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Topical Hypochlorous Acid (HOCl) as a Potential Treatment of Pruritus
Abstract
Topical hypochlorous acid (HOCl) has recently been proposed as a treatment of pruritus. However, it is not known whether topical HOCl decreases or promotes pruritus. This review sheds light on this poorly understood subject. This article describes the pathophysiology of pruritus, current treatments of pruritus, and how pH determines the properties of HOCl in solution. The article then proposes two mechanisms by which HOCl may reduce pruritus: 1) HOCl is microbicidal to cutaneous pathogens, especially Staphylococcus aureus in atopic dermatitis; 2) HOCl is anti-inflammatory and reduces the activities of histamine, leukotriene B4, and interleukin-2, all of which are implicated in the pathophysiology of itch. Lastly, this article describes conditions under which HOCl may actually cause pruritus as an adverse effect. For example, HOCl increases the activity of nerve growth factor, which promotes itch. Prolonged or high-dose HOCl exposure may also cause irritant contact dermatitis, or less commonly, allergic contact dermatitis.
... IL-6, IKK) and mediators of tissue remodeling (e.g. MMP7, TIMP-1), causing effects that are mostly consistent with modulation, attenuation, and resolution of inflammatory tissue responses (35,(80)(81)(82)(83)(84)(85)(86)(87)(88)(89). Specifically, inactivation of IKK (inhibitor of IkB kinase) through oxidation (Cys114/115) is thought to cause the hypochlorite-dependent attenuation of psoriasis observable upon topical application (35). ...
... Also, it has been hypothesized that DBPs in drinking water correlate with risk of skin cancer (172). Importantly, HOCl-based therapeutics optimized for topical delivery are now serving as pharmaceutical formulations for wound management, scar prevention, diabetic ulcers, atopic dermatitis, pruritus, psoriasis, and seborrheic dermatitis (84,168,173,174). Suppression of inflammatory gene expression with downregulation of iNOS and COX-2 downstream of HOCldependent IKK inactivation represents the crucial mechanistic basis underlying HOCl-dependent therapeutic efficacy targeting psoriasis and radiation dermatitis (35). ...
A multitude of extrinsic environmental factors (referred to in their entirety as the ‘skin exposome’) impact structure and function of skin and its corresponding cellular components. The complex (i.e. additive, antagonistic, or synergistic) interactions between multiple extrinsic (exposome) and intrinsic (biological) factors are important determinants of skin health outcomes. Here, we review the role of hypochlorous acid (HOCl) as an emerging component of the skin exposome serving molecular functions as an innate immune factor, environmental toxicant, and topical chemopreventive agent targeting solar UV-induced skin cancer. HOCl [and its corresponding anion (OCl⁻; hypochlorite)], a weak halogen-based acid and powerful oxidant, serves two seemingly unrelated molecular roles: (i) as an innate immune factor [acting as a myeloperoxidase (MPO)-derived microbicidal factor] and (ii) as a chemical disinfectant used in freshwater processing on a global scale, both in the context of drinking water safety and recreational freshwater use. Physicochemical properties (including redox potential and photon absorptivity) determine chemical reactivity of HOCl towards select biochemical targets [i.e. proteins (e.g. IKK, GRP78, HSA, Keap1/NRF2), lipids, and nucleic acids], essential to its role in innate immunity, antimicrobial disinfection, and therapeutic anti-inflammatory use. Recent studies have explored the interaction between solar UV and HOCl-related environmental co-exposures identifying a heretofore unrecognized photo-chemopreventive activity of topical HOCl and chlorination stress that blocks tumorigenic inflammatory progression in UV-induced high-risk SKH-1 mouse skin, a finding with potential implications for the prevention of human nonmelanoma skin photocarcinogenesis.
... [28] HOCL 0.01% has been shown in a number of studies to have comparable antimicrobial activity to Betadine and may cover additional viruses and bacterial species more effectively [ Table 1]. [16,[29][30][31][32][33][34][35][36][37][38] A number of studies have demonstrated that HOCL is a naturally occurring anti-inflammatory agent that functions well as an antiseptic preparation. [18,19] Gold et al. found that HOCL 0.01% significantly reduced inflammation and was effective in killing >99.9% of tested microbes. ...
... [17] This may in part be explained by the ability of HOCL to mediate inflammatory cytokines, such as reducing the activity of leukotriene B4, histamine and interleukin-2, all of which are involved in the development of pruritus and irritation. [31] Finally, when HOCL is employed as a washout, it serves to remove residual irritant particles of Betadine, without diluting its antimicrobial effect, since it is a comparable antimicrobial. ...
Purpose:
Current ocular antiseptic practice for intravitreal injection (IVI) employs 5% povidone-iodine (Betadine®) drops which frequently cause ocular discomfort and prolonged irritation. In an effort to improve comfort while maintaining efficacy, we studied a hypochlorous acid (HOCL 0.01%) spray washout prior to injection.
Methods:
Patients had received a minimum of 3 IVIs prepared with Betadine®antisepsis prior to entry in this study. Their subsequent IVIs were prepared with Betadine®followed by HOCL 0.01% washout. Facets of comfort were measured by a Likert-scaled questionnaire to compare their experiences after IVI.
Results:
Thirty-seven participants were enrolled. Addition of HOCL 0.01% spray after Betadine®reduced the duration of discomfort (P = 0.001) and need for artificial tears postinjection (P = 0.003). It improved their reported quality of life (P = 0.04) and sleep (P = 0.01). There were neither HOCL-related side effects nor endophthalmitis during this study.
Conclusion:
Topical HOCL 0.01% spray after topical Betadine®antisepsis significantly improved patient comfort following IVIs.
... Hypochlorous acid (HOCl) is more reactive than NaOCl, with a potentially greater irritant effect on the skin. 33 HOCl has been shown to decrease numerous inflammatory cytokines, including tumor necrosis factor-a, interferon gamma, IL-2, and histamine, as well as nuclear factor kappa light-chain enhancer of activated B cellsemediated pathways in experimental models. [33][34][35][36] Topical HOCl was studied as a potential treatment for pruritus and found to significantly reduce scratching behavior in mouse models of AD. 37 In a recent case series, 7 days of treatment of patients with AD with topical hydrogel containing 0.008% HOCl and 0.002% NaOCl significantly reduced pruritus. ...
... 33 HOCl has been shown to decrease numerous inflammatory cytokines, including tumor necrosis factor-a, interferon gamma, IL-2, and histamine, as well as nuclear factor kappa light-chain enhancer of activated B cellsemediated pathways in experimental models. [33][34][35][36] Topical HOCl was studied as a potential treatment for pruritus and found to significantly reduce scratching behavior in mouse models of AD. 37 In a recent case series, 7 days of treatment of patients with AD with topical hydrogel containing 0.008% HOCl and 0.002% NaOCl significantly reduced pruritus. 38 PR022 is a topical formulation of HOCl that is being studied for the treatment of mild-to-moderate AD, with preclinical studies demonstrating lesional improvement with topical application. ...
Background:
A wide array of miscellaneous agents is being studied for the treatment of atopic dermatitis (AD), including targeted topical, oral systemic and biologic agents.
Objective:
To review the known efficacy and safety to-date for such agents being studied for the treatment of AD.
Methods:
A non-systematic review of the literature was performed. PubMed and ClinicalTrials.gov were searched for studies assessing agents not described in previous chapters for the treatment of AD. Randomized controlled trials (RCTs) were primarily sought, but other study types were also included if they contained pertinent data. Agents are presented by mechanism of action, with analysis of mechanism of action and data regarding efficacy and safety in AD patients.
Results:
Data regarding the following agents are presented: omiganan (antimicrobial peptide), tapinarof (non-steroidal anti-inflammatory agent), PR022 (hypochlorous acid), asimadoline (kappa opioid agonist), DS107 (dihomo-gamma-linolenic acid), ZPL-389 (histamine H4 receptor antagonist), secukinumab (interleukin 17A inhibitor), fezakinumab (interleukin 22 inhibitor).
Limitations:
Limited clinical data exists for many of the described agents.
Conclusions:
As recent research has improved our understanding of AD pathogenesis, various agents with unique mechanisms of action have been studied for the treatment of AD. Many of these hold great therapeutic promise for AD, and continued research and development is warranted.
... However, evidence evaluating whether these recommendations have been put into practice is lim- ited. 4,5 As a result of this preliminary work, a formal review of current dermatology teaching at the university level is underway. This aims to document the current situation in greater detail and explore additional areas such as student assessment methods. ...
