CHERICOF COUGH FORMULA

Indications

• Allergic rhinitis (hay fever)
• Urticaria (hives)
• Allergic conjunctivitis
• Pruritus (itching) associated with allergic reactions
• Common cold symptoms

Dosage

Children: For children, dosing should be determined based on age and weight, and it is recommended to refer to the BNF for Children for specific guidelines.

Adults: For adults, the usual dosage is 4 mg every 4 to 6 hours, not exceeding 24 mg in a 24-hour period.

Mechanism of action

Chlorpheniramine exerts its effects by acting as a competitive antagonist of the H1 histamine receptor. By blocking histamine's action, it alleviates symptoms such as sneezing, itching, and runny nose associated with allergic reactions. Additionally, it has anticholinergic properties, which can contribute to its drying effects on secretions.

Pharmacodynamics

Chlorpheniramine demonstrates a dose-dependent reduction in allergy symptoms by inhibiting histamine-mediated effects. Its anticholinergic activity can also lead to effects such as reduced mucus production and sedation. The drug's effects typically begin within 1 to 2 hours of administration and can last for several hours, depending on the dose and formulation.

Pharmacokinetics

Chlorpheniramine is well absorbed from the gastrointestinal tract, with peak plasma concentrations occurring approximately 2 to 6 hours after oral administration. It is metabolized primarily in the liver via cytochrome P450 enzymes and has a half-life of about 20 hours. The drug is excreted mainly in the urine. Due to its lipophilic nature, chlorpheniramine readily crosses the blood-brain barrier, which accounts for its sedative properties.

Contra-indications

• Hypersensitivity to chlorpheniramine or any of its components
• Severe asthma exacerbation
• Use in neonates or premature infants

Adverse effects

• Drowsiness
• Dizziness
• Dry mouth
• Constipation
• Blurred vision
• Urinary retention
• Tachycardia

Interactions

• Increased sedative effects when taken with alcohol or other CNS depressants
• Anticholinergic effects may be enhanced when used with other anticholinergic drugs
• May interfere with the action of certain medications for Parkinson's disease

Precautions

• Use with caution in patients with glaucoma
• Caution in patients with prostatic hypertrophy
• Caution in patients with cardiovascular diseases
• May impair ability to drive or operate machinery due to sedative effects

Pregnancy

Chlorpheniramine is classified as category B; it should only be used if clearly needed and prescribed by a healthcare provider.

Breast-feeding

Chlorpheniramine is excreted in breast milk and may cause sedation in the nursing infant. Caution is advised.

Storage

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

Formulations

• Tablets
• Syrup
• Extended-release formulations

Indications

• Respiratory conditions (e.g., asthma, chronic obstructive pulmonary disease)
• Cough (e.g., as an antitussive)
• Anxiety and sleep disorders (when associated with specific formulations)

Dosage

Children: Refer to the BNF for Children for appropriate dosing information, as it is determined based on weight and age for the specific formulation.

Adults: Refer to the specific product monograph for dosing information, as it varies based on the drug formulation and indication.

Mechanism of action

Hydrobromides often act as competitive antagonists or agonists at specific receptor sites, depending on the drug involved. The exact mechanism can vary widely, but many hydrobromide-containing drugs modulate neurotransmitter activity, impacting various pathways in the body such as those involved in the central nervous system or respiratory function. The metabolic pathways include Phase I reactions primarily mediated by cytochrome P450 enzymes, which facilitate the functionalization and clearance of these compounds.

Pharmacodynamics

The pharmacodynamics of hydrobromide salts are largely determined by the specific drug they are associated with. Generally, hydrobromides may exhibit effects such as sedation, bronchodilation, or antitussive actions. The efficacy and adverse effects are influenced by the drug's receptor selectivity, affinity, and the pharmacological properties inherent to the parent compound.

Pharmacokinetics

Hydrobromides typically exhibit variable pharmacokinetic profiles depending on the specific drug formulation. They are generally absorbed rapidly following oral administration, with peak plasma concentrations occurring within a few hours. Metabolism primarily occurs in the liver through cytochrome P450 enzymes, particularly CYP2E1, among others. The elimination half-life varies but is often in the range of several hours, allowing for once or twice-daily dosing in many formulations. Excretion is usually via the kidneys, with metabolites being eliminated in urine.

