Fresh Carrier for an Old Topical Local Anesthetic: Benzocaine in Nanostructured Lipid Carriers.

Nanostructured lipid carriers (NLC) have emerged as innovative drug delivery systems, offering distinct advantages over other lipid-based carriers, such as liposomes and solid lipid nanoparticles. Benzocaine (BZC), the oldest topical local anesthetic in use, undergoes metabolism by pseudocholinesterase, leading to the formation of p-aminobenzoic acid, a causative agent for allergic reactions associated with prolonged BZC usage. In order to mitigate adverse effects and enhance bioavailability, BZC was encapsulated within NLC. Utilizing a 23 factorial design, formulations comprising cetyl palmitate (solid lipid), propylene glycol monocaprylate (liquid lipid), and Pluronic F68 as surfactants were systematically prepared, with variations in the solid/liquid lipid mass ratios (60:40-80:20%), total lipid contents (15-25%), and BZC concentrations (1-3%). The optimized formulation underwent characterization by dynamic light scattering, differential scanning calorimetry, Raman imaging, X-ray diffraction, small-angle neutron scattering, nanotracking analysis, and transmission electron microscopy (TEM)/cryo-TEM, providing insights into the nanoparticle structure and the incorporation of BZC into its lipid matrix. NLCBZC exhibited a noteworthy encapsulation efficiency (%EE = 96%) and a 1 year stability when stored at 25 °C. In vitro kinetic studies and in vivo antinociceptive tests conducted in mice revealed that NLCBZC effectively sustained drug release for over 20 h and prolonged the anesthetic effect of BZC for up to 18 h. We therefore propose the use of NLCBZC to diminish the effective anesthetic concentration of benzocaine (from 20 to 3% or less), thus minimizing allergic reactions that follow the topical administration of this anesthetic and, potentially, paving the way for new routes of BZC administration in pain management.

Effectiveness of pre-injection use of cryoanesthesia as compared to topical anesthetic gel in reducing pain perception during palatal injections: a randomized controlled trial.

Background: Palatal injections are often painful. We aimed to compare topical ice and 20% benzocaine gel for pre-injection anesthesia before greater palatine nerve block (GPNB) injections. Methods: A randomized split-mouth clinical trial was conducted among patients aged 15-60-years needing bilateral GPNB injections. A total of 120 palatal sites from 60 patients were randomly allocated to Group A (topical ice) or Group B (20% benzocaine gel). Pain was evaluated using sound, eye, motor (SEM), and the visual analog scale (VAS) in both groups. Inferential analysis was performed using the Mann-Whitney U test. Results: The mean age of the participants was 20.5 ± 3.9 years. The median VAS score for group A was 11 (Q1 - Q3: 5.25 - 21.75), which was slightly higher than the 10 (Q1 - Q3: 4.0 - 26.75) reported in group B. However, the difference was not statistically significant (P = 0.955). The median SEM score for group A and group B was 3.5 (Q1 - Q3: 3.0 - 4.0) and 4.0 (Q1 - Q3: 3.0 - 4.0), respectively, which was statistically insignificant (P = 0.869). Conclusion: Using ice as a form of topical anesthetic for achieving pre-injection anesthesia before GPNB was as effective as 20% benzocaine gel.

Plant Growth Promotion and Plant Disease Suppression Induced by Bacillus amyloliquefaciens Strain GD4a.

