Antibacterial; antifungal
Broad-spectrum antiseptic active against Gram-positive and Gram-negative bacteria as well as yeast (Candida albicans) [3].
Hexetidine targets microbial cell membranes and disrupts their integrity. As an antimicrobial agent, it acts by binding to the bacterial cell membrane and altering its permeability, leading to the leakage of intracellular contents and cell death. It has broad-spectrum activity against bacteria and fungi. Its mechanism is thought to involve interactions with membrane phospholipids, but the exact molecular target is not fully characterized.

Hexetidine-containing mouthwash as a monotherapy or as an adjunct can be used in oral hygiene in the prevention of plaque accumulation and gingival inflammation.[3]

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In vitro, Hexetidine demonstrates antimicrobial activity against a range of bacteria and fungi. It inhibits the growth of various oral pathogens and has been used in mouthwashes for its antiseptic properties. The compound's activity is concentration-dependent, with higher concentrations providing more effective antimicrobial effects. It is not known to have significant activity against mammalian cells at therapeutic concentrations.

Reduction in the number of colony-forming units of Candida albicans after immersion of the dentures with chlorhexidine digluconate 0.12% was significantly greater than that of the group using hexetidine 0.1% and those of the control group. Hexetidine 0.1% solution tested for the first time as a product of disinfection of the acrylic dentures showed average results after immersion of 8 night hours for 4 days and was less effective than chlorhexidine digluconate 0.12%.[1]
In clinical trials, hexetidine mouthwash as a monotherapy or adjunct to oral hygiene was evaluated. Short-term studies (<4 weeks) showed a statistically significant difference in favour of hexetidine on plaque scores compared with negative control (placebo), but it was less effective than positive control (chlorhexidine). One long-term study (≥4 weeks, 6-week duration) found a statistically significant effect of 0.1% hexetidine versus placebo on plaque reduction, while another long-term study (≥4 weeks) did not. With respect to gingivitis and bleeding, neither of the two long-term studies found a statistically significant difference between hexetidine and either placebo or 0.1% chlorhexidine. In a 6-week study, 0.1% hexetidine significantly reduced plaque (from 69.0 to 41.4), bleeding on marginal probing (from 0.65 to 0.40), and gingival index (from 1.11 to 0.47) from baseline to end, but no significant difference versus chlorhexidine or placebo was observed for gingival parameters [3].
In vivo, Hexetidine is used as an antiseptic and antifungal agent in oral hygiene products. It is effective in reducing plaque formation and gingivitis when used as a mouthwash. It has also been studied for its potential use in other topical applications. Its antimicrobial effects are localized to the site of application, with minimal systemic absorption.

In vitro antimicrobial susceptibility assays for Hexetidine are performed using standard broth dilution or agar diffusion methods. Various bacterial and fungal strains are cultured in appropriate media and exposed to varying concentrations of Hexetidine. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) are determined. The compound's activity against oral pathogens is typically assessed using strains such as Streptococcus mutans and Candida albicans.

In vitro cell-based assays for Hexetidine are performed using oral epithelial or fibroblast cell lines to assess cytotoxicity. Cells are cultured in appropriate media and treated with Hexetidine at various concentrations. Cell viability is measured by MTT or neutral red uptake assays. The compound's selectivity index is calculated by comparing its cytotoxic concentration to its antimicrobial concentration.

A total of 60 denture wearers (20 men, 40 women; age range 40-80 years) with clinical evidence of DS were randomly divided into 2 test groups and 1 control group. The dentures of each test group were treated by immersion in one of the two mouthwashes while those of the control group were immersed in distilled water. Swab samples from the palatal surfaces of the upper dentures were collected before and after of cleaner use and examined mycologically.[1]

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In vivo animal studies for Hexetidine are not extensively detailed in the available literature. The compound has been used in clinical studies for its effects on plaque formation and gingivitis. Animal models of oral infection could be used to assess its efficacy, but specific protocols are not widely available.

Absorption, Distribution and Excretion
Because heratodin is cationic, it is absorbed by the mucous membranes and dental plaque after oral administration and is difficult to remove. Human studies using radiolabeled heratodin have shown that after a single mouthwash, heratodin can remain on the oral mucosa for 8 to 10 hours, and its presence can be detected in oral tissues for up to 65 hours after administration.

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Oral retention of hexetidine is low, as salivary bacterial counts return to initial values after 70-90 minutes following rinsing. Substantivity (duration of suppression of salivary bacterial counts) is markedly less than that of chlorhexidine, with a statistically insignificant trend of persistence between 1 and 3 hours compared with saline. Increasing frequency of use to three times a day may provide additional benefits to gingival health compared to twice a day [3].
Specific pharmacokinetic properties of Hexetidine are not extensively characterized. As a topical agent, it has minimal systemic absorption when applied to the oral mucosa. It is primarily active at the site of application. The compound is metabolized in the liver, and its metabolites are excreted in urine. Its half-life and other PK parameters are not well-documented.