... Many investiga- tors have demonstrated the significant anti-microbial activity in vitro of hypochlorous acid against common bacteria, improved healing of ulcers as well as anti- pruritic potential. 2,3,5 The efficacy of hypochlorous acid combined with the more practical application of our preparations to body parts such as the face compared to bleach baths further highlights the potential of this agent to not only porphyria but other dermatological conditions with risk of secondary infection such as atopic dermatitis. ...
... HOCl could diminish the degranulation of mast-cell and cytokine release induced by immunoglobulin E and induce advantageous effects of keratinocytes and fibroblast migration. [9][10][11] Previous research has been conducted to explore the use of HOCl ions in various health and sanitation contexts. Recent studies have been conducted to explore the potential of using HOCl ions in diabetic mice for wound healing. ...
Background
People who suffered type 2 diabetes have impaired healing of wounds due to the large number of circulating inflammatory cells resulting from high blood sugar levels. The wound healing process involves various complex processes including the degradation of extracellular matrix, a process characterized by an increase in matrix metalloproteinase-9 (MMP-9). Conventional management of diabetic wounds usually involves systemic blood sugar control and topical antimicrobial treatment, including hydrogen peroxide and povidone-iodine, which are known to be cytotoxic to the cells involved in the wound healing cascade. Finding a safe, non-toxic, and effecting wound cleansing still poses a challenge, and hypochlorous acid (HOCl) could act as a potential candidate.
Purpose
Unveiling an HOCl ion as an agent for diabetic wound management and MMP-9 as a marker for delayed diabetic wound healing.
Methods
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Flow Diagram is used to find and select related, eligible literatures for the review. The authors used several databases such as Pro Quest, Scopus, Springer link and Science Direct. In addition, and to expand the data, the database on Google Scholar was also opened. Then, the compiled data are analyzed to form results and discussions to the research question.
Results
Five eligible articles passed the inclusion criteria and reviewed for data synthesis. From 5 pieces of literature, it was found that the use of HOCl ions can be a good choice of topical agent in the management of diabetic wounds and decrease the activity of MMP-9, which act as a marker for delayed healing of diabetic wounds.
Conclusion
Topical agent, in this case HOCl ion, shows good results and can be used as an option in the management of diabetic wounds and MMP-9 can be used as a predictive marker in the management of diabetic wounds.
... Відомі дані про те, що гіпохлоритна кислота доволі легко окиснює амінокислоти -як вільні, так і ті, що містяться в складі поліпептидів, а також активно реагує з нуклеїновими кислотами (Kotsiumbas & Velichenko, 2009). Експериментально доведено також, що порушення бар'єрних властивостей плазматичної мембрани спричинює порушення внутрішньоклітинного гомеостазу, а в кінцевому результаті -призводить до руйнування внутрішньоклі-тинних органел (Henri Rosen, 1998;Kotsiumbas & Velichenko, 2009;Pelgrift & Friedman, 2013). ...
The article presents the materials for the study of the antimicrobial action against the test strains of microorganisms: E. coli, S. aureus, P. aeruginosa, B. subtilis, C. albicans, as well as the disinfecting properties of hypochlorite acid (HClO), obtained by the electrolysis method. It has been established that hypochlorous acid exhibits pronounced bactericidal, sporicidal, and fungicidal effects, has multifunctional and long-term activity against various bacteria and fungi, and is safe for the environment. The conducted studies established that the effectiveness of the antimicrobial action of hypochlorous acid depended on the type of microorganisms, concentration, and duration of exposure. The minimum bactericidal concentration of hypochlorous acid for E. coli and P. aeruginosa was 100 mg/l; for S. aureus and the yeast-like fungus C. albicans, it was at the level of 150 mg/l. The product under study showed bactericidal activity against E. coli, S. aureus, P. aeruginosa, B. subtilis, and C. albicans at a concentration of 500 mg/l after exposure for 30 minutes. Under the presence of a protein load, the ability of hypochlorous acid to disinfect an object from spore-forming microorganisms B. subtilis at the level of 2.8 lg was confirmed. At the same time, the obtained results indicated the absence of a linear relationship between the amount of organic load and sporicidal activity. To achieve a 100% fungicidal effect against A. niger in the presence of a protein load, the concentration of the tested agent should not be less than 700 mg/l, and the contact time should not be less than 3 hours. The use of HOCl, obtained by electrolysis, as a veterinary remedy is effective, as it has a high safety profile and a favorable therapeutic index and mimics the reaction of the immune system of animals to invasive microorganisms. Namely, it affects the microbial cell's physicochemical processes, disrupts the plasma membrane's permeability, and interferes with its normal functioning, which in turn leads to inhibition of activity or death in general. HOCl is one of the few substances of natural origin that is safe for humans and animals and lethal to almost all known pathogens.
... Дослідженнями останніх десятиліть встановлено, що всі вищі багатоклітинні організми, включаючи людину, синтезують в особливих клітинних структурах гіпохлоритну кислоту та високоактивні метастабільні кисневомісні сполуки для знешкодження сторонніх мікроорганізмів і речовин (Pelgrift & Friedman, 2013;Abuhaimed & Abou Neel, 2017;Hunchak et al., 2022). ...
The article presents materials on developing quality control methods for hypochlorite acid obtained by electrochemical synthesis. Electrochemical synthesis of hypochlorous acid was carried out using a combined electrochemical-pyrolytic method. The electrocatalytic activity of the obtained materials in the hypochlorite acid synthesis reaction was evaluated under the electrolysis of 0.05 M NaCl solutions in a duct cell with a Ti cathode at 25 ºС. The cathode area was varied, so the cathode current density was 40 mA/cm2. The pH of the solutions was monitored with a pX-150MI universal ionometer. The volumetric current density in the channel cell was 2.4 A/dm3, and the volumetric rate of solution supply was 9.5 l/h. The authors developed an original method of iodometric titration, which is based on the sequential determination of the content of hypochlorite ions, their total content with chlorite ions, and the total content simultaneously with chlorite and chlorate ions. The content of individual components of the mixture is determined as the difference between the total content of ions and the content of hypochlorite ions. The iodometric method of titration of oxidants is based on the reaction of replacing oxygen-containing compounds of chlorine with elemental iodine with its subsequent titration with standard solutions of sodium thiosulfate. It is proposed to fix the endpoint of the titration potentiometrically, which allows you to speed up the analysis, and it is also relatively easy to automate it using an automatic titrator. The content of oxygen-containing compounds in the solutions depends on the oxidation conditions and the specified operating modes of the electrochemical catalyst. The solution's acidity determines the presence of hypochlorous acid and can be calculated based on the equilibrium constant of its dissociation. The developed analysis methods will allow the control of the quality of veterinary drugs based on hypochlorous acid obtained by electrochemical synthesis.
... On the other hand, HAW is acidic and available in lower concentrations (80 mg/L or less), allowing for direct use without further dilution. Importantly, HAW, with its near-neutral pH, does not cause irritation to organs and mucous membranes (Pelgrift and Friedman, 2013). ...
It is essential to employ efficient measures to prevent the transmission of pathogenic agents during a pandemic. One such method involves using hypochlorous acid (HClO) solution. The oxidative properties of HClO water (HAW) can contribute to its ability to eliminate viral particles. Here, we examined a highly purified slightly acidic hypochlorous acid water (Hp-SA-HAW) obtained from the reverse osmosis membrane treatment of an electrolytically-generated SA-HAW for its anti-viral activity and mode of action on viral proteins. Hp-SA-HAW exhibited broad-spectrum antiviral effects against various viruses, including adenovirus, hepatitis B virus, Japanese encephalitis virus (JEV), and rotavirus. Additionally, Hp-SA-HAW treatment dose-dependently resulted in irreversibly aggregated multimers of the JEV envelope and capsid proteins. However, Hp-SA-HAW treatment had no discernible effect on viral RNA, indicating that Hp-SA-HAW acts against amino acids rather than nucleic acids. Furthermore, Hp-SA-HAW substantially reduced the infectivity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including the ancestral variant and other multiple variants. Hp-SA-HAW treatment induced the aggregation of the SARS-CoV-2 spike and nuclear proteins and disrupted the binding of the purified spike protein of SARS-CoV-2 to human ACE2. This study demonstrates that the broad-spectrum virucidal activity of highly purified HClO is attributed to viral protein aggregation of virion via protein oxidation.