Botrytis cinerea, the causative agent of gray mold disease (GMD), invades plants to obtain nutrients and disseminates through airborne conidia in nature. Bacillus amyloliquefaciens strain GD4a, a beneficial bacterium isolated from switchgrass, shows great potential in managing GMD in plants. However, the precise mechanism by which GD4a confers benefits to plants remains elusive. In this study, an A. thaliana-B. cinerea-B. amyloliquefaciens multiple-scale interaction model was used to explore how beneficial bacteria play essential roles in plant growth promotion, plant pathogen suppression, and plant immunity boosting. Arabidopsis Col-0 wild-type plants served as the testing ground to assess GD4a's efficacy. Additionally, bacterial enzyme activity and targeted metabolite tests were conducted to validate GD4a's potential for enhancing plant growth and suppressing plant pathogens and diseases. GD4a was subjected to co-incubation with various bacterial, fungal, and oomycete pathogens to evaluate its antagonistic effectiveness in vitro. In vivo pathogen inoculation assays were also carried out to investigate GD4a's role in regulating host plant immunity. Bacterial extracellular exudate (BEE) was extracted, purified, and subjected to untargeted metabolomics analysis. Benzocaine (BEN) from the untargeted metabolomics analysis was selected for further study of its function and related mechanisms in enhancing plant immunity through plant mutant analysis and qRT-PCR analysis. Finally, a comprehensive model was formulated to summarize the potential benefits of applying GD4a in agricultural systems. Our study demonstrates the efficacy of GD4a, isolated from switchgrass, in enhancing plant growth, suppressing plant pathogens and diseases, and bolstering host plant immunity. Importantly, GD4a produces a functional bacterial extracellular exudate (BEE) that significantly disrupts the pathogenicity of B. cinerea by inhibiting fungal conidium germination and hypha formation. Additionally, our study identifies benzocaine (BEN) as a novel small molecule that triggers basal defense, ISR, and SAR responses in Arabidopsis plants. Bacillus amyloliquefaciens strain GD4a can effectively promote plant growth, suppress plant disease, and boost plant immunity through functional BEE production and diverse gene expression.

Novel Microemulsion Containing Benzocaine and Fusidic Acid Simultaneously: Formulation, Characterization, and In Vitro Evaluation for Wound Healing.

Modern drug carrier technologies, such as microemulsions with small droplet sizes and high surface areas, improve the ability of low water solubility active ingredients to permeate and localize. The goal of this study was to create microemulsion formulations for wound healing that contained both fusidic acid (FA), an antibacterial agent, and benzocaine (BNZ), a local anesthetic. Studies on characterization were carried out, including viscosity, droplet size, and zeta potential. The drug-loaded microemulsion had a stable structure with -3.014 ± 1.265 mV of zeta potential and 19.388 ± 0.480 nm of droplet size. In both in vitro release and ex vivo permeability studies, the microemulsion was compared with Fucidin cream and oily BNZ solution. According to the drug release studies, BNZ release from the microemulsion and the BNZ solution showed a similar profile (p > 0.05), while FA release from the microemulsion had a higher drug release compared to Fucidin cream (p < 0.001). The microemulsion presented lower drug permeation (p > 0.05) for both active ingredients, on the other hand, provided higher drug accumulation compared to the control preparations. Moreover, according to the results of in vitro wound healing activity, the microemulsion indicated a dose-dependent wound healing potential with the highest wound healing activity at the highest concentrations. To the best of our knowledge, this developed BNZ- and FA-loaded microemulsion would be a promising candidate to create new opportunities for wound healing thanks to present the active ingredients, which have low water solubility, in a single formulation and achieved higher accumulation than control preparations.

The Effects of Caustic Soda and Benzocaine on Directed Grooming to the Eyestalk in the Glass Prawn, Palaemon elegans, Are Consistent with the Idea of Pain in Decapods.

Acceptance of the possibility of pain in animals usually requires that various criteria are fulfilled. One such criterion is that a noxious stimulus or wound would elicit directed rubbing or grooming at the site of the stimulus. There is also an expectation that local anaesthetics would reduce these responses to damage. These expectations have been fulfilled in decapod crustaceans but there has been criticism of a lack of replication. Here, we report an experiment on the effects of a noxious chemical, sodium hydroxide, applied to one eyestalk of the glass prawn. This caused an immediate escape tail-flick response. It then caused nipping and picking with the chelipeds at the treated eyestalk but much less so at the alternative eyestalk. Prior treatment with benzocaine also caused an immediate tail-flick and directed behaviour, suggesting that this agent is aversive. Subsequently, however, it reduced the directed behaviour caused by caustic soda. We thus demonstrated responses that are consistent with the idea of pain in decapod crustaceans.

Fibrillar Hydrogel Based on Cellulose Nanocrystals Crosslinked via Diels-Alder Reaction: Preparation and pH-Sensitive Release of Benzocaine.