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Use only if clearly needed and the potential benefits justify the potential risks to the fetus.

Breast-feeding

Caution is advised; consider the importance of the drug to the mother against potential risks to the breastfeeding infant.

Storage

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

Indications

• Cough suppression
• Management of dry cough
• Symptomatic relief in upper respiratory tract infections

Dosage

Children: Refer to established guidelines or consult a healthcare professional for appropriate dosing.

Adults: Refer to established guidelines or consult a healthcare professional for appropriate dosing.

Mechanism of action

Maleatedexomethorphan functions as a non-opioid cough suppressant. Its action is believed to be mediated through sigma-1 receptor agonism and interaction with NMDA receptors, which modulates the cough reflex at the level of the brain and spinal cord. This mechanism is thought to result in reduced sensitivity of the cough center to peripheral stimuli, thereby alleviating cough.

Pharmacodynamics

The pharmacodynamic profile of maleatedexomethorphan includes its ability to alter neurotransmitter release in the central nervous system, leading to decreased neuronal excitability and reduced cough reflex. It does not possess the addictive properties of opioids, making it a safer alternative for the management of cough. The onset of action is generally rapid, with effects lasting for several hours, depending on the formulation.

Pharmacokinetics

Maleatedexomethorphan is absorbed well after oral administration, with peak plasma concentrations typically occurring within 1 to 3 hours. It is metabolized primarily in the liver through cytochrome P450 enzymes, particularly CYP2D6, which can exhibit genetic variability among individuals affecting drug metabolism. The elimination half-life can range from 3 to 6 hours, with metabolites excreted mainly in urine. Due to its metabolism, caution is advised in patients with liver impairment or those taking concomitant medications that affect CYP2D6 activity.

Contra-indications

• Hypersensitivity to maleatedexomethorphan or any of its excipients
• Severe respiratory depression
• Persistent cough associated with excessive secretions
• Use in patients taking monoamine oxidase inhibitors (MAOIs) within the last 14 days

Adverse effects

• Dizziness
• Drowsiness
• Nausea
• Vomiting
• Constipation
• Confusion
• Dry mouth
• Headache
• Allergic reactions including rash, itching, and swelling

Interactions

• Increased risk of CNS depression when used with alcohol, sedatives, or tranquilizers
• Potential interactions with other cough suppressants
• May interact with medications that affect CYP450 enzymes

Precautions

• Use with caution in patients with a history of substance abuse
• Caution in patients with a history of respiratory diseases
• Monitor for signs of misuse or overdose
• Caution in elderly patients or those with hepatic impairment

Pregnancy

Limited data is available on the use of maleatedexomethorphan during pregnancy. It should only be used if clearly needed and the benefits outweigh the risks.

Breast-feeding

It is not known whether maleatedexomethorphan is excreted in human breast 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.

Formulations

• Oral syrup
• Tablets
• Capsules

Dosage

Children: Aniline is not indicated for therapeutic use in paediatrics.

Adults: Aniline is not indicated for therapeutic use in adults.

Mechanism of action

Aniline exposure leads to cellular toxicity in the spleen, characterized by iron overload, oxidative stress, and activation of redox-sensitive transcription factors. These changes may regulate genes associated with tumorigenic responses. Specifically, aniline has been shown to induce the proliferation of splenocytes by affecting G1 phase cell cycle proteins, including cyclins and cyclin-dependent kinases (CDKs), ultimately resulting in increased splenocyte proliferation and potential tumorigenesis.

Pharmacodynamics

Aniline's toxic effects are largely mediated through its impact on cellular proliferation and oxidative stress within the spleen. The induction of cyclins D1, D2, D3, and E and the phosphorylation of retinoblastoma protein (pRB) contribute to abnormal cell cycle progression and increased splenocyte proliferation, which are critical factors in aniline's potential carcinogenicity.

Pharmacokinetics

The pharmacokinetics of aniline involve absorption through various routes, including inhalation and dermal exposure, leading to systemic distribution. Metabolism occurs primarily in the liver, where aniline can undergo various biotransformation pathways. Elimination typically occurs through urinary excretion of metabolites. The precise pharmacokinetic parameters, including half-life and volume of distribution, are not well-established, and further studies are needed to delineate these characteristics.