... In recent years, these solutions have begun to be widely used in practice, the scope of their application in human and veterinary medicine is expanding, and much positive experience has been gained in their use. In addition to a broad spectrum of antimicrobial action, such drugs have several other advantages, especially the biogenic nature, which causes the absence of allergic reactions (McKenna & Davies, 1988;Prütz, 1996;Rosen et al., 1998;Ono et al., 2012;Pelgrift & Friedman, 2013;Taharaguchi et al., 2014). Hypochlorous acid is the predominant form of oxygencontaining compounds of chlorine (I) in aqueous solutions in the pH 4-8 range. ...
The article presents materials on the electrochemical synthesis of hypochlorous acid and its pharmacological and toxicological evaluation. In the market of veterinary drugs, special attention has been paid to long-known, potent detoxifying antimicrobial agents based on active oxygen obtained by the electrolysis method. In addition to a broad spectrum of antimicrobial action, such drugs have several other advantages, especially the biogenic nature, which causes the absence of allergic reactions. New electrocatalysts were proposed for the electrochemical synthesis of hypochlorous acid, which was produced according to the following method using a combined electrochemical-pyrolytic method. VT1-0 technical titanium was used as a current collector. The current collectors were subjected to several preliminary preparation steps, such as NaOH degreasing and etching in 6 M HCl. Initial nanotubes were obtained by anodizing Ti foil in ethylene glycol with 0.3 wt.% ammonium fluoride and 2 vol.% water for 4 hours. The electrochemical reduction was carried out in 1 M HClO4 by cathodic polarization for 1 hour. Later, a thin discontinuous layer of platinum or consecutive layers of platinum-palladium were applied to the base by electrodeposition. Nitrite electrolytes for platinization and phosphate-palladation were used for this purpose. Depending on the task, platinum, and palladium on the ground's surface varied from 0.1 to 2.0 mg/cm2. The obtained material was heat-treated in an air atmosphere. At this stage, the surface layers of composites were formed due to the oxidation of the base and encapsulation of platinum and palladium particles in titanium oxide. It was established that the solution of hypochlorous acid, obtained by the electrolysis method, is a low-hazard substance that belongs to the fourth class of toxicity. Its half-lethal dose (DL50) is not determined. The fact that, in nature, hypochlorite acid is formed by granulocytes of neutrophils involved in the last link of phagocytosis confirms that the resulting solution is low-toxic, environmentally safe, and incapable of causing side effects and distant consequences. The obtained results proved the perspective of using new technology for producing hypochlorite acid for veterinary medicine; its development is highly relevant, clinically expedient, and economically justified.
... • Bromine and HBrO are more stable at neutral pH and more compatible with the physiological pH of the periocular skin area, compared to HClO solutions, used in the same setting [18]; • Br-species are more effective bactericidal on acneic skin compared to Cl-species [15,19,20]. ...
Aims: Blepharitis is a chronic inflammation of the periocular skin area and it is characterized by eye itching, burning, dryness and irritation, with progression to chronic dry eye syndrome, where the eyelids margins of blepharitis patients are frequently colonized by bacteria. The aim of the present study was to investigate the in vitro bactericidal activity (BA) of a stabilized active bromine solution (MDI-102) at neutral pH for the potential use in the treatment and prevention of blepharitis. Methods and Results: The kinetic experiments have been conducted both in clean and in dirty conditions (by using bovine albumin solution as the interfering substance) at different ranges of concentration. The results show the topical solution to be capable of inactivating, in less than 0.5 minutes, more than 99.9% of several bacterial species involved in the clinical manifestations of blepharitis: Enterococcus hirae, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus epidermidis, and Serratia marcescens. Dirty condition tests confirm the results shown without albumin (clean conditions). Conclusions: MDI-102 is considered not irritating and dermatologically tested. This study demonstrates that MDI-102 active bromine solution can markedly reduce (in vitro) the bacterial activity, responsible of clinical manifestation of blepharitis. Thus, MDI-102 can be considered a promising tool for the periocular area and eyelids cleaning for blepharitis patients. Significance and Impact of the Study: The use of this formulation may contribute in the long-term prevention and hygienic treatment of blepharitis condition. Furthermore, MDI-102 can be considered as an alternative to reduce the use and the abuse of topical antibiotics in the daily practice, which may contribute to the increase of resistance to the antibiotics in the clinical setting.
... HOCl and NCT are known to affect events mediated by an array of cytokines, including IL-1B, IL-2, Il-4, IL-12, and IL-13. [17][18][19]51 Our data indicate that HOCl, HOBr, and NCT are all capable of altering IL-6 binding to IL-6R. ...
Interleukin-6 (IL-6) has been implicated in the pathogenesis of inflammatory events including those seen with COVID-19 patients. Positive clinical responses to monoclonal antibodies directed against IL-6 receptors (IL-6Rs) suggest that interference with IL-6-dependent activation of pro-inflammatory pathways offers a useful approach to therapy. We exposed IL-6 to hypochlorous acid (HOCl) in vitro at concentrations reported to develop in vivo. After HOCl treatment, binding of IL-6 to IL-6R was reduced in a dose-dependent manner using a bioassay with human cells engineered to provide a luminescence response to signal transduction upon receptor activation. Similar results followed the exposure of IL-6 to N-chlorotaurine (NCT) and hypobromous acid (HOBr), two other reactive species produced in vivo. SDS-PAGE analysis of HOCl-treated IL-6 showed little to no fragmentation or aggregation up to 1.75 mM HOCl, suggesting that the modifications induced at concentrations below 1.75 mM took place on the intact protein. Mass spectrometry of trypsin-digested fragments identified oxidative changes to two amino acid residues, methionine 161 and tryptophan 157, both of which have been implicated in receptor binding of the cytokine. Our findings suggest that exogenous HOCl and NCT might bring about beneficial effects in the treatment of COVID-19. Further studies on how HOCl and HOBr and their halogenated amine derivatives interact with IL-6 and related cytokines in vivo may open up alternative therapeutic interventions with these compounds in COVID-19 and other hyperinflammatory diseases.
... HOCl is an endogenously produced molecule by activated neutrophils and monocytes during injury via myeloperoxidase mediated peroxidation of chloride ions which mediates the destruction of microorganisms [28,29]. In addition to microbicidal effects, HOCl has shown anti-inflammatory effects by increasing TGF-β activity, decreasing MMP, and reducing both histamine & leukotriene activities [30]. Due to its diverse immunological advantages, it has been investigated as a possible wound care agent in different studies [31]. ...
Background: Sulfur Mustard is a strong vesicant and chemical warfare agent that imposes toxicity to the lungs, eyes, and skin after accidental or intended exposure.
Objectives: The current study was intended to explore in vitro and in vivo decontamination properties of electrolytically generated HOCl (hypochlorous acid) against CEES (2-chloroethyle ethyle sulphide), a known sulfur mustard simulant & vesicating agent.
Methods: In vitro studies were carried out using UV spectroscopy and GC-MS methods. In vivo studies were perfomred in Strain A and immune compromised mice by subcutaneous as well as prophylactic topical administrion of HOCl pretreated CEES. The blister formation and mortality were considered as end-point. Histopathological study was conducted on skin samples by H & E method. DNA damage studies measuring γ-H2AX and ATM has been carried out in human blood using flow cytometry. Anti-bacterial action was tested by employing broth micro dilution methods. Comparative study was also carried out with known oxidizing agents.
Results: The topical application of pre-treated CEES at 5, 30 min and 1 h time points showed significant (p<0.001) inhibition of blister formation. DNA damage study showed reduced mean flourences intensity of DSBs nearly 17-20 times, suggesting that HOCl plays a protective role against DNA damage. Histopathology showed no sign of necrosis in the epidermis upto 5 min although moderate changes were observed at 30 min. Pretreated samples were analyzed for detection of reaction products with m/z value of 75.04, 69.08, 83.93, 85.95, 123.99, 126.00, and 108.97. HOCl showed strong bactericidal effect at 40 ppm. The absorbance spectra of HOCl treated CEES showed lowered peaks in comparison to CEES alone and other oxidizing agents
... However, an important factor affecting the fish culture is bacterial contamination (El-Shorbagy et al., 2012). Moreover, the excessive use of antimicrobials since the past century to inhibit bacterial infections in aquaculture has resulted in the development of resistant strains (Stratev andOdeyemi, 2016Tuševljak et al., 2013), rendering the existing treatments ineffective (Adeshina et al., 2017Pelgrift andFriedman, 2013). For example, several isolated bacteria from Nile tilapia have a wide range of antibiotic resistance, such as tetracycline, erythromycin, and streptomycin (Márquez et al., 2018). ...
