokines by this compound. In contrast to earlier results, where NCT was suggested to act primarily down-regulatory on Th2 cells, we propose also a strong suppressive effect of NCT on Th1-type immunity.

Tolerability of N-chlorotaurine in the guinea pig middle ear: a pilot study using an improved application system.

The tissue tolerance of N-chlorotaurine (NCT), a mild endogenous antimicrobial oxidant, has been investigated by application to the guinea pig middle ear. The animals were implanted with a novel cannula system that allows chronic external drug delivery to the round window niche. In the first part of the study, 3 animals each received 100 microL of 0.1% NCT (5.5 mmol/L) and 1% NCT, respectively, in aqueous solution twice daily for 8 days. In the second part, NCT was dissolved in phosphate-buffered saline solution to 300 milliosmolar (isotonic), and 27 microL was injected in 3 additional animals twice daily for 7 days. The guinea pigs injected with 100 microL of NCT developed immediate dizziness and nystagmus and did not thrive. Other reactions included mucosal thickening in the middle ear, rupture of the tympanic membrane, and blood and gelatinous material in the cochlea accompanied by hair cell loss and a 10- to 90-dB elevation of the hearing threshold as determined by auditory brain stem responses. The effects seemed to be dose-dependent, but the rate of variability was high across animals. In contrast, the guinea pigs treated with 27 microL of isotonic NCT showed no signs of discomfort, no or only moderate thickening of the middle ear mucosa, no shift of the hearing threshold, and no hair cell loss. Positive control animals injected with 10% neomycin sulfate developed extensive hair cell loss. Provided that the membranes of the inner ear are intact and that low single-dose volumes are used to avoid increased middle ear pressure, isotonic NCT seems to be well tolerated in the tympanic cavity. The new drug delivery system proved to be advantageous for ototoxicity studies.

In Vitro Study on the Influence of N-Chlorotaurine on the Ciliary Beat Frequency of Nasal Mucosa

The aim of this study was to investigate the in vitro effects of N-chlorotaurine (NCT), a new endogenous antimicrobial agent, on the nasal ciliary beat frequency (CBF) in nasal mucosa samples of 10 adult patients who underwent conchotomy. CBF was measured by a photometric technique, combining a light microscope, a photometer, a photograph multiplier, and a computed analyzing unit. CBF decreased approximately 10% after 20 minutes of incubation in aqueous 1% NCT solution compared with 3% in 0.9% saline, and 0.1 and 0.01% NCT had no effect. However, a solution of 7% cocaine, which is used routinely for shrinking the nasal mucosa before rhinoscopy lowered the CBF to 50% after the same incubation time. These results confirm the very low toxic potential of NCT, and they are fundamental for clinical investigations regarding its topical application in the nasal and paranasal sinuses.

Chemical properties of N-chlorotaurine sodium, a key compound in the human defence system.

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.

Enhanced fungicidal activity of N-chlorotaurine in nasal secretion.

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.

Tolerance of N-Chlorotaurine, a New Antimicrobial Agent, in Infectious Conjunctivitis – A Phase II Pilot Study

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.

The postantibiotic effect of N-chlorotaurine on Staphylococcus aureus. Application in the mouse peritonitis model.

This study was designed to investigate the delay of regrowth (postantibiotic effect) in the presence of N-chlorotaurine (NCT), an endogenous active N-chlorine compound, of Staphylococcus aureus, strain Smith diffuse. The low reactivity of NCT enabled clear temporal separation of the postantibiotic and killing effect to be defined. Delay of regrowth proved to be dependent both on concentration of NCT, and incubation time. The maximum delay was 3 h. Using the model of lethal staphylococcal peritonitis in mice, in-vivo delay of regrowth of bacteria pretreated with N-chlorotaurine could be demonstrated to correlate with survival. It is concluded that the postantibiotic effect of N-chlorotaurine could be an important factor on decreasing virulence of bacteria. This effect was observed after relatively short incubation times.