Toxicological Information
Antidote and Emergency Treatment
Immediate First Aid: Ensure adequate decontamination has been performed. If the patient stops breathing, begin artificial respiration immediately, preferably using a machine on demand, bag-valve-mask, or simple breathing mask (if trained). Perform cardiopulmonary resuscitation (CPR) if necessary. Immediately flush contaminated eyes with running water. Do not induce vomiting. If vomiting occurs, tilt the patient forward or place them in the left lateral decubitus position (head down if possible) to maintain an open airway and prevent aspiration. Keep the patient calm and maintain normal body temperature. Seek medical attention. /Class A and Class B Toxins/
Basic Management: Establish an open airway (using an oropharyngeal or nasopharyngeal airway if necessary). Suction if necessary. Observe for signs of respiratory failure and provide assisted ventilation if necessary. Administer oxygen using a non-invasive breathing mask at a flow rate of 10 to 15 liters per minute. Monitor for pulmonary edema and treat as necessary… Monitor for shock and treat as necessary… Predict seizures and treat as necessary… If eyes become contaminated, rinse immediately with water. During transport, continuously rinse eyes with 0.9% normal saline (NS)... Do not use emetics. If swallowed, rinse mouth; if the patient is able to swallow, has a strong gag reflex, and does not drool, administer 5 mL/kg to 200 mL of water to dilute... After cleansing, cover skin burns with a dry, sterile dressing... /Class A and B Poisons/
Advanced Treatment: For patients with impaired consciousness, severe pulmonary edema, or severe respiratory distress, consider oropharyngeal or nasopharyngeal endotracheal intubation to control the airway. Positive pressure ventilation using a bag-valve-mask may be effective. Consider medical treatment for pulmonary edema... For severe bronchospasm, consider the use of β-receptor agonists, such as salbutamol... Monitor heart rhythm and treat arrhythmias if necessary... Initiate intravenous infusion of 5% glucose solution/SRP: "Keep the vessels open," minimum flow rate. If signs of hypovolemia appear, administer 0.9% normal saline (NS) or lactated Ringer's solution. For hypotension accompanied by signs of hypovolemia, administer fluids with caution. Be alert for signs of fluid overdose… Use diazepam or lorazepam to treat seizures… Use promecaine hydrochloride as an adjunct to eye irrigation…

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Non-human toxicity values: Oral LD50 in rats is 610-1430 mg/kg

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Side effects reported: extrinsic tooth stain (4% in hexetidine group vs 66% in chlorhexidine group), change in taste sensation, and sensitivity of the oral mucosa. A higher concentration (0.14%) caused more adverse effects than 0.1%. Dark stain was more pronounced on teeth among smokers [3].
Hexetidine is generally well-tolerated when used as a topical antiseptic. It may cause local irritation or allergic reactions in some individuals. Systemic toxicity is rare due to minimal absorption. It is contraindicated in patients with known hypersensitivity to the compound. It is not intended for systemic use.

[1]. J Int Oral Health. 2015 Aug;7(8):5-8.
[2]. https://en.wikipedia.org/wiki/Hexetidine
[3]. Int J Dent Hyg . 2011 Aug;9(3):182-90. doi: 10.1111/j.1601-5037.2010.00478.x.

1,3-Bis(2-ethylhexyl)-5-methyl-1,3-diazinane-5-amine is an organic nitrogen heterocyclic compound and an organic heteromonocyclic compound. It is a bactericidal and antifungal preservative. It is formulated as a mouthwash at a concentration of 0.1% for the treatment of local infections and oral hygiene. (Excerpt from Martindale Pharmacopoeia, 30th edition, page 797)

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hexetidine is formulated as a mouthwash available worldwide with indications for oropharyngeal conditions. It has been proposed as an adjunct to oral hygiene and for treatment of gingivitis, stomatitis, aphthous ulcers, dental ulcers and halitosis. Previous uses included treatment of vaginitis and cervicitis. The authors conclude that considering potential benefits in light of observed side effects, hexetidine appears to be a poor alternative to chlorhexidine [3].
Hexetidine Racemate is an antimicrobial agent used in oral hygiene products for its antibacterial and antifungal properties. It has a molecular formula of C₂₁H₄₅N₃ and a molecular weight of 339.60 g/mol. Hexetidine is effective in reducing plaque formation and gingivitis. This product is for research and topical use.

C21H45N3

339.6

339.361

C, 74.27; H, 13.36; N, 12.37

141-94-6

3607

Colorless to light yellow liquid

0.9±0.1 g/cm3

388.2±0.0 °C at 760 mmHg

Freezing point = 70 °C

175.0±13.8 °C

0.0±0.8 mmHg at 25°C

1.467

7.15

1

3

12

24

292

0

NC1(C)CN(CC(CC)CCCC)CN(CC(CC)CCCC)C1

DTOUUUZOYKYHEP-UHFFFAOYSA-N

InChI=1S/C21H45N3/c1-6-10-12-19(8-3)14-23-16-21(5,22)17-24(18-23)15-20(9-4)13-11-7-2/h19-20H,6-18,22H2,1-5H3

5-Amino-1,3-bis(2-ethylhexyl)hexahydro-5-methylpyrimidine

NSC 17764; Hexetidine; NSC-17764; Oraldene; Sterisil; Hexoral; Glypesin; Hextril; Elsix; NSC17764

2934.99.03.00

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~200 mg/mL (~588.93 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (6.12 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (6.12 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (6.12 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)