To find potential alternatives for certain conventional antibiotics, we investigated the effects of silver nanoparticles (AgNPs) synthesized using Moringa oleifera extract on serum biochemistry, immunological, inflammatory, oxidative, and histological alterations, and DNA damage in Oreochromis niloticus infected with Aeromonas hydrophila. For determining the concentration of AgNPs, 110 fish were used; 11 groups were challenged with Aeromonas hydrophila (each group = 10 fish) and exposed to different concentrations of AgNPs (0, 0.4, 0.8, 1.2, 1.6, 2, 2.4, 2.8, 3.2, 3.6, and 4.0 mg/L) as immersion. Another 360 fish were categorized into eight groups: G1 was non-infected with Aeromonas hydrophila and treated with 0 mg/L AgNPs, G2 was infected and treated with 0 mg/L AgNPs, G3, G4, and G5 were non-infected and treated with 0.4, 0.8, and 1.2 mg/L AgNPs, respectively. G6, G7, and G8 were infected and treated with 0.4, 0.8, and 1.2 mg/L AgNPs, respectively, for seven days. Infection with Aeromonas hydrophila significantly altered the health and reduced lysozyme, hepatic CAT, and hepatic SOD activity, and IgM, complement 3, total protein, albumin, globulin, serum nitric oxide, and IL-10 levels, with a significant increase in the activity of ALT, AST, LDH, and levels of urea, creatinine, bilirubin, hepatic MDA, and inflammatory biomarkers (IL-1β and IL-6). Moreover, the infection produced a prominent genotoxic effect and impaired the architecture of hepatic, renal, splenic, and gill tissues with a strong expression of NF-kB. Fish exposed to different treatments of AgNPs showed improvement in these markers with a significant reduction in the mortality rate. Interestingly, the submersion of infected fish in 0.8 mg/L AgNPs produced the best result. These results showed that green biosynthesis of AgNPs is non-cytotoxic and provides an alternative antimicrobial compound against hepatotoxic, splenotoxic, nephrotoxic, genotoxic, and immunosuppressive impacts of Aeromonas hydrophila in Nile tilapia.
... It has been reported that topical HOCl formulations lead to the relief of itch in human patients with AD; however, the specific anti-pruritic mechanism of action remains unclear [110]. HOCl has been shown to decrease numerous inflammatory cytokines, including TNF-α, interferon gamma, IL-2, and histamine as well as nuclear factor kappa light-chain enhancer of activated B cell-mediated pathways in experimental models [111,112]. In a case series, patients with AD received 7 days of treatment with a topical hydrogel containing 0.008% HOCl and 0.002% sodium hypochlorite (NaOCl) that demonstrated significantly reduced pruritus. ...
Introduction: Atopic dermatitis (AD) is perhaps the most common inflammatory skin disorder worldwide, with an increasing incidence in developed countries. The mainstay treatment for patients with AD are topical therapies, which are used not only by the mild patients, but also by the moderate-to-severe patients, in conjunction with systemic treatment. While topical steroids and calcineurin antagonists are widely used, these are associated with long-term cutaneous adverse effects (AEs) or a black box warning, preventing their chronic use.
Areas covered: The aim of this review is to provide a comprehensive overview of new and upcoming topical therapies currently in development and undergoing clinical trials, as well as their safety and efficacy profiles, and discuss current topicals used in the management of AD.
Expert opinion: AD is a heterogenous disease with a complex pathophysiology. Treatments available to date for AD provide disease control, however patients struggle to find an optimized therapeutic regimen they may use long term and without severe effects. Novel therapies are currently under investigation, with the hope of shifting the paradigm of AD management from symptom control to disease eradication.
... 2 Hypochlorous acid (HOCl) has been identified as a treatment for pruritus. 3 There are 2 mechanisms by which HOCl may reduce pruritus: 1) by its microbicidal qualities, particularly in the case of Staphylococcus aureus; and 2) by its antiinflammatory qualities, which help reduce the activity of histamine, leukotriene B4, and interleukin-2, all of which contribute to the pathophysiology of itch. [4][5][6][7] Here we present the results of a 3-day study designed to evaluate the effect of HOCl on pruritus in patients with AD. ...
Not AvailableDisclosure: Study supported by Intraderm.
A theoretical study simulating the hypohalogenation reaction of cysteine (CSy) and N-acetylcysteine (NAC) has been performed with the objective of obtaining the energetic, electronic and kinetic properties for the reactions at room temperature and body temperature and considering neutral and basic conditions in aqueous medium. The study has been performed using the M06-HF, M06-2X, MPWB1K, BHANDHLYP density functional methods and with the MP2 method along with either the 6-311+G(d, p) basis set or the extended 6-311++G(3df,3pd) basis set. The results of the study indicate that all reactions proceed through the formation of the reactant complex structure, which is stabilised by the formation of intermolecular hydrogen bond between the reactant species. The reactions are also thermodynamically preferred to take place at room temperature. The reaction involving hypochlorous acid is faster and more thermodynamically preferred to the reaction involving hypochlorite anion, both at room temperature and at body temperature. The relative magnitude for the rate constant involving CSy and NAC is dependent on the pH of the solution. A comparison of the calculation methods utilised for the study suggests that the best methods for estimation of the rate constant are those containing both the HF-like exchange and the kinetic density components.
Blepharitis is a chronic inflammation of the periocular skin area and it is characterized by eye itching, burning, dryness and irritation, with progression to chronic dry eye syndrome, where the eyelids margins of blepharitis patients are frequently colonized by bacteria.
The aim of the present study was to investigate the in vitro bactericidal activity (BA) of a stabilized active bromine solution (MDI-102) at neutral pH for the potential use in the treatment and prevention of blepharitis.
The time kill assays have been conducted both in clean and in dirty conditions (by using bovine albumin solution as the interfering substance) at different ranges of concentration.
The results show the topical solution to be capable of inactivating, in less than 0.5 minutes, more than 99.9% of several bacterial species involved in the clinical manifestations of blepharitis: Enterococcus hirae, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus epidermidis, Serratia marcescens. Dirty condition tests confirm the results shown without albumin (clean conditions).
This study demonstrates that MDI-102 active bromine solution can markedly reduce (in vitro) the bacterial activity, responsible of clinical manifestation of blepharitis. Thus, MDI-102 can be considered a promising tool for the periocular area and eyelids cleaning for blepharitis patients.
The use of this formulation may contribute in the long-term prevention and hygienic treatment of blepharitis condition. Furthermore, MDI-102 can be considered as an alternative to reduce the use and the abuse of topical antibiotics in the daily practice, which may contribute to the increase of resistance to the antibiotics in the clinical setting.
Interleukin-6 (IL-6) has been implicated in the pathogenesis of acute inflammatory events in COVID-19 patients. We exposed IL-6 to hypochlorous acid (HOCl) in vitro at concentrations reported to develop in vivo. After HOCl treatment the cytokine failed to bind to IL-6 receptors in a bioassay using engineered human cells. Similar results followed exposure of IL-6 to N-chlorotaurine (NCT) and hypobromous acid (HOBr). SDS-PAGE analysis of HOCl-treated IL-6 showed neither fragmentation nor aggregation, suggesting that the modifications induced by these agents occurred on the intact protein. Mass spectrometry of intact and trypsin-digested fragments identified oxidative changes limited to two amino acid residues, methionine 161 and tryptophan 157, both of which have been implicated in receptor binding of the cytokine. Further studies on the effects of hypohalous acids and their halogenated amine derivatives on IL-6 and related cytokines is needed.
Cleansing provides an opportunity to remove pathogens from the wound bed, thereby preventing an increase in the bioburden and delayed healing. This article describes the reported efficacy of hypochlorous acid-containing wound cleansers.
Background:
Hypochlorous acid (HOCl), a naturally occurring molecule produced by the immune system, is highly active against bacterial, viral, and fungal microorganisms. Moreover, HOCl is active against biofilm and increases oxygenation of the wound site to improve healing. Natural HOCl is unstable; through technology, it can be stabilized into an effective topical antiseptic agent.
