DEQUADIN-MENTHOL COMBINATION PRODUCT LOZENGE

Indications

• Bacterial vaginosis
• Trichomonal infections
• Other vaginal and vulval infections

Dosage

Adults: For adults aged 18 to 55 years, 10 mg once daily for 6 days, inserted intravaginally.

Mechanism of action

Dequalinium chloride disrupts bacterial cell membranes by diffusing through the cell wall, leading to increased cell permeability. It denatures proteins involved in bacterial metabolism and inhibits mitochondrial ATP synthesis by targeting F1-ATPase, thereby depleting bacterial energy sources. Additionally, it can intercalate into DNA, which may lead to cell lysis. These actions result in rapid bactericidal effects against various pathogens.

Pharmacodynamics

In vitro studies demonstrate that dequalinium is effective against both gram-positive and gram-negative bacteria, as well as fungi and protozoa. It exhibits rapid bactericidal and fungicidal activity, with effects observable within 30 to 60 minutes. Dequalinium's minimal inhibitory concentration (MIC) against relevant vaginal pathogens varies significantly, underscoring its potent antimicrobial properties. Moreover, it has shown potential anticancer effects in human leukemia cells through modulation of signaling pathways.

Pharmacokinetics

Dequalinium is administered intravaginally, where it acts locally with minimal systemic absorption. The pharmacokinetic profile in terms of absorption, distribution, metabolism, and excretion has not been extensively characterized, but its local action limits systemic exposure and potential side effects.

Contra-indications

• Vaginal ulceration
• Increased risk of infection

Adverse effects

• Skin reactions
• Constipation
• Diarrhoea
• Dizziness
• Gastrointestinal discomfort
• Headache
• Increased risk of infection
• Nausea
• Vertigo
• Vomiting
• Vulvovaginal irritation

Interactions

• Damages latex condoms and diaphragms
• Avoid use of non-latex condoms and intravaginal devices

Precautions

• Use during pregnancy only if essential due to limited information available

Pregnancy

Manufacturer advises to avoid unless essential; limited information available.

Storage

Store in a cool, dry place, away from direct sunlight.

Formulations

• Dequalinium chloride 10 mg vaginal tablets
• Fluomizin 10 mg vaginal tablets

Indications

• Topical pain relief
• Muscle aches
• Joint pain
• Inflammation

Dosage

Children: For children, the

Adults: For topical application, camphor is usually applied as needed to the affected area, following the instructions on the specific product used. Consult the product label or a healthcare professional for detailed dosing guidelines.

Mechanism of action

Camphor activates the transient receptor potential vanilloid 1 (TRPV1) and TRPV3 channels, which are involved in sensing pain and temperature. It requires higher concentrations to activate TRPV1 compared to capsaicin but notably desensitizes TRPV1 more rapidly and completely. This action is enhanced under inflamed conditions through phospholipase C-coupled receptor stimulation. The distinct activation pathways of camphor contribute to its analgesic effects, making it effective in reducing pain sensitivity.

Pharmacodynamics

The pharmacodynamic properties of camphor are primarily related to its interaction with TRPV1 and TRPV3 channels. By activating these receptors, camphor induces a sensation of warmth and can result in analgesia through sensory nerve excitation and subsequent desensitization. This mechanism is similar to that of other topical analgesics like capsaicin and menthol but is characterized by a faster desensitization of TRPV1. Additionally, camphor's effects may include local vasodilation and increased blood flow to the area of application, which can further alleviate pain and inflammation.

Pharmacokinetics

Camphor is absorbed through the skin when applied topically. Its pharmacokinetic profile involves distribution to various tissues, where it can exert local effects. The metabolism of camphor occurs primarily in the liver, and it is eliminated from the body mainly through urine. The onset of action is typically rapid due to its topical application, and the duration of effect may vary depending on the formulation and concentration used.

Adverse effects

• Skin irritation
• Allergic reactions
• Nausea
• Vomiting
• Dizziness

Precautions

• Use with caution in individuals with sensitive skin
• Avoid contact with eyes and mucous membranes
• Do not apply to broken or irritated skin
• Keep out of reach of children

Pregnancy

Camphor should be used with caution during pregnancy. It is advisable to consult a healthcare professional before use.

Breast-feeding

Camphor should be used with caution while breastfeeding. Consult a healthcare professional for advice.

Storage

Store in a cool, dry place, away from direct sunlight and heat.

Formulations

• Topical ointments
• Liniments
• Creams
• Gels

Indications

• Bacterial infections
• Fungal infections
• Protozoal infections
• Local antiseptic applications
• HIV-1 infection
• Leukemia treatment

Dosage

Children: Refer to the BNF for Children for specific dosing guidelines.