A fibrillar hydrogel was obtained by covalent crosslinking via Diels-Alder reaction of two types of cellulose nanocrystals (CNCs) with furan and maleimide groups. Gelation has been studied at various ratios of components and temperatures in the range from 20 to 60 °C. It was shown that the rheological properties of the hydrogel can be optimized by varying the concentration and ratio of components. Due to the rigid structure of the CNCs, the hydrogel could be formed at a concentration of at least 5 wt%; however, it almost does not swell either in water with pH 5 or 7 or in the HBSS buffer. The introduction of aldehyde groups into the CNCs allows for the conjugation of physiologically active molecules containing primary amino groups due to the formation of imine bonds. Here, we used benzocaine as a model drug for conjugation with CNC hydrogel. The resulting drug-conjugated hydrogel demonstrated the stability of formulation at pH 7 and a pH-sensitive release of benzocaine due to the accelerated hydrolytic cleavage of the imine bond at pH < 7. The developed drug-conjugated hydrogel is promising as wound dressings for local anesthesia.

Efficacy of benzocaine and lidocaine bioadhesive patches in various minor oral surgical procedures in children - An evaluative study.

Context: The key to successful management of a child in the dental clinic depends greatly on providing painless anaesthesia. Topical anaesthesia using bioadhesive patches may be a breakthrough in this field. Aims: The purpose of the study was to compare the efficacy of Benzocaine and Lidocaine bioadhesive patches in reducing pain associated with various minor oral surgical procedures in children. Methods and Materials: Hundred subjects, aged 6-9 years, requiring various minor oral surgical procedures such as extractions of primary teeth, nerve blocks, mucocele excision or drainage of abscesses were divided equally into Groups 1 and 2. In Group 1, custom fabricated Benzocaine patches were placed for 5 minutes at the target site prior to the procedure, and in Group 2, Lidocaine patches were used in the same manner. Each subject completed a visual analogue scale (VAS) and Wong-Baker Faces pain scale (FPS) after each procedure. Pulse rate and saturation of peripheral oxygen were assessed using pulse oximeter. The duration of the study was from September 2014 to September 2015. Statistical Analysis Used: The statistical analysis was done using paired t test, ANOVA and Bonferroni post hoc analysis. P value less than 0.05 were considered as statistically significant. Results: A significant difference in pain scores was observed favouring the use of Benzocaine over Lidocaine patches (P < 0.05). However, no significant differences in pulse oximeter readings were observed. Conclusions: A statistically significant reduction in pain rating scores was observed in the Benzocaine group after a five-minute application of the patch.

Atlantic Salmon Gill Epithelial Cell Line (ASG-10) as a Suitable Model for Xenobiotic Biotransformation.

Fish are exposed to xenobiotics in the water. Uptake occurs mainly through the gills, which function as an exchange point with the environment. The gills' ability to detoxify harmful compounds by biotransformation is an essential protection mechanism. The enormous numbers of waterborne xenobiotics requiring ecotoxicological assessment makes it necessary to replace in vivo fish studies with predictive in vitro models. Here, we have characterized the metabolic capacity of the ASG-10 gill epithelial cell line from Atlantic salmon. Inducible CYP1A expression was confirmed by enzymatic assays and immunoblotting. The activities of important cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes were established using specific substrates and metabolite analysis by liquid chromatography (LC) triple quadrupole mass spectrometry (TQMS). Metabolism of the fish anesthetic benzocaine (BZ) in ASG-10 confirmed esterase and acetyl transferase activities through the production of N-acetylbenzocaine (AcBZ), p-aminobenzoic acid (PABA) and p-acetaminobenzoic acid (AcPABA). Moreover, we were able to determine hydroxylamine benzocaine (BZOH), benzocaine glucuronide (BZGlcA) and hydroxylamine benzocaine glucuronide (BZ(O)GlcA) by LC high-resolution tandem mass spectrometry (HRMS/MS) fragment pattern analysis for the first time. Comparison to metabolite profiles in hepatic fractions, and in plasma of BZ-euthanized salmon, confirmed the suitability of the ASG-10 cell line for investigating biotransformation in gills.

Controllable formation of polydopamine on carbon dots for ultrasensitive detection of alkaline phosphatase and ratiometric fluorescence immunoassay of benzocaine.