Aim:
This paper focuses on the use of topical stabilized HOCl in wound and scar management for pre-, peri-, and postprocedures-including its ability to reduce the occurrence hypertrophic scars and keloids. The role of the product in other skin conditions is beyond the scope of this article.
Methods:
A panel comprising clinicians with experience in cosmetic and surgical procedures met late 2018 to discuss literature search results and their own current clinical experience regarding topical stabilized HOCl. The panel of key opinion leaders in dermatology and plastic surgery defined key insights and consensus statements on the direction of use for the product.
Results:
Topical stabilized HOCl provides an optimal wound healing environment and, when combined with silicone, may be ideal for reducing scarring. Additionally, in contrast to chlorhexidine, HOCl, used as an antiseptic skin preparation, raises no concerns of ocular- or ototoxicity.
Conclusions:
For wound care and scar management, topical stabilized HOCl conveys powerful microbicidal and antibiofilm properties, in addition to potency as a topical wound healing agent. It may offer physicians an alternative to other less desirable wound care measures.
Sodium hypochlorite (NaOCl) is the active ingredient in household bleach and is a very common chemical. It has been used in
medical and commercial situations dating back to the 18th century for its disinfectant properties, including topical use in
medicine as an antiseptic. For this indication, NaOCl is a proven and safe chemical. However, exposure of NaOCl beyond topical
use, whether it is intentional or accidental, is associated with significant risks due to its strong oxidizing properties.
Potentially damaging scenarios include ingestion, inhalation, deposition into tissue or injection into the bloodstream. All
of these scenarios can lead to significant morbidity and even mortality. In this review, we examine the toxicity associated
with NaOCl exposure and analyze potential mechanisms of injury, placing special emphasis on the potential for renal toxicity.
Due to the extreme ease of access to household bleach products and its use in medicine, it is important for the clinician
to understand the potential damage that can occur in NaOCl exposures so that complications can be prevented before they arise.
Itch is the most common symptom described by our patients. Treating this symptom can be challenging. A revolution is ongoing in understanding the pathophysiology of itch and will allow this challenge to be met. The present authors review and update the current understanding of the pathophysiology of itch.
Itch-specific neurons have been sought for decades. The existence of such neurons has been doubted recently as a result of the observation that itch-mediating neurons also respond to painful stimuli. We genetically labeled and manipulated MrgprA3(+) neurons in the dorsal root ganglion (DRG) and found that they exclusively innervated the epidermis of the skin and responded to multiple pruritogens. Ablation of MrgprA3(+) neurons led to substantial reductions in scratching evoked by multiple pruritogens and occurring spontaneously under chronic itch conditions, whereas pain sensitivity remained intact. Notably, mice in which TRPV1 was exclusively expressed in MrgprA3(+) neurons exhibited itch, but not pain, behavior in response to capsaicin. Although MrgprA3(+) neurons were sensitive to noxious heat, activation of TRPV1 in these neurons by noxious heat did not alter pain behavior. These data suggest that MrgprA3 defines a specific subpopulation of DRG neurons mediating itch. Our study opens new avenues for studying itch and developing anti-pruritic therapies.
Significance:
When neutrophils kill microorganisms, they ingest them into phagosomes and bombard them with a burst of reactive oxygen species.
Recent advances:
This review focuses on what oxidants are produced and how they kill. The neutrophil NADPH oxidase is activated and shuttles electrons from NADPH in the cytoplasm to oxygen in the phagosomal lumen. Superoxide is generated in the narrow space between the ingested organism and the phagosomal membrane and kinetic modeling indicates that it reaches a concentration of around 20 μM. Degranulation leads to a very high protein concentration with up to millimolar myeloperoxidase (MPO). MPO has many substrates, but its main phagosomal reactions should be to dismutate superoxide and, provided adequate chloride, catalyze efficient conversion of hydrogen peroxide to hypochlorous acid (HOCl). Studies with specific probes have shown that HOCl is produced in the phagosome and reacts with ingested bacteria. The amount generated should be high enough to kill. However, much of the HOCl reacts with phagosomal proteins. Generation of chloramines may contribute to killing, but the full consequences of this are not yet clear.
Critical issues:
Isolated neutrophils kill most of the ingested microorganisms rapidly by an MPO-dependent mechanism that is almost certainly due to HOCl. However, individuals with MPO deficiency rarely have problems with infection. A possible explanation is that HOCl provides a frontline response that kills most of the microorganisms, with survivors killed by nonoxidative processes. The latter may deal adequately with low-level infection but with high exposure, more efficient HOCl-dependent killing is required.
Future directions:
Better quantification of HOCl and other oxidants in the phagosome should clarify their roles in antimicrobial action.
Interleukin-31 (IL-31) is a recently discovered cytokine expressed in many human tissues, and predominantly by activated CD4(+) T cells. IL-31 signals through a heterodimeric receptor consisting of IL-31 receptor alpha (IL-31RA) and oncostatin M receptor beta (OSMR). Earlier studies have shown involvement of IL-31 and its receptor components IL-31RA and OSMR in atopic dermatitis, pruritus and Th2-weighted inflammation at the mRNA level. The aim of this study was to investigate IL-31 protein expression in skin of such conditions. Immunohistochemical staining for IL-31, IL-31RA and OSMR was performed in formalin-fixed paraffin-embedded biopsy specimens. IL-31 expression was increased in the inflammatory infiltrates from skin biopsies taken from subjects with atopic dermatitis, compared with controls (p ≤ 0.05). IL-31, IL-31RA and OSMR protein immunoreactivity was not increased in biopsies from subjects with other Th2-weighted and pruritic skin diseases. Our results confirm, at the protein level, the relationship between IL-31 expression and atopic dermatitis. Our results do not support a general relationship between expression of IL-31/IL-31R and pruritic or Th2-mediated diseases.
Oxidative degradation of biological substrates by hypochlorous acid has been examined under reaction conditions similar to those found in active phagosomes. Iron sulfur proteins are bleached extremely rapidly, followed in decreasing order by beta-carotene, nucleotides, porphyrins, and heme proteins. Enzymes containing essential cysteine molecules are inactivated with an effectiveness that roughly parallels the nucleophilic reactivities of their sulfhydryl groups. Other compounds, including glucosamines, quinones, riboflavin, and, except for N-chlorination, phospholipids, are unreactive. Rapid irreversible oxidation of cytochromes, adenine nucleotides, and carotene pigments occurs when bacterial cells are exposed to exogenous hypochlorous acid; with Escherichia coli, titrimetric oxidation of cytochrome was found to coincide with loss of aerobic respiration. The occurrence of these cellular reactions implicates hypochlorous acid as a primary microbicide in myeloperoxidase-containing leukocytes; the reactivity patterns observed are consistent with the view that bactericidal action results primarily from loss of energy-linked respiration due to destruction of cellular electron transport chains and the adenine nucleotide pool.
In origin, itch can be cutaneous ("pruritoceptive", e.g. dermatitis), neuropathic (e.g. multiple sclerosis), neurogenic (e.g. cholestasis), mixed (e.g. uraemia) or psychogenic. Although itch of cutaneous origin shares a common neural pathway with pain, the afferent C-fibres subserving this type of itch are a functionally distinct subset: they respond to histamine, acetylcholine and other pruritogens, but are insensitive to mechanical stimuli. Histamine is the main mediator for itch in insect bite reactions and in most forms of urticaria, and in these circumstances the itch responds well to H(1)-antihistamines. However, in most dermatoses and in systemic disease, low-sedative H(1)-antihistamines are ineffective. Opioid antagonists relieve itch caused by spinal opioids, cholestasis and, possibly, uraemia. Ondansetron relieves itch caused by spinal opioids (but not cholestasis and uraemia). Other drug treatments for itch include rifampicin, colestyramine and 17-alpha alkyl androgens (cholestasis), thalidomide (uraemia), cimetidine and corticosteroids (Hodgkin's lymphoma), paroxetine (paraneoplastic itch), aspirin and paroxetine (polycythaemia vera) and indometacin (some HIV+ patients). If the remedies specified fail, paroxetine and mirtazapine should be considered. Ultraviolet B therapy, particularly narrow-band UVB, may be superior to drug treatment for itch in uraemia.
