Dolutegravir Dispersible Tablets 10mg

Indications

• HIV infection without resistance to other inhibitors of HIV integrase
• HIV infection in patients with resistance to other inhibitors of HIV integrase (specialist use only)

Dosage

Children: Refer to BNF for Children for appropriate dosing.

Adults: 50 mg once daily.

Mechanism of action

Dolutegravir inhibits the HIV integrase enzyme by binding to its active site, blocking the strand transfer step of retroviral DNA integration into the host cell genome. This step is essential for the replication of HIV, and by preventing this integration, dolutegravir effectively inhibits viral activity and replication.

Pharmacodynamics

Clinical trials have demonstrated that dolutegravir leads to a rapid and dose-dependent reduction of HIV-1 RNA in infected subjects. The antiviral response can be sustained for several days following the last dose, indicating its long half-life and strong binding affinity. This characteristic contributes to a high barrier to the development of resistance, making dolutegravir a potent option in combination therapy regimens.

Pharmacokinetics

Dolutegravir exhibits favorable pharmacokinetics, with a mean elimination half-life of approximately 14 hours. It is well absorbed following oral administration, with food enhancing its bioavailability. The drug is metabolized primarily by UGT1A1 and UGT1A9 enzymatic pathways, and it is excreted mainly via feces. Drug interactions may occur, particularly with medications that induce or inhibit UGT enzymes.

Contra-indications

• Hypersensitivity to dolutegravir or any of its excipients

Adverse effects

• Nausea
• Vomiting
• Drowsiness
• Increased weight
• Skin reactions
• Sleep disorders
• Hepatotoxicity
• Pancreatitis
• Osteonecrosis

Interactions

• Moderate increase in exposure with dopaminergic receptor agonists
• Moderate increase in exposure with pramipexole
• Moderate increase in exposure with metformin
• Moderate increase in exposure with atazanavir
• Unknown decrease in exposure with carbamazepine
• Unknown decrease in exposure with oxcarbazepine
• Unknown decrease in exposure with phenytoin
• Unknown decrease in exposure with primidone
• Unknown increase in exposure with encorafenib
• Unknown increase in concentration with fampridine

Precautions

• Use with caution in patients with HIV-1 subtype A6/A1, or BMI of 30 kg/m2 or more
• Caution in severe hepatic impairment
• Patients or carers should be advised on how to recognize signs of hypersensitivity

Pregnancy

Avoid unless potential benefit outweighs risk, no information available.

Breast-feeding

Avoid; may be present in milk for up to 12 months or longer after last prolonged-release injection.

Storage

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

Formulations

• Tablets: 50 mg and 30 mg
• Powder and solvent for solution for injection

Indications

• Digestive aid for individuals with difficulty digesting cellulose-rich foods
• Support for gastrointestinal health
• Use in food processing to enhance fiber breakdown

Dosage

Children: Refer to specific product guidelines or consult a pediatric healthcare professional for appropriate dosing.

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

Mechanism of action

Cellulase works by cleaving the β-1,4-glycosidic bonds in cellulose, resulting in the formation of cellobiose and subsequently glucose. This enzymatic action facilitates the degradation of plant cell walls, leading to the release of fermentable sugars that can be utilized by various organisms and processes.

Pharmacodynamics

Cellulase enhances the digestion and absorption of cellulose-rich foods, improving overall nutrient availability. It aids the breakdown of dietary fibers, which may help alleviate gastrointestinal discomfort and support digestive health. The enzyme's activity is influenced by factors such as pH, temperature, and the presence of other substrates.

Pharmacokinetics

The pharmacokinetics of cellulase have not been extensively studied in humans, as it is generally used as a dietary supplement or in food processing rather than a pharmaceutical agent. When ingested, cellulase is typically active in the gastrointestinal tract, where it acts locally. It is not absorbed into the bloodstream, and its effects are limited to the digestive system.

Adverse effects

• Bloating
• Diarrhea
• Abdominal cramps
• Nausea