Sensing alkaline phosphatase (ALP) activity with high sensitivity and accuracy is critical for both ALP-related health and food safety supervision and the development of ALP-triggered immunoassay platforms. Herein, an ultrasensitive ratiometric fluorescence (RF) sensing system based on the controllable formation of luminescent polydopamine and efficient quenching of carbon dots was proposed for the ALP activity assay, achieving quantitative detection in the range of 0.01-100 mU/L. Furthermore, this RF sensing system was integrated with an ALP-based ELISA platform to construct an RF-ELISA for benzocaine, a potentially abused anesthetic in edible fish, and ultrasensitive assay at the level of fg/mL was realized. This ratiometric strategy-based platform effectively shields various interferences through the self-calibration effect, thus providing more accurate and reliable quantification results. This study not only offers an efficient method for ultratrace detection of ALP and benzocaine but also proposes a universal platform for ultrasensitive detection of diverse targets in food analysis by replacing the recognition unit.

Hemolysis and acquired methemoglobinemia associated with lidocaine and benzocaine topical application: a case report.

BACKGROUND: Topical anesthetics are commonly used over the counter, and one of the adverse effects of these medications is methemoglobinemia, which is a serious and life-threatening condition. CASE PRESENTATION: We describe a 25-year-old Persian male presenting with generalized weakness, dizziness, headache, and cyanosis. In addition, he had genital warts starting 3 weeks ago, which were self-treated with podophyllin, resulting in itching and pain. He used over-the-counter topical anesthetics, including benzocaine and lidocaine, to reduce the symptoms. According to the lab data, signs and symptoms of methemoglobinemia and hemolysis were diagnosed. Considering the hemolysis, ascorbic acid was used for treatment. The patient was discharged after 5 days with normal arterial blood gas and pulse oximetry and no signs and symptoms. CONCLUSION: This case highlights that self-administration of some topical anesthetics may lead to potentially fatal conditions.

Recurrent Methemoglobinemia From Over-the-Counter Medication.

A 53-year-old female with a history of rheumatoid arthritis presented with acute-on-chronic shortness of breath. She had severe lung disease secondary to chronic obstructive pulmonary disease (COPD) and recurrent pneumonia. She was found to have recurrent methemoglobinemia and presented to the hospital with refractory hypoxemia. She was given intravenous (IV) methylene blue, and transfused 2 units of packed red blood cells. Her methemoglobin levels again trended up during hospitalization and after identifying and discontinuing the offending agent, an over-the-counter (OTC) benzocaine gel, her methemoglobin level was normalized and she never had a recurrence. The severity of presentation from methemoglobinemia is increased in patients with anemia, heart disease, and pulmonary disease.

Supramolecular assembly of benzocaine bearing cyclodextrin cavity via host-guest complexes on polyacrylonitrile as an electrospun nanofiber.

Nanofibers (NFs) can be encapsulated with cyclodextrins (CDs) based host-guest complexes (HCs) in order to enable many biological applications. Here, benzocaine (BNZ) forms HCs with ß-cyclodextrin (ß-CD) that are co-precipitated and further added to polyacrylonitrile (PAN) solution for making BNZ:ß-CD-HCs/PAN NFs material with the aid of electrospinning technique. The marginal increase in absorbance and fluorescence intensity along with the shift in spectral maxima of BNZ in the presence of ß-CD suggested the host-guest interaction between BNZ and ß-CD. NFs showed a uniform and clean morphology in SEM images and interestingly, the ICs revealed that significantly thinner in terms of average fiber diameter (AFD) than those of free BNZ on PAN medium. BNZ molecule is completely included in the PAN surface as the result of NFs and thus, the original sharp peaks for the BNZ have vanished and the peaks are much broader for the BNZ and BNZ:ß-CD-HCs. BNZ is also found to be a good candidate for anti-inflammatory, anti-oxidant, and anti-diabetic. The results showed an improved activity when it is in the form of HCs on a PAN medium. Making HCs of drugs could be significant in biological applications.

Injectable and topical local anesthetics for acute dental pain: 2 systematic reviews.