Proteinase-activated receptor-2 belongs to a new subfamily of G-protein-coupled receptors. Its precise role during inflammation and the underlying mechanisms is still unclear. Our study establishes that PAR-2 plays a direct proinflammatory role during cutaneous inflammation in mice and humans in vivo. In a model of experimentally induced allergic (ACD) and toxic (ICD) contact dermatitis (CD) we show that ear swelling responses, plasma extravasation, and leucocyte adherence were significantly attenuated in PAR-2 null mutant (PAR-2-/-) mice compared with wild-type (PAR-2+/+) mice, especially at early stages. The proinflammatory effects by PAR-2 activation were significantly diminished using nitric oxide-synthase inhibitors, while NF-kappaB and neuropeptides appear to play a minor role in these mechanisms. PAR-2-mediated up-regulation of E-selectin and cell adhesion molecule ICAM-1; enhanced plasma extravasation was observed in humans and mice and of interleukin-6 in mice in vivo. Thus, PAR-2 may be a beneficial therapeutic target for the treatment of inflammatory skin diseases.
Chronic periodontitis is a multi-factorial disease involving anaerobic bacteria and the generation of an inflammatory response, including the production of metalloproteinases, pro-inflammatory cytokines, and eicosanoids. Hypochlorous acid (HOCl) and taurine-N-monochloramine (TauCl) are the end-products of the neutrophilic polymorphonuclear leukocyte (PMN) respiratory burst. They act synergistically to modulate the inflammatory response. In the extracellular environment, HOCl and TauCl may directly neutralize interleukin 6 (IL-6) and several metalloproteinases, while HOCl increases the capacity of alpha(2)-macroglobulin to bind Tumor Necrosis Factor-alpha, IL-2, and IL-6, and facilitates the release of various growth factors. TauCl inhibits the production of inflammatory mediators, prostaglandins, and nitric oxide. HOCl activates tyrosine kinase signaling cascades, generating an increase in the production of extracellular matrix components, growth factors, and inflammatory mediators. Thus, HOCl and TauCl appear to play a crucial role in the periodontal inflammatory process. Taken together, these findings may offer opportunities for the development of novel host-modulating therapies for the treatment of periodontitis.
Transforming growth factor-beta (TGF-beta) is a potent regulatory cytokine with diverse effects on hemopoietic cells. The pivotal function of TGF-beta in the immune system is to maintain tolerance via the regulation of lymphocyte proliferation, differentiation, and survival. In addition, TGF-beta controls the initiation and resolution of inflammatory responses through the regulation of chemotaxis, activation, and survival of lymphocytes, natural killer cells, dendritic cells, macrophages, mast cells, and granulocytes. The regulatory activity of TGF-beta is modulated by the cell differentiation state and by the presence of inflammatory cytokines and costimulatory molecules. Collectively, TGF-beta inhibits the development of immunopathology to self or nonharmful antigens without compromising immune responses to pathogens. This review highlights the findings that have advanced our understanding of TGF-beta in the immune system and in disease.
Hypochlorous acid (HOCl), a major inorganic bactericidal compound of innate immunity, is effective against a broad range of microorganisms. Owing to its chemical nature, HOCl has never been used as a pharmaceutical drug for treating infection. In this article, we describe the chemical production, stabilization, and biological activity of a pharmaceutically useful formulation of HOCl.
Stabilized HOCl is in the form of a physiologically balanced solution in 0.9% saline at a pH range of 3.5 to 4.0. Chlorine species distribution in solution is a function of pH. In aqueous solution, HOCl is the predominant species at the pH range of 3 to 6. At pH values less than 3.5, the solution exists as a mixture of chlorine in aqueous phase, chlorine gas, trichloride (Cl(3) (-)), and HOCl. At pH greater than 5.5, sodium hypochlorite (NaOCl) starts to form and becomes the predominant species in the alkaline pH. To maintain HOCl solution in a stable form, maximize its antimicrobial activities, and minimize undesirable side products, the pH must be maintained at 3.5 to 5.
Using this stabilized form of HOCl, the potent antimicrobial activities of HOCl are demonstrated against a wide range of microorganisms. The in vitro cytotoxicity profile in L929 cells and the in vivo safety profile of HOCl in various animal models are described.
On the basis of the antimicrobial activity and the lack of animal toxicity, it is predicted that stabilized HOCl has potential pharmaceutical applications in the control of soft tissue infection.
Cowhage spicules provide an important model for histamine-independent itch. We determined that the active component of cowhage, termed mucunain, is a novel cysteine protease. We isolated mucunain and demonstrate that both native and recombinant mucunain evoke the same quality of itch in humans. We also show that mucunain is a ligand for protease-activated receptors two and four. These results support and expand the relationship between proteases, protease-activated receptors, and itch.
Itch, the hallmark of atopic dermatitis, has a significant impact on quality of life for patients with this disease. Various central and peripheral mediators have been suggested to play a role in the pathophysiology of atopic eczema itch. Significant cross-talk occurs among stratum corneum, keratinocytes, immune cells, and nerve fibers, which are in close proximity to one another and induce itch. The impaired barrier function associated with the itch-scratch cycle further augments this vicious cycle. Recent advances in our understanding of itch pathophysiology shed light on peripheral and central neural sensitization of nerve fibers that contribute significantly to itch in atopic dermatitis. Recently, several new mediators have been described as associated with itch in atopic dermatitis, including serine proteases, interleukin 31, and nerve growth factor. This review covers the peripheral and central mechanisms and mediators involved in pathogenesis of itch in atopic dermatitis.
Atopic eczema is one of the most common skin disorders in young children and also affects adults. Staphylococcus aureus infection is the most frequent complication of atopic eczema and is involved in the worsening of the disease. Antibiotic therapy against S. aureus has been an important component of treatment for atopic eczema but there are concerns about antibiotic overuse and increasing bacterial resistance. This has led some clinicians to recommend the use of homemade remedies such as bleach baths as an adjunctive treatment for patients with infected atopic eczema, despite the fact that there have been few published studies in this area. Balancing safety concerns with efficacious treatment is of particular importance in the paediatric population. This review discusses the historical use of bleach in medicine as well as its recent use for atopic eczema. Further, the chemistry and safety of bleach as well as alternative therapies are examined.
Points out that the Henderson-Hasselbalch equation is an approximation and not equivalent to the mass action law. Keywords (Audience): Second-Year Undergraduate
Many students of chemistry have wondered if putting the mass action expression in logarithmic format should have warranted immortalization of the names Henderson and Hasselbalch. With focus on this question, this article examines the evolution of the Henderson-Hasselbalch equation and presents a critical evaluation of its usefulness. The discussion centers on the titration of a weak acid with sodium hydroxide. Approximate pH values obtained from the Henderson-Hasselbalch equation are compared with exact hydrogen ion concentrations and the percentage errors are displayed as a function of the acid dissociation constant and buffer composition (titration mixture). Keywords (Audience): Upper-Division Undergraduate
Some electrical properties of the skin may be related to the water content of the horny layer, and measurements of impedance and/or capacitance have been used to assess the hydration state of the skin surface. This study was designed to compare three commercially available instruments used in dermato-cosmetic research, namely, the Corneometer CM 825, the Nova DPM 9003 and the Skicon-200.
Comparative measurements were carried out with the three instruments in vivo on the volar part of the forearms of 12 human volunteers.
The decrease in hydration induced by an irritant cationic detergent, and the increase of hydration after application of a moisturizer cream under occlusion could be easily measured with the three instruments. High degrees of correlation were obsewed between the three instruments over a broad range of hydration values of the skin.
This comparative study performed under controlled environmental conditions reveals that the three instruments give validated coherent information concerning relative changes in hydration of the upper layers of the epidermis.
Interactions between bleaching agents containing sodium hypochlorite (NaOCl) and human stratum corneum are complex and not fully understood. The same applies when NaOCl is used as a war gas decontaminant. In this study data yielded byin vivotesting and anex vivobioassay are compared. Fifteen volunteers received patch tests of a neat proprietary NaOCl bleaching agent for 15, 30, 45, 60, and 90 min. No clinical reaction was seen. Reflectance colorimetry, transepidermal water loss (TEWL), and capacitance were measured for 72 hr after patch removal. Squamometry was also performed usingd-Squames and colorimetry of the samples. In addition, theex vivocorneoxenometry bioassay was conducted on various dilutions of the bleach. Data reveal that conductance and squamometry were more sensitive than TEWL to disclose the action of bleach upon the stratum corneum. Corneoxenometry proved to be a good predictiveex vivobioassay, indicating the same information as thein vivotests. Both squamometry and corneoxenometry appear valuable and complementary in assessing infraclinical damages of human skin by a NaOCl bleaching agent.