Adverse effects

• Toxicity to the spleen
• Splenomegaly
• Hyperplasia
• Fibrosis
• Sarcomas of the spleen
• Iron overload
• Oxidative stress

Pregnancy

Not established. Use with caution and only if clearly needed.

Breast-feeding

Not established. Caution is advised.

Storage

Store in a cool, dry place, away from light and moisture.

Formulations

• Aniline
• Phenylamine

Mechanism of action

Aniline exposure is associated with toxicity to the spleen leading to splenomegaly, hyperplasia, fibrosis and a variety of sarcomas of the spleen on chronic exposure. In earlier studies, we have shown that aniline exposure leads to iron overload, oxidative stress and activation of redox-sensitive transcription factors, which could regulate various genes leading to a tumorigenic response in the spleen. However, molecular mechanisms leading to aniline-induced cellular proliferation in the spleen remain largely unknown. This study was, therefore, undertaken on the regulation of G1 phase cell cycle proteins (cyclins), expression of cyclin-dependent kinases (CDKs), phosphorylation of retinoblastoma protein (pRB) and cell proliferation in the spleen, in an experimental condition preceding a tumorigenic response. Male SD rats were treated with aniline (0.5 mmol/kg/day via drinking water) for 30 days (controls received drinking water only), and splenocyte proliferation, protein expression of G1 phase cyclins, CDKs and pRB were measured. Aniline treatment resulted in significant increases in splenocyte proliferation, based on cell counts, cell proliferation markers including proliferating cell nuclear antigen (PCNA), nuclear Ki67 protein (Ki67) and minichromosome maintenance (MCM), MTT assay and flow cytometric analysis. Western blot analysis of splenocyte proteins from aniline-treated rats showed significantly increased expression of cyclins D1, D2, D3 and E, as compared to the controls. Similarly, real-time PCR analysis showed significantly increased mRNA expression for cyclins D1, D2, D3 and E in the spleens of aniline-treated rats. The overexpression of these cyclins was associated with increases in the expression of CDK4, CDK6, CDK2 as well as phosphorylation of pRB protein. Our data suggest that increased expression of cyclins, CDKs and phosphorylation of pRB protein could be critical in cell proliferation, and may contribute to aniline-induced tumorigenic response in the spleen. Mechanisms by which aniline exposure elicits splenotoxicity, especially a tumorigenic response, are not well-understood. Earlier, we have shown that aniline exposure leads to oxidative DNA damage and up-regulation of OGG1 and NEIL1/2 DNA glycosylases in rat spleen. However, the contribution of endonuclease III homolog 1 (NTH1) and apurinic/apyrimidinic endonuclease 1 (APE1) in the repair of aniline-induced oxidative DNA damage in the spleen is not known. This study was, therefore, focused on examining whether NTH1 and APE1 contribute to the repair of oxidative DNA lesions in the spleen, in an experimental condition preceding tumorigenesis. To achieve this, male SD rats were subchronically exposed to aniline (0.5 mmol/kg/day via drinking water for 30 days), while controls received drinking water only. By quantitating the cleavage products, the activities of NTH1 and APE1 were assayed using substrates containing thymine glycol (Tg) and tetrahydrofuran, respectively. Aniline treatment led to significant increases in NTH1- and APE1-mediated BER activity in the nuclear extracts of spleen of aniline-treated rats compared to the controls. NTH1 and APE1 mRNA expression in the spleen showed 2.9- and 3.2-fold increases, respectively, in aniline-treated rats compared to the controls. Likewise, Western blot analysis showed that protein expression of NTH1 and APE1 in the nuclear extracts of spleen from aniline-treated rats was 1.9- and 2.7-fold higher than the controls, respectively. Immunohistochemistry indicated that aniline treatment also led to stronger immunoreactivity for both NTH1 and APE1 in the spleens, confined to the red pulp areas. These results, thus, show that aniline exposure is associated with induction of NTH1 and APE1 in the spleen. The increased repair activity of NTH1 and APE1 could be an important mechanism for the removal of oxidative DNA lesions. These findings thus identify a novel mechanism through which NTH1 and APE1 may regulate the repair