BACKGROUND: Local anesthesia is essential for pain control in dentistry. The authors assessed the comparative effect of local anesthetics on acute dental pain after tooth extraction and in patients with symptomatic irreversible pulpitis. TYPES OF STUDIES REVIEWED: The authors searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and the US Clinical Trials registry through November 21, 2020. The authors included randomized controlled trials (RCTs) comparing long- vs short-acting injectable anesthetics to reduce pain after tooth extraction (systematic review 1) and evaluated the effect of topical anesthetics in patients with symptomatic pulpitis (systematic review 2). Pairs of reviewers screened articles, abstracted data, and assessed risk of bias using a modified version of the Cochrane risk of bias 2.0 tool. The authors assessed the certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: Fourteen RCTs comparing long- vs short-acting local anesthetics suggest that bupivacaine may decrease the use of rescue analgesia and may not result in additional adverse effects (low certainty evidence). Bupivacaine probably reduces the amount of analgesic consumption compared with lidocaine with epinephrine (mean difference, -1.91 doses; 95% CI, -3.35 to -0.46; moderate certainty) and mepivacaine (mean difference, -1.58 doses; 95% CI, -2.21 to -0.95; moderate certainty). Five RCTs suggest that both benzocaine 10% and 20% may increase the number of people experiencing pain reduction compared with placebo when managing acute irreversible pulpitis (low certainty). PRACTICAL IMPLICATIONS: Bupivacaine may be superior to lidocaine with epinephrine and mepivacaine with regard to time to and amount of analgesic consumption. Benzocaine may be superior to placebo in reducing pain for 20 through 30 minutes after application.

Assessment of Binary Agarose-Carbopol Buccal Gels for Mucoadhesive Drug Delivery: Ex Vivo and In Vivo Characterization.

Agarose (AG) is a naturally occurring biocompatible marine seaweed extract that is converted to hydrocolloid gel in hot water with notable gel strength. Currently, its mucoadhesion properties have not been fully explored. Therefore, the main aim of this study was to evaluate the mucoadhesive potential of AG binary dispersions in combination with Carbopol 934P (CP) as mucoadhesive gel preparations. The gels fabricated via homogenization were evaluated for ex vivo mucoadhesion, swelling index (SI), dissolution and stability studies. The mucoadhesive properties of AG were concentration dependent and it was improved by the addition of CP. Maximum mucoadhesive strength (MS) (27.03 g), mucoadhesive flow time (FT) (192.2 min), mucoadhesive time in volunteers (MT) (203.2 min) and SI (23.6% at 4 h) were observed with formulation F9. The mucoadhesive time investigated in volunteers (MT) was influenced by AG concentration and was greater than corresponding FT values. Formulations containing 0.3%, w/v AG (F3 and F9) were able to sustain the release (~99%) for both drugs till 3 h. The optimized formulation (F9) did not evoke any inflammation, irritation or pain in the buccal cavity of healthy volunteers and was also stable up to 6 months. Therefore, AG could be considered a natural and potential polymer with profound mucoadhesive properties to deliver drugs through the mucosal route.

Determination of Benzocaine in Pharmaceutical Formulations by Indirect SERRS Assay Combined with Azo Coupling.

Coupled with an azo coupling reaction, a simple, rapid, sensitive, and effective surface-enhanced resonance Raman scattering (SERRS) detection method for benzocaine was developed. In our study, benzocaine which is used clinically as a local anesthetic was derived with p-aminothiophenol into a corresponding azo product within 5 min, resulting in a strong SERRS response with the simple addition of Ag NPs excited with a 532 nm laser. The linear correlation between SERRS intensity of dominant bands and logarithm of benzocaine concentration was investigated for quantitative determination. The method reached a limit of detection (LOD) down to 0.139 and 0.0788 µg/mL calculated with two peak intensity ratios (I1568/I2260 and I1331/I2260), which is comparable to most studies reported previously, and meanwhile had superiority in simplicity and rapidness. The quantitative measurements for pharmaceutical preparations with benzocaine were conducted without complex extraction and enrichment processes. It was indicated that the SERRS assay combined with azo derivatization reaction has implications for practical applications in more complicated systems involving biological samples, in which appropriate and simplified pretreatments were conducted to remove interfering components.

A Multi-Site Assessment of Anesthetic Overdose, Hypothermic Shock, and Electrical Stunning as Methods of Euthanasia for Zebrafish (Danio rerio) Embryos and Larvae.