Hypochlorous acid (HOCl) is generated by myeloperoxidase using chloride and hydrogen peroxide as substrates. HOCl and its conjugate base (OCl(-)) bind to the heme moiety of hemoglobin (Hb) and generate a transient ferric species whose formation and decay kinetics indicate it can participate in protein aggregation and heme destruction along with subsequent free iron release. The oxidation of the Hb heme moiety by OCl(-) was accompanied by marked heme destruction as judged by the decrease in and subsequent flattening of the Soret absorbance peak at 405 nm. HOCl-mediated Hb heme depletion was confirmed by HPLC analysis and in-gel heme staining. Exposure of Hb to increasing concentrations of HOCl produced a number of porphyrin degradation products resulting from oxidative cleavage of one or more of the carbon-methene bridges of the tetrapyrrole ring, as identified by their characteristic HPLC fluorescence and LC-MS. A nonreducing denaturing SDS-PAGE showed several degrees of protein aggregation. Similarly, porphyrin degradation products were identified after exposure of red blood cells to increasing concentrations of HOCl, indicating biological relevance of this finding. This work provides a direct link between Hb heme destruction and subsequent free iron accumulation, as occurs under inflammatory conditions where HOCl is formed in substantial amounts.
Classification of itch into four categories-pruritoceptive, neurogenic, neuropathic, and psychogenic-has proven to be of utility to clinicians and investigators. Itch is recognized to be transmitted by dedicated afferent neurons, and a matrix of cerebral cortical loci involved in perception and the desire to scratch has been recognized. This highlights the multidimensional nature of the itch sensation. Some of the many mediators of itch, especially relevant in pruritogenic itch, are the result of cross-talk between dermal mast cells and adjacent cutaneous afferents. Keratinocytes of the epidermis express many neuropeptides, and their receptors are far from passive bystanders in the neurophysiology of itch. Mediators can also act centrally (eg, opioid peptides that act on micro receptors in the central nervous system). The pathophysiology of pruritus in neurogenic itch caused by common systemic diseases is gradually being elucidated, especially in the itch of cholestasis, although the molecular basis of itching in chronic renal failure remains elusive. Better understanding of the mediators of itch and their receptors has led to the imminent development of novel anti-itch compounds, including interleukin-31 inhibitors, histamine H4-receptor antagonists, and neurokinin-1 receptor antagonists.
Pruritus is the predominant symptom of skin disease. Owing to the poorly understood pathophysiology, the development of effective treatment modalities for pruritus has proven to be particularly difficult. At present, there is no universally accepted therapy for itch. The purpose of this review is to provide an update on the treatment of pruritus.
An overview of current, emerging and possible future therapies for pruritus is provided.
Insights into possible treatment regimes for pruritus in different clinical scenarios.
The therapy of pruritus is challenging and at present takes on an individualistic approach. Recent advancements in the mechanisms that underlie this distressing symptom have identified new targets for future therapy.
In atopic dermatitis, the concentration in the skin of sphingosylphosphorylcholine (SPC), which is produced from sphingomyelin by sphingomyelin deacylase, is increased. In the present study, we investigated the itch-eliciting activity of SPC and related substances and the mechanisms of SPC action in mice. An intradermal injection of SPC, but not sphingomyelin and sphingosine, induced scratching, an itch-associated response, which was not suppressed by a deficiency in mast cells or the H(1) histamine receptor antagonist terfenadine. The action of SPC was inhibited by the mu-opioid receptor antagonist naltrexone. SPC action also was inhibited by the 5-lipoxygenase inhibitor zileuton and the leukotriene B(4) antagonist ONO-4057, but not by the cyclooxygenase inhibitor indomethacin. Moreover, SPC action was inhibited by the antiallergic agent azelastine, which suppresses the action and production of leukotriene B(4). Administration of SPC to the skin and to primary cultures of keratinocytes increased leukotriene B(4) production. SPC increased intracellular Ca(2+) ion concentration in primary cultures of dorsal root ganglion neurons and keratinocytes. These results suggest that SPC induces itching through a direct action on primary afferents and leukotriene B(4) production of keratinocytes. Sphingomyelin deacylase and SPC receptors may be previously unreported targets for antipruritic drugs.
The recommended concentration for patch testing with sodium hypochlorite [NaOCl] (bleach) is 1%, generally obtained by diluting commercial bleach. In doing so, other active (potentially irritant) components of bleach, especially hypochlorous acid [HOCl] and sodium hydroxide [NaOH], are neglected. Magnitudes of potential irritant species other than NaOCl, such as alkalinity, are ordinarily not labeled on the product, though they may vary considerably between brands. Thus, patch testing with 1% hypochlorite obtained by diluting different brand bleaches can potentially elicit non-specific irritant responses, also depending upon the test volume applied. In this study, skin irritation induced by 24-h patch testing with 20 microliters or 100 microliters, with constant NaOCl concentration (1%) and different NaOH concentrations (0.01-1.0%), was studied in adult human volunteers, by means of visual scores and skin color reflectance measurements. No irritation was elicited by application of 20 microliters 1% OCl-, independent of the NaOH concentration. However, all solutions induced significant irritation in a volume of 100 microliters. Skin reactions did not show a straight pH dose response, a maximum reaction being seen to the solution containing 0.1% NaOH. Skin surface pH values had increased when monitored immediately after removal of the patch material. However, 24 h later, baseline values were again reached at most sites, demonstrating an efficient buffering capacity of human skin, even after challenge with alkaline solutions of pH 13.4. We suggest that a non-irritant concentration for diagnostic patch testing for allergic contact dermatitis with an aluminum chamber, using 17 microliters to 20 microliters test volume, could be as high as 1% NaOCl and 1% NaOH.
Observation of an individual with immediate-type reaction following exaggerated dermal exposure to hypochlorite-containing cleaning products prompted review of similar hypersensitivity reactions attributed to hypochlorite or other highly reactive chemicals. This review confirms isolated incidences of hypochlorite sensitivity of the delayed type (allergic contact dermatitis), as well as immediate-type reactions from inhalation or topical challenge of sensitized individuals. We conclude that it is possible that excessive and prolonged exposure to hypochlorite may in some cases result in irritation and damage to the skin. This potentially gives rise to altered proteins which in rare cases may cause hypersensitivity. This reaction is common to other reactive small molecules with a strong irritant action.
Bleaches based on solutions of sodium hypochlorite (NaOCl) are widely used in the household to disinfect and clean hard surfaces and to bleach the laundry. A review of both published and unpublished toxicological data is presented. In addition, the results of a survey of human accidents with hypochlorite bleaches by the Poison Control Centers of France, Italy, Belgium, Greece, Turkey, Spain and Portugal for the period 1989-1992 are presented. The data show that acute accidental exposure to household bleach in use or in foreseeable misuse situations results, in the great majority of the cases, in minor, transient adverse effects on health, with no permanent sequelae. Ingestion is the most frequent route of exposure, followed by inhalation of gases evolved by mixing sodium hypochlorite bleach with acid or alkaline products. All evidence presented confirms the normal safety profile of hypochlorite-based bleaches to be similar to that of other 'generally recognized as safe' household products.
The migration of neutrophils through the endothelium at sites of inflammation may be facilitated by oxidant-mediated disruption of cellular junctions. The present study examined the effects of noncytotoxic concentrations of the membrane-penetrating neutrophil oxidants hypochlorous acid (HOCI) and monochloramine (NH2Cl), or the membrane-impermeant taurine chloramine (taurine NCl), on cultured bovine aorta endothelial monolayers. HOCl (25 microM) or NH2Cl (10 microM), but not taurine NCl (100 microM), caused a reversible shortening of the cytoskeletal actin microfilaments, cell retraction, and increased permeability within 2 min. These effects were accompanied by an increase in intracellular zinc concentration as well as the oxidation of intracellular glutathione and protein sulfhydryls. The zinc ionophore pyrithione also increased permeability. HOCl or NH2Cl, but not taurine NCl, also rapidly increased microvascular permeability in isolated perfused rat lungs. The data suggest that HOCl and NH2Cl can increase endothelial permeability by causing very rapid cytoskeletal shortening and cell retraction, possibly as a result of the oxidation of intracellular sulfhydryls and mobilization of zinc.
