Bravecto® Plus 500/25 mg

Mechanism of action

Acetone acts as a solvent and is utilized in various biochemical pathways. It participates in the biosynthesis of isopropanol and is involved in the degradation pathways where it converts into other metabolites such as methylglyoxal and acetoacetate. It also plays a role in pyruvate fermentation and is integral to the fermentation processes in Clostridium acetobutylicum.

Pharmacodynamics

Acetone has a low molecular weight and is highly volatile, which allows it to penetrate biological membranes easily. Its pharmacological effects are primarily due to its role as a solvent and its ability to influence metabolic processes. Acetone can affect lipid metabolism and may impact energy homeostasis by influencing the balance between fat and carbohydrate utilization.

Pharmacokinetics

Acetone is rapidly absorbed through inhalation and dermal exposure. It is distributed throughout the body and can cross the blood-brain barrier. Metabolism occurs primarily in the liver where acetone is converted into acetoacetate and other metabolites. The elimination of acetone occurs mainly through renal excretion, with a half-life varying based on the route of exposure and individual metabolism.

Pregnancy

Acetone is classified as a pregnancy category C drug. Its effects during pregnancy are not well-studied, and caution should be exercised.

Breast-feeding

There is limited information on the excretion of acetone in breast milk. Caution is advised when using acetone during breastfeeding.

Storage

Store in a cool, dry place, away from heat and direct sunlight. Keep tightly closed in original container.

Indications

• Food preservative
• Antioxidant in cosmetics and pharmaceuticals
• Research on oxidative stress

Dosage

Children: Refer to BNF for Children for specific pediatric dosing information.

Adults: Refer to BNF for specific dosing guidelines as it varies based on the formulation and intended use.

Mechanism of action

BHT exhibits a pro-oxidative effect as a phenolic antioxidant, particularly in the presence of initiators like paraquat. It has been shown to chemically donate electrons to paraquat, leading to the generation of reactive oxygen species, which can result in chromosomal damage. This mechanism involves the reduction of paraquat cation to paraquat monocation radical and the subsequent accumulation of oxidative stress in cells.

Pharmacodynamics

As an antioxidant, BHT primarily functions by disrupting lipid peroxidation processes, protecting cellular components from oxidative damage. However, its pro-oxidative actions in combination with certain chemicals may lead to increased oxidative stress and cytotoxicity. The dual role of BHT as both an antioxidant and a pro-oxidant complicates its pharmacodynamic profile, particularly in the context of its interactions with other substances.

Pharmacokinetics

BHT is absorbed in the gastrointestinal tract when ingested, and it is metabolized in the liver. The elimination half-life and metabolic pathways of BHT are not extensively documented, but it is known to undergo biotransformation to various metabolites. The distribution in body tissues can vary based on the dosage and individual metabolism, and it is excreted primarily through urine and feces.

Pregnancy

There are limited data on the use of butylhydroxytoluene (BHT) in pregnancy. It is advised to use caution and consult healthcare professionals before use.

Breast-feeding

Limited information is available regarding the excretion of butylhydroxytoluene in human milk. Caution is recommended when considering use during breastfeeding.

Storage

Store in a cool, dry place away from direct sunlight. Keep container tightly closed.

Formulations

• Food additive
• Cosmetic ingredient

Indications

• Insect repellent for mosquitoes
• Insect repellent for ticks
• Protection against biting insects

Dosage

Children: Refer to BNF for Children for specific dosage guidelines based on age and weight, as recommendations may vary.

Adults: Apply to exposed skin as needed, avoiding contact with eyes and mouth. Reapply after swimming or sweating, and follow product-specific guidance for concentration and frequency of use.

Mechanism of action

The exact mechanism of action of DEET is not fully elucidated, but it is believed to block the olfactory receptors in insects that are sensitive to 1-octen-3-ol, a compound found in human sweat. This blockade disrupts the insects' ability to sense human presence, thereby reducing their biting and feeding behavior. Additionally, DEET has been shown to bind to specific odorant binding proteins and receptors in certain mosquito species, further contributing to its repellent effects.

Pharmacodynamics

When used appropriately, DEET is designed for topical application on human skin to repel insects. At recommended doses, systemic absorption is minimal, which reduces the risk of toxicity. The repellent action primarily works by interfering with insects' sensory perception, leveraging the size and biological differences between humans and insects to create an effective barrier.