Adults: Refer to the BNF for specific dosing guidelines.

Mechanism of action

Dequalinium acts by disrupting bacterial cell permeability upon absorption into the bacterial cell surface. It denatures proteins involved in the respiratory chain and glycolysis, thus impairing bacterial metabolism. The drug inhibits mitochondrial ATP synthesis by blocking bacterial F1-ATPase, leading to energy depletion. Additionally, it intercalates with nucleic acids, potentially causing cell lysis through osmotic imbalance.

Pharmacodynamics

In vitro studies show that dequalinium exhibits rapid bactericidal and fungicidal activity against both gram-positive and gram-negative organisms, with sensitivity varying between species. Its minimal inhibitory concentration (MIC) against vaginal pathogens can range from 0.2 to ≥ 1024 µg/mL. Dequalinium also demonstrates anticancer effects by inducing apoptosis in leukemia cells through modulation of redox balance and downregulation of specific signaling pathways. Furthermore, it has noted antiviral properties, particularly against HIV-1.

Pharmacokinetics

The pharmacokinetics of dequalinium are characterized by rapid uptake by bacteria, leading to effective concentrations at the site of action. Its accumulation in mitochondria contributes to its mechanism as a mitochondrial poison. Specific absorption, distribution, metabolism, and excretion profiles in humans are not well-documented, necessitating cautious use in clinical settings.

Adverse effects

• Local irritation
• Allergic reactions
• Nausea
• Vomiting

Precautions

• Use with caution in patients with known hypersensitivity to dequalinium or quaternary ammonium compounds.
• Monitor for signs of local irritation or allergic reaction.

Pregnancy

There is limited data on the use of dequalinium in pregnancy. Use only if clearly needed and if the benefits outweigh the risks.

Breast-feeding

It is not known whether dequalinium is excreted in human milk. Caution is advised when administering to breastfeeding women.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Topical solution
• Vaginal tablets

Indications

• Topical analgesic for muscle and joint pain
• Cough suppressant in cough drops and lozenges
• Relief of minor throat irritation
• Cooling agent in various cosmetic and personal care products

Dosage

Children: Refer to BNF for Children for specific dosing guidelines, as doses may vary based on age and formulation.

Adults: For topical use, apply a thin layer to the affected area not more than 3 to 4 times daily. For cough drops, follow the product-specific instructions as per the formulation.

Mechanism of action

Menthol acts as an agonist for the transient receptor potential subtype M8 (TRPM8), a non-selective cation channel that is activated by cold temperatures. This activation leads to calcium influx in mast cells, inducing the release of histamine, which can trigger allergic responses such as urticaria, asthma, and rhinitis. Menthol's ability to induce histamine release via TRPM8 suggests potential therapeutic applications for TRPM8 antagonists in managing cold- and menthol-induced allergies.

Pharmacodynamics

Menthol produces a cooling effect by stimulating sensory neurons that convey cold sensations. It interacts with TRPM8 channels, leading to the activation of intracellular signaling pathways that can result in vasodilation and increased blood flow to the area of application. This cooling sensation can provide symptomatic relief in conditions characterized by pain or irritation.

Pharmacokinetics

Menthol is absorbed through the skin and mucous membranes, with systemic effects depending on the route of administration. Its bioavailability can vary, and it is metabolized primarily in the liver. The elimination half-life and excretion pathways have not been extensively characterized, but menthol is generally considered to have a rapid onset of action with effects lasting for a few hours.

Adverse effects

• Allergic reactions
• Urticaria
• Asthma
• Rhinitis
• Skin irritation

Precautions

• Use with caution in patients with known allergies to menthol or related compounds
• May exacerbate asthma in sensitive individuals

Pregnancy

There are no well-controlled studies of menthol in pregnant women. Menthol should be used during pregnancy only if clearly needed.

Breast-feeding

Menthol is excreted in breast milk. Caution should be exercised when administering to nursing mothers.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• Topical ointment
• Cream
• Liquid

Mechanism of action

Dequalinium has multiple modes of action. Dequalinium absorbs into the bacterial cell surface and diffuses through the cell wall, disrupting bacterial cell permeability. It is taken up by the bacteria rapidly. Once in the bacteria, dequalinium denatures proteins involved in the respiratory chain and glycolysis of bacteria, interfering with bacterial cell metabolism and ribosomal protein synthesis. By inhibiting bacterial F1-ATPase, dequalinium inhibits mitochondrial ATP synthesis and blocks glucose metabolism. These molecular actions ultimately deplete bacterial energy sources. As dequalinium accumulates in the mitochondria, it is considered a mitochondrial poison. Dequalinium can also precipitate nucleic acids, as it can intercalate one of its quinoline chromophores between DNA base pairs. Depending on the drug concentration, dequalinium can lyse the bacterial cell by promoting osmotic imbalance.

Pharmacodynamics

_In vitro_, dequalinium possesses antimicrobial activity against gram-positive and gram-negative bacteria, yeasts, and protozoa. Dequalinium has a rapid bactericidal and fungicidal action. The antiparasitic and antiviral properties of dequalinium have also been noted. For example, dequalinium can bind to the membrane-proximal external region (MPER) of the spike envelope of the human immunodeficiency virus HIV-1. As with other quaternary ammonium compounds similar to dequalinium, gram-positive bacteria are more sensitive to dequalinium than gram-negative bacteria. The bactericidal and fungicidal effects of dequalinium can occur within 30 to 60 minutes. According to _in vitro_ studies, the minimal inhibitory concentration (MIC) for dequalinium against relevant vaginal pathogens ranges from 0.2 to ≥ 1024 µg/mL. There is evidence that dequalinium exhibits anticancer activity in human leukemia cells: dequalinium induces a cytotoxic effect by altering redox balance, downregulating Raf/MEK/ERK1/2 and PI3K/Akt signalling pathways, and promoting apoptosis of leukemic cells. Dequalinium was also shown to block small conductance Ca²⁺-activated K⁺ channels, called SK channels, which are often expressed in some cancer cells to play a role in cell proliferation and migration. One study showed that dequalinium reduced macrophage motility in mice, inhibiting macrophage infiltration of irradiated tumours and attenuating local metastasis. Interestingly, dequalinium was shown to modulate and induce self-oligomerization of alpha-synuclein, a synaptic protein known to cause aggregates in several neurodegenerative disorders. This finding highlights the neuroprotective actions of dequalinium; however, further investigations are warranted as dequalinium is a neurotoxic agent.

Mechanism of action

Camphor is a naturally occurring compound that is used as a major active ingredient of balms and liniments supplied as topical analgesics. ... Capsaicin and menthol, two other topically applied agents widely used for similar purposes, are known to excite and desensitize sensory nerves by acting on two members of transient receptor potential (TRP) channel superfamily: heat-sensitive TRP vanilloid subtype 1 (TRPV1) and cold-sensitive TRP channel M8, respectively. Camphor has recently been shown to activate TRPV3, and here /investigators/ show that camphor also activates heterologously expressed TRPV1, requiring higher concentrations than capsaicin. Activation was enhanced by phospholipase C-coupled receptor stimulation mimicking inflamed conditions. Similar camphor-activated TRPV1-like currents were observed in isolated rat DRG neurons and were strongly potentiated after activation of protein kinase C with phorbol-12-myristate-13-acetate. Camphor activation of rat TRPV1 was mediated by distinct channel regions from capsaicin, as indicated by camphor activation in the presence of the competitive inhibitor capsazepine and in a capsaicin-insensitive point mutant. Camphor did not activate the capsaicin-insensitive chicken TRPV1. TRPV1 desensitization is believed to contribute to the analgesic actions of capsaicin. /The authors/ found that, although camphor activates TRPV1 less effectively, camphor application desensitized TRPV1 more rapidly and completely than capsaicin. Conversely, TRPV3 current sensitized after repeated camphor applications, which is inconsistent with the analgesic role of camphor. /Investigators/ also found that camphor inhibited several other related TRP channels, including ankyrin-repeat TRP 1 (TRPA1). The camphor-induced desensitization of TRPV1 and block of TRPA1 may underlie the analgesic effects of camphor.

Mechanism of action

Dequalinium has multiple modes of action. Dequalinium absorbs into the bacterial cell surface and diffuses through the cell wall, disrupting bacterial cell permeability. It is taken up by the bacteria rapidly. Once in the bacteria, dequalinium denatures proteins involved in the respiratory chain and glycolysis of bacteria, interfering with bacterial cell metabolism and ribosomal protein synthesis. By inhibiting bacterial F1-ATPase, dequalinium inhibits mitochondrial ATP synthesis and blocks glucose metabolism. These molecular actions ultimately deplete bacterial energy sources. As dequalinium accumulates in the mitochondria, it is considered a mitochondrial poison. Dequalinium can also precipitate nucleic acids, as it can intercalate one of its quinoline chromophores between DNA base pairs. Depending on the drug concentration, dequalinium can lyse the bacterial cell by promoting osmotic imbalance.

Pharmacodynamics

_In vitro_, dequalinium possesses antimicrobial activity against gram-positive and gram-negative bacteria, yeasts, and protozoa. Dequalinium has a rapid bactericidal and fungicidal action. The antiparasitic and antiviral properties of dequalinium have also been noted. For example, dequalinium can bind to the membrane-proximal external region (MPER) of the spike envelope of the human immunodeficiency virus HIV-1. As with other quaternary ammonium compounds similar to dequalinium, gram-positive bacteria are more sensitive to dequalinium than gram-negative bacteria. The bactericidal and fungicidal effects of dequalinium can occur within 30 to 60 minutes. According to _in vitro_ studies, the minimal inhibitory concentration (MIC) for dequalinium against relevant vaginal pathogens ranges from 0.2 to ≥ 1024 µg/mL. There is evidence that dequalinium exhibits anticancer activity in human leukemia cells: dequalinium induces a cytotoxic effect by altering redox balance, downregulating Raf/MEK/ERK1/2 and PI3K/Akt signalling pathways, and promoting apoptosis of leukemic cells. Dequalinium was also shown to block small conductance Ca²⁺-activated K⁺ channels, called SK channels, which are often expressed in some cancer cells to play a role in cell proliferation and migration. One study showed that dequalinium reduced macrophage motility in mice, inhibiting macrophage infiltration of irradiated tumours and attenuating local metastasis. Interestingly, dequalinium was shown to modulate and induce self-oligomerization of alpha-synuclein, a synaptic protein known to cause aggregates in several neurodegenerative disorders. This finding highlights the neuroprotective actions of dequalinium; however, further investigations are warranted as dequalinium is a neurotoxic agent.

Mechanism of action

Exposure to low temperatures often causes allergic responses or urticaria. Similarly, menthol, a common food additive is also known to cause urticaria, asthma, and rhinitis. However, despite the obvious clinical implications, the molecular mechanisms responsible for inducing allergic responses to low temperatures and menthol have not been determined. Because a non-selective cation channel, transient receptor potential subtype M8 (TRPM8) is activated by cold and menthol, we hypothesized that this channel mediates cold- and menthol-induced histamine release in mast cells. Here, we report that TRPM8 is expressed in the basophilic leukemia mast cell line, RBL-2H3, and that exposure to menthol or low temperatures induced Ca(2+) influx in RBL-2H3 cells, which was reversed by a TRPM8 blocker. Furthermore, menthol, a TRPM8 agonist, induced the dose-dependent release of histamine from RBL-2H3 cells. When TRPM8 transcripts were reduced by siRNA (small interfering RNA), menthol- and cold-induced Ca(2+) influx and histamine release were significantly reduced. In addition, subcutaneous injection of menthol evoked scratching, a typical histamine-induced response which was reversed by a TRPM8 blocker. Thus, our findings indicate that TRPM8 mediates the menthol- and cold-induced allergic responses of mast cells, and suggest that TRPM8 antagonists be viewed as potential treatments for cold- and menthol-induced allergies. /DL-Menthol/ Menthol's characteristic cooling sensation is due, in part, to the activation of sensory neurons generally termed transient receptor potential (TRP) channels, in particular transient receptor potential melastatin family member 8 (TRPM8) and transient receptor potential subfamily A, member 1 (TRPA1). Menthol acts upon TRPM8 receptors by rapidly increasing intracellular calcium and mobilizing calcium flux through the channels to induce cold response signals at the application site. Aside from its cold-inducing sensation capabilities, menthol exhibits cytotoxic effects in cancer cells, induces reduction in malignant cell growth, and engages in synergistic excitation of GABA receptors and sodium ion channels resulting in analgesia. /DL-Menthol/ In recent years, the transient receptor potential melastatin member 8 (TRPM8) channel has emerged as a promising prognostic marker and putative therapeutic target in prostate cancer. We have found that forced overexpression of TRPM8 in PC-3 cells can inhibit the cell proliferation and motility probably through the TRPM8 activation. In this study, we aimed to investigate whether activating the TRPM8 channel by its selective agonist menthol can inhibit the proliferation and motility of androgen-independent prostate cancer (AIPC) with remarkable expression of TRPM8. Menthol is a naturally occurring compound, which has been widely used in cosmetics and pharmaceutical products, and also as flavoring in food. DU145 cells are androgen-independent but have a remarkable expression of TRPM8. The demonstration of the existence of TRPM8 and the absence of TRPA1 in DU145 cells provided the foundation for the following experiments, because both TRPM8 and TRPA1 are molecular targets of menthol. The outcome of MTT assay indicated that menthol inhibited the cell growth (p < 0.01). Cell cycle distribution and scratch assay analysis revealed that menthol induced cell cycle arrest at the G(0)/G(1) phase (p < 0.01). Furthermore, menthol inhibited the migration of DU145 cells by downregulating the focal-adhesion kinase. So it suggests that the activation of the existing TRPM8 channels may serve as a potential and pragmatic treatment for those AIPC with remarkable expression of TRPM8, and menthol is a useful compound for future development as an anticancer agent. /DL-Menthol/