Contact urticaria has been reported following skin contact with a multitude of substances ranging from simple chemicals to macromolecules. Its prevalence amongst the general population is unknown, but it may be a relatively common and under-recognized phenomenon. Non-immunological (irritant) causes typically elicit mild localized reactions, which clear within hours. Such agents can be found widely in food, cosmetics and medicaments. The lower diagnostic end-point for nonimmunological contact urticaria has been the subject of debate, which makes interpretation of the literature difficult. Immunological (allergic) contact urticaria is due to immediate-type hypersensitivity, and occurs most commonly in atopic individuals. It is mediated primarily by histamine, and may be associated with systemic, and potentially life-threatening symptoms. Natural rubber latex is one of the most important causes today, and the recent 'epidemic' of latex protein allergy has helped draw attention to this subject. Immunological contact urticaria to animal or vegetable matter may occasionally affect those who handle food, and other occupations such as agricultural and veterinary workers. This may be associated with development of a protein contact dermatitis. The diagnosis of immunological contact urticaria can often be confirmed by simple investigations such as skin prick testing or measurement of specific IgE.
Neurotrophins and their receptors play an important role in cutaneous nerve development and reconstruction after injury. Recent developments indicate that this group of molecules not only exert a neurotrophic action, but are also involved in immune responses and inflammation. Prurigo nodularis is a skin disease characterized by neurohyperplasia and intense itch. In the present study, the localization and distribution of nerve growth factor (NGF) and its receptors were explored by immunohistochemical methods, with the aim of detecting the cause of the neurohyperplasia in the disease. In normal healthy volunteers and in uninvolved skin, NGF immunoreactivity was seldom seen in the basal layer of the epidermis or in the dermis. In prurigo nodularis skin, there was also very little NGF immunoreactivity in the epidermis. However, in the dermis, a huge number of cells showed an NGF-like immunoreactivity. In normal skin of healthy volunteers, only a weak staining for tyrosine kinase A (trkA) was seen in the epidermis, whereas in the dermis, there was no trkA staining seen at all. However, in the prurigo nodularis tissue, the hyperplastic nerves clearly showed trkA immunoreactivity, and it seemed that the staining was only present in the axons. By NGF and p75 NGF receptor double-labelling, both immunoreactivities showed weak staining in the epidermis and dermis of normal skin. However, in the dermis of prurigo nodularis, strong staining for both NGF and NGF receptor antibodies was seen. NGF receptor-immunoreactive nerves were more dense in areas where there were more NGF-immunoreactive cells. The results indicate that in prurigo nodularis skin, NGF is overexpressed, locally infiltrated inflammatory cells may be the source of this NGF, and NGF and its receptors may contribute to the neurohyperplasia of the disease.
Neutrophilic polymorphonuclear leukocytes (neutrophils) are highly specialized for their primary function, the phagocytosis and destruction of microorganisms. When coated with opsonins (generally complement and/or antibody), microorganisms bind to specific receptors on the surface of the phagocyte and invagination of the cell membrane occurs with the incorporation of the microorganism into an intracellular phagosome. There follows a burst of oxygen consumption, and much, if not all, of the extra oxygen consumed is converted to highly reactive oxygen species. In addition, the cytoplasmic granules discharge their contents into the phagosome, and death of the ingested microorganism soon follows. Among the antimicrobial systems formed in the phagosome is one consisting of myeloperoxidase (MPO), released into the phagosome during the degranulation process, hydrogen peroxide (H2O2), formed by the respiratory burst and a halide, particularly chloride. The initial product of the MPO-H2O2-chloride system is hypochlorous acid, and subsequent formation of chlorine, chloramines, hydroxyl radicals, singlet oxygen, and ozone has been proposed. These same toxic agents can be released to the outside of the cell, where they may attack normal tissue and thus contribute to the pathogenesis of disease. This review will consider the potential sources of H2O2 for the MPO-H2O2-halide system; the toxic products of the MPO system; the evidence for MPO involvement in the microbicidal activity of neutrophils; the involvement of MPO-independent antimicrobial systems; and the role of the MPO system in tissue injury. It is concluded that the MPO system plays an important role in the microbicidal activity of phagocytes.
Pruritus in patients with psoriasis has been reported to be more common than previously thought.
To determine the actual prevalence of pruritus in psoriasis according to severity of psoriasis and to verify the hypothesis of involvement of neuropeptides and their receptors in psoriatic pruritus.
We analysed questionnaire replies from 152 patients with chronic plaque-type psoriasis and we assayed the expression of neuropeptides and their receptors in lesional skin biopsies obtained from psoriatic patients with pruritus compared with those from psoriatic patients without pruritus, nonlesional skin of patients with pruritic psoriasis and normal controls by confocal laser scanning microscopy.
Of the 152 patients with psoriasis, 112 (73.7%) had pruritus, and these patients had a higher mean Psoriasis Area and Severity Index (PASI) score than psoriatic patients without pruritus. There was positive correlation between the PASI score and the intensity of pruritus. Keratinocytes in the psoriatic plaques of patients with pruritus showed consistently increased expression of substance P receptor (SPR), high-affinity nerve growth factor receptor (TrkA) and calcitonin gene-related peptide receptor (CGRPR).
Pruritus is a common feature in psoriasis. Considering the well-known roles of neuropeptides in pathogenesis of both psoriasis and pruritus, increased SPR, TrkA and CGRPR may be involved in the pathogenesis of pruritus in psoriasis and in the severity of psoriasis.
We aimed to trace the historical origins of 0.9% saline, how it came to be used so commonly today, and to consider whether its continued use can be justified.
We searched the Medline, Science Citation Index, ScienceDirect and Google databases using the key words saline, physiological, salt solution, sodium chloride, 0.9%, intravenous, injection, fluid, cholera, resuscitation, parenteral, history, historical and origins.
The use of 0.9% saline is believed to have originated during the cholera pandemic that swept across Europe in 1831. However, an examination of the composition of the fluids used by the pioneering physicians of that era reveals solutions that bear no resemblance to 0.9% or so-called 'normal' saline which appears to have very little scientific or historical basis for its routine use, except for Hamburger's in vitro studies of red cell lysis.
The currently used 0.9% saline solution is without convincing historical basis. Given that the composition of 0.9% sodium chloride is dissimilar to most solutions used in the past, and is in no way 'normal' or 'physiological', our current practice may be based on historical fallacy and misconception.
Skin surface acidity can be measured according to two criteria, its value given by pH and its strength determined by the ability of the skin to resist an acidic/alkaline aggression (i.e. acidic/alkaline resistance and neutralization tests). It is the quantitative extent to which the skin resists these changes that defines the term buffer capacity or acid/alkali resistance and neutralization capacity of skin. We review studies investigating the possible mechanisms contributing to the buffering capacity of the epidermis via alkali/acidic aggression tests. This paper discerns which components of the epidermis are most likely responsible for the epidermal buffering ability.
Fitzpatrick's Color Atlas and Synopsis of Clinical Dermatology
- K Wolff
- R A Johnson
Wolff K, Johnson RA. Fitzpatrick's Color Atlas and Synopsis of
Clinical Dermatology.6th ed. New York: McGraw Hill; 2009:21,
32, 358 -365.
This review article gives an overview of the pathophysiology of itch, including the four types of pruritus, neurophysiology of pruritus, and mediators of itch. The article concludes by relating these concepts to systemic pharmacologic therapy of pruritus
- M W Greaves
• Greaves MW. Pathogenesis and treatment of pruritus. Curr Allergy
Asthma Rep. 2010;10(4):236-42. This review article gives an overview of the pathophysiology of itch, including the four types of
pruritus, neurophysiology of pruritus, and mediators of itch. The
article concludes by relating these concepts to systemic pharmacologic therapy of pruritus.
This poster gives an overview of the anti-inflammatory effects of HOCl and suggests that they may serve as a mechanism by
- A J Friedman
- K Cash
- B Berman
• Friedman AJ, Cash K, Berman B. Hypochlorous Acid is Antiinflammatory and Immunomodulatory. Poster. Presented at the
Winter Clinical Dermatology Conference, Kauai, HI, January 18,
2013. This poster gives an overview of the anti-inflammatory effects
of HOCl and suggests that they may serve as a mechanism by which
HOCl could reduce pruritus.
Basic & Clinical Pharmacology
- B G Katzung
- S B Masters
- A J Trevor
Katzung BG, Masters SB, Trevor AJ. Basic & Clinical Pharmacology. 12th ed. New York: McGraw Hill Medical; 2012:24 -26, 275,
277 -278, 307, 319, 546, 643 -644, 988, 1076.