Pharmacokinetics

DEET is absorbed through the skin, but the extent of absorption is generally low when applied at recommended concentrations. It is metabolized in the liver, and its metabolites are primarily excreted in urine. The duration of action can vary based on the concentration of DEET used and the environmental conditions during application.

Adverse effects

• Skin irritation
• Allergic reactions
• Headache
• Nausea
• Dizziness

Precautions

• Use with caution in individuals with a history of skin sensitivities
• Avoid application on broken or irritated skin
• Keep away from eyes and mouth

Pregnancy

The safety of diethyltoluamide during pregnancy has not been fully established. Use only if necessary and after consulting a healthcare provider.

Breast-feeding

Caution is advised when using diethyltoluamide while breastfeeding. Consult a healthcare provider before use.

Storage

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

Formulations

• Topical solution
• Spray
• Lotion

Mechanism of action

Dimethylacetamide acts as a solvent that facilitates various biochemical processes. It participates in metabolic pathways where it may enhance the transfer of electrons within the respiratory chain, such as the transfer from NADH to cytochrome bo oxidase and other substrates like succinate and pyruvate.

Pharmacodynamics

Dimethylacetamide exhibits properties that may affect the solubility and bioavailability of drugs. Its role as a solvent can enhance the dissolution of active pharmaceutical ingredients, potentially increasing their effectiveness. However, specific pharmacodynamic effects of dimethylacetamide itself are less characterized in terms of direct physiological impact on human systems.

Pharmacokinetics

The pharmacokinetics of dimethylacetamide, including absorption, distribution, metabolism, and excretion, are not thoroughly documented in clinical literature. As a solvent, it is expected to be absorbed through the skin or lungs and may undergo metabolic processes in the liver. The exact elimination half-life and clearance rates in humans are not well established.

Pregnancy

Safety in pregnancy has not been established. It is advised to avoid use unless clearly needed.

Breast-feeding

Limited data available, exercise caution and consult healthcare professionals.

Storage

Store in a cool, dry place, protected from light. Keep container tightly closed.

Indications

• Flea infestation
• Tick infestation
• Prevention of flea and tick infestations

Dosage

Children: Refer to the BNF for Children for appropriate paediatric dosing information regarding fluralaner.

Adults: Refer to the BNF for specific adult dosing guidelines, as fluralaner dosing may vary based on the weight of the animal and the formulation used.

Mechanism of action

Fluralaner acts as a potent inhibitor of the insect GABA-gated chloride channels and the glutamate-gated chloride channels. By blocking these channels, fluralaner disrupts the normal function of the nervous system in parasites, leading to paralysis and death of the flea and tick species.

Pharmacodynamics

Fluralaner exhibits a high level of selectivity for the target channels found in arthropods, resulting in reduced toxicity to mammals. Its efficacy against fleas and ticks is attributed to its ability to cause rapid paralysis and mortality in these parasites upon exposure.

Pharmacokinetics

Fluralaner is absorbed rapidly after oral administration, reaching peak plasma concentrations within 1-2 days. It has a high volume of distribution and is extensively metabolized in the liver. The elimination half-life ranges from several days to weeks, depending on the species treated. Fluralaner is excreted primarily in feces, with minimal renal excretion.

Adverse effects

• Vomiting
• Diarrhea
• Anorexia
• Lethargy
• Hypersensitivity reactions

Precautions

• Use with caution in animals with a history of seizures
• Not recommended for use in breeding, pregnant, or lactating animals

Pregnancy

Safety during pregnancy has not been established.

Breast-feeding

Safety during lactation has not been established.

Storage

Store at room temperature, protect from moisture and light.

Formulations

• Oral solution
• Topical solution

Indications

• Solvent for poorly soluble drugs
• Enhancement of drug bioavailability in formulations

Dosage

Children: Refer to specific product guidelines for dosing, as glycofurol is primarily used as an excipient and does not have established dosing regimens.

Adults: Refer to specific product guidelines for dosing, as glycofurol is primarily used as an excipient and does not have established dosing regimens.