Euthanasia in zebrafish (Danio rerio) younger than 5 days post fertilization (dpf) is poorly described in the literature, and standardized protocols are lacking, most likely because larvae not capable of independent feeding are often not protected under national legislations. We assessed the euthanasia efficacy in laboratories in different countries of a one hour anesthetic overdose immersion with buffered lidocaine hydrochloride (1 g/L, with or without 50 mL/L of ethanol), buffered tricaine (1 g/L), clove oil (0.1%), benzocaine (1 g/L), or 2-phenoxyethanol (3 mL/L), as well as the efficacy of hypothermic shock (one hour immersion) and electrical stunning (for one minute), on zebrafish at <12 h post fertilization (hpf), 24 hpf, and 4 dpf. Based on the survival/recovery rates 24 h after treatment, the most effective methods were clove oil, lidocaine with ethanol, and electrical stunning. For 4 dpf larvae, signs of aversion during treatment demonstrated that all anesthetics, except lidocaine, induced aversive behavior. Therefore, the most suited euthanasic treatment was lidocaine hydrochloride 1 g/L, buffered with 2 g/L of sodium bicarbonate and mixed with 50 mL/L of ethanol, which euthanized both embryos and larvae in an efficient and stress-free manner. Electrical stunning also euthanized embryos and larvae efficiently and without signs of aversion; this method needs further assessment in other laboratories to draw firm conclusions.

Antibacterial and anticancer profiling of new benzocaine derivatives: Design, synthesis, and molecular mechanism of action.

The need for new chemotherapeutics to overcome development of resistance merits research to discover new agents. Benzocaine derivatives are essential compounds in medicinal chemistry due to their various biological activities including antibacterial and anticancer activities. Therefore, this study focuses on the synthesis of new benzocaine derivatives 3a-e, 6, 7a and 7b, 8, 10-14, and 16a-d and their in vitro evaluation as antibacterial agents against gram +ve and -ve strains and as anticancer agents against HepG-2, HCT-116, and MCF-7 human cancer cell lines. The obtained results demonstrated that thiazolidines 6 and 7b showed higher antibacterial and anticancer activity in comparison with the reference drugs. In addition, 6 and 7b showed high potency as inhibitors toward their biological targets, that is DNA gyrase and human topoisomerase IIα, as compared to the reference standard drugs novobiocin and etoposide, respectively. Molecular docking demonstrated that both compounds could identify the active site of their target enzymes and develop effective binding interactions. Absorption, distribution, metabolism and elimination (ADME) and drug-likeness predictions of both compounds showed that they both have good ADME profiles and no structural alerts that might cause toxicity. Based on this, 6 and 7b could serve as lead compounds for the design of more potent antibacterial and anticancer agents.

Local and Regional Anesthesia in Zoological Companion Animal Practice.

Local anesthetics provide analgesia and can be incorporated into multimodal anesthetic protocols. They work by blocking the voltage-dependent sodium ion channels along neurons that mediate nociception. Systemically, these drugs can be cardiotoxic in a dose-dependent manner. Lidocaine and bupivacaine are the most commonly used local anesthetics and their use has been reported in all classes of vertebrates. Despite anecdotal reports to the contrary, zoologic companion animals are unlikely to be more susceptible to the cardiotoxic effects of local anesthetics than domestic small animals. Local anesthetics can be clinically useful for analgesia and anesthesia in zoologic companion animal practice.

A Rare Case of Benzocaine-Induced Methemoglobinemia.

Methemoglobinemia is a severely dangerous condition that can be induced by congenital mutations or can be acquired. One of the ways to acquire methemoglobinemia is by using topical anesthetics during procedures, such as nasogastric (NG) tube placement, transesophageal echocardiogram (TEE), esophagogastroduodenoscopies (EGD), and during endoscopic retrograde cholangiopancreatography (ERCP). Herein, we present the case of a 35-year-old lady who presented to the hospital for an initial hysterectomy. However, due to topical anesthetic use during an NG tube placement, she developed methemoglobinemia. She then developed hypoxia, an altered mental status, and had elevated methemoglobinemia levels. She denied any previous episode of methemoglobinemia and had no family history of the condition as well. She was rapidly given methylene blue, which resolved her symptoms and induced normal methemoglobin levels on subsequent arterial blood gas analysis. Those who are unknowingly susceptible to developing methemoglobinemia and receive anesthetics during hospital procedures are at risk for serious adverse effects and clinical deterioration if not treated correctly. Therefore, it is important to recognize the clinical signs of methemoglobinemia as soon as they appear and have the required treatment readily available, as any delay could result in dangerous consequences for the patient.