Mechanism of action

Glycofurol acts as a solvent and stabilizing agent, enhancing the solubility and bioavailability of certain drugs. It does not have a specific pharmacological action on biological targets but rather facilitates the delivery of other active pharmaceutical ingredients through its properties as a solvent.

Pharmacodynamics

As a solvent, glycofurol aids in the dissolution of hydrophobic drugs, improving their absorption and effectiveness. Its role is primarily supportive, enhancing the pharmacological effects of co-administered compounds rather than exhibiting direct therapeutic activity itself.

Pharmacokinetics

Glycofurol is absorbed when administered and is metabolized in the liver. Its elimination half-life and specific metabolic pathways have not been extensively characterized, but it is generally expected to be eliminated via renal pathways. The exact pharmacokinetic profile may vary depending on the formulation and the presence of other active ingredients.

Pregnancy

Glycofurol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. There is insufficient data on its safety in pregnancy.

Breast-feeding

It is unknown whether glycofurol is excreted in human milk. Caution should be exercised when administering to breastfeeding women.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Indications

• Enhanced absorption of poorly soluble drugs
• Improved therapeutic effectiveness of various medications

Dosage

Children: Refer to specific drug formulations for dosing information, as dosages can vary widely based on the active ingredient.

Adults: Refer to specific drug formulations for dosing information, as dosages can vary widely based on the active ingredient.

Mechanism of action

Micronization itself does not alter the pharmacological activity of the drug; rather, it enhances the drug's absorption characteristics. This is particularly significant for drugs that are poorly soluble, as increased absorption can lead to more effective therapeutic outcomes.

Pharmacodynamics

The pharmacodynamics of micronized drugs remain consistent with the pharmacological profile of the active ingredient. Micronized drugs often exhibit enhanced onset of action due to increased absorption rates, leading to quicker therapeutic effects. However, the specific effects will depend on the drug and its mechanism of action.

Pharmacokinetics

Micronization can significantly influence the pharmacokinetics of a drug by improving its absorption in the gastrointestinal tract. This may lead to increased peak plasma concentrations and altered time to peak effect. The elimination half-life and volume of distribution may remain unchanged, but the overall bioavailability may be improved.

Pregnancy

Micronized formulations should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Consultation with a healthcare provider is recommended.

Breast-feeding

Caution is advised when using micronized drugs while breastfeeding. The effects on the infant should be considered, and consultation with a healthcare provider is recommended.

Storage

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

Indications

• Onchocerciasis
• River blindness

Dosage

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

Adults: Refer to the BNF for specific dosing guidelines.

Mechanism of action

Moxidectin selectively binds to the parasite's GABA-A and glutamate-gated chloride ion channels, essential for the functioning of invertebrate nerve and muscle cells. This binding increases the permeability of the cell membranes, allowing an influx of chloride ions, which results in flaccid paralysis of the parasite without directly killing it.

Pharmacodynamics

Moxidectin has shown remarkable efficacy against _Onchocerca volvulus_, demonstrating a superior ability to reduce microfilarial loads in infected individuals compared to ivermectin. The administration of moxidectin leads to a significant decrease in microfilariae levels to undetectable amounts, making it suitable for mass drug administration, while maintaining safety.

Pharmacokinetics

Moxidectin is well absorbed after oral administration with a long half-life, allowing for less frequent dosing compared to other treatments. Its pharmacokinetic profile supports its use in mass treatment strategies for onchocerciasis, although specific parameters such as absorption rate, distribution volume, and elimination route require detailed clinical studies for comprehensive understanding.

Pregnancy

There are no adequate data from the use of moxidectin in pregnant women. Use only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is unknown whether moxidectin is excreted in human breast milk. Caution should be exercised when moxidectin is administered to a nursing woman.

Storage

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

Dosage

Children: Refer to specific drug information for paediatric dosing guidance, as it varies widely depending on the particular nonmicronized drug in question.

Adults: Refer to specific drug information for dosing guidance, as it varies widely depending on the particular nonmicronized drug in question.

Mechanism of action

The mechanism of action for nonmicronized drugs varies widely depending on the specific active pharmaceutical ingredient. Generally, nonmicronized drugs may require higher doses or longer administration times to achieve therapeutic effects due to their larger particle size, which can affect dissolution and absorption rates in the gastrointestinal tract.

Pharmacodynamics

Pharmacodynamics for nonmicronized drugs depends on the specific drug's action on target receptors, enzymes, or ion channels. Many drugs exert their effects through competitive inhibition, receptor activation, or modulation of physiological pathways. The pharmacodynamics can be influenced by the drug's solubility and absorption characteristics, which are altered in nonmicronized forms.

Pharmacokinetics

The pharmacokinetics of nonmicronized drugs typically involve absorption, distribution, metabolism, and excretion processes that may differ from micronized drugs. Nonmicronized drugs may have slower absorption rates due to their larger particle size, potentially leading to a prolonged onset of action. Metabolism and excretion depend on the specific drug's properties, but larger particles may also affect how the drug is processed by the liver and kidneys.

Pregnancy

Safety during pregnancy has not been established. Use only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Caution is advised as it is not known whether the drug is excreted in human milk. Use only if the potential benefit justifies the potential risk to the infant.

Storage

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

Mechanism of action

Pro-oxidative effect of phenolic antioxidant (vitamin E) in combination with the initiators on human low-density lipoprotein is known. /It has been/ reported that oxidative stress induced by vitamin E in combination with the herbicide paraquat enhances structural chromosomal damage in cultured anuran leukocytes. In the present study, the phenolic antioxidant vitamin E-synthetic-analogue 2,6-di-tert-butyl-p-cresol (BHT) in combination with paraquat was found to enhance structural chromosomal damage in cultured Pelophylax (Rana) nigromaculatus leukocytes more than paraquat only and paraquat plus nicotinamido adenine dinucleotido phosphate served as positive control, although BHT only had no effect on induction of structural chromosomal damage. Paraquat plus BHT-enhanced structural chromosomal damage was inhibited by combination of the superoxide dismutase mimic Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin and the hydrogen peroxide scavenger catalase. In test based on reduction of paraquat cation, BHT was found to reduce paraquat cation chemically to paraquat monocation radical. These results suggest that BHT functions in chemically donating electron to paraquat and thereby induces an acute accumulation of reactive oxygen species, resulting in increase in chromosomal damage. Promotion of lung tumors in mice by the food additive butylated hydroxytoluene (BHT) is mediated by electrophilic metabolites produced in the target organ. Identifying the proteins alkylated by these quinone methides (QMs) is a necessary step in understanding the underlying mechanisms. Covalent adducts of the antioxidant enzymes peroxiredoxin 6 and Cu,Zn superoxide dismutase were detected previously in lung cytosols from BALB/c mice injected with BHT, and complimentary in vitro studies demonstrated that QM alkylation causes inactivation and enhances oxidative stress. In the present work, adducts of another protective enzyme, carbonyl reductase (CBR), were detected by Western blotting and mass spectrometry in mitochondria from lungs of mice one day after a single injection of BHT and throughout a 28-day period of weekly injections required to achieve tumor promotion. BHT treatment was accompanied by the accumulation of protein carbonyls in lung cytosol from sustained oxidative stress. Studies in vitro demonstrated that CBR activity in lung homogenates was susceptible to concentration- and time-dependent inhibition by QMs. Recombinant CBR underwent irreversible inhibition during QM exposure, and mass spectrometry was utilized to identify alkylation sites at Cys 51, Lys 17, Lys 189, Lys 201, His 28, and His 204. Except for Lys 17, all of these adducts were eliminated as a cause of enzyme inhibition either by chemical modification (cysteine) or site-directed mutagenesis (lysines and histidines). The data demonstrated that Lys 17 is the critical alkylation target, consistent with the role of this basic residue in NADPH binding. These data support the possibility that CBR inhibition occurs in BHT-treated mice, thereby compromising one pathway for inactivating lipid peroxidation products, particularly 4-oxo-2-nonenal. These data, in concert with previous evidence for the inactivation of antioxidant enzymes, provide a molecular basis to explain lung inflammation leading to tumor promotion in this two-stage model for pulmonary carcinogenesis.

Mechanism of action

The exact mechanism(s) of action by which both (a) insects are repelled by diethyltoluamide (DEET), and (b) humans can be affected deleteriously by exposure to toxic amounts of DEET have not yet been formally elucidated. Research is ongoing regarding the exact mechanism of action by which DEET is capable of repelling insects. However, the most longstanding mechanism proposes that the DEET chemical blocks the olfactory receptors of insects for the volatile 1-octen-3-ol compound that is an element in human sweat and breath. As a consequence, this proposed mechanism suggests that the blockade of insects' senses for this 1-octen-3-ol blinds and prevents the triggering of their biting and/or feeding instinct on humans and other animals that produce that compound. Nevertheless, this theory has not yet been fully elucidated. Furthermore, recent studies have demonstrated that DEET binds to certain molecular targets like the Anopheles gambiae odorant binding protein 1 (AgamOBP1) with high shape complementarity and the antennae-specific odorant receptor CquiOR136 of the southern house mosquito, Culex quinquefasciatus. In southern house mosquitos with reduced CquiOR136 transcript levels, behavioral tests demonstrated that this phenotype showed demonstrably lower responses/repulsion to DEET. Again, however, such findings require continued research and do not formally elucidate the mechanism of action by which DEET can repel insects. And finally, the mechanism of toxicity in which DEET is capable of eliciting effects of neurotoxicity in humans who have been exposed to toxic levels of the agent is also poorly understood. A recent study proposes that DEET is capable of blocking Na+ and K+ channels in the rat animal model. This ion channel blocking activity of DEET in neurons may subsequently contribute to the kind of neuro-sensory adverse effects like numbness experienced after inadvertent application to the lips or mouth of humans. Recent studies suggest that N, N-diethyl-meta-toluamide (DEET) is an acetylcholinesterase inhibitor and that this action may result in neurotoxicity and pose a risk to humans from its use as an insect repellent. We investigated the mode of action of DEET neurotoxicity in order to define the specific neuronal targets related to its acute toxicity in insects and mammals. Although toxic to mosquitoes (LD50 ca. 1.5 ug/mg), DEET was a poor acetylcholinesterase inhibitor (<10% inhibition), even at a concentration of 10 mM. IC50 values for DEET against Drosophila melanogaster, Musca domestica, and human acetylcholinesterases were 6-12 mM. Neurophysiological recordings showed that DEET had excitatory effects on the housefly larval central nervous system (EC50: 120 uM), but was over 300-fold less potent than propoxur, a standard anticholinesterase insecticide. Phentolamine, an octopamine receptor antagonist, completely blocked the central neuroexcitation by DEET and octopamine, but was essentially ineffective against hyperexcitation by propoxur and 4-aminopyridine, a potassium channel blocker. DEET was found to illuminate the firefly light organ, a tissue utilizing octopamine as the principal neurotransmitter. Additionally, DEET was shown to increase internal free calcium via the octopamine receptors of Sf21 cells, an effect blocked by phentolamine. DEET also blocked Na(+) and K(+) channels in patch clamped rat cortical neurons, with IC50 values in the micromolar range. These findings suggest DEET is likely targeting octopaminergic synapses to induce neuroexcitation and toxicity in insects, while acetylcholinesterase in both insects and mammals has low (mM) sensitivity to DEET. The ion channel blocking action of DEET in neurons may contribute to the numbness experienced after inadvertent application to the lips or mouth of humans.

Pharmacodynamics

When used appropriately, diethyltoluamide (DEET) containing products are designed to be applied directly to people's skin as a means to elicit a repelling action to keep insects from targeting human skin. At the amounts and doses recommended for use on human children and adults, noticeable absorption or systemic exposure is not expected. Owing to the proportional difference in size between humans and insects, however, the exposure of insects to the applied DEET (whether topically or via inhalation of DEET) is expected to be enough to interfere with the insects' sensory attraction to human skin.

Mechanism of action

Moxidectin selectively binds to the parasite's GABA-A and glutamate-gated chloride ion channels which are vital for the function of invertebrate nerve and muscle cells. It presents activity against the parasite but it does not kill him. Once moxidectin is bound, there is an increased permeability leading to an influx of chloride ions and flaccid paralysis of the parasite.

Pharmacodynamics

Moxidectin has been reported to be highly effective against _Onchocerca volvulus_ when compared to ivermectin. When moxidectin was administered in infected individuals, the microfilarial load in the skin was lower even when compared to the current therapy, ivermectin. The levels of microfilarial got reduced to an undetectable level while being safe to be used in mass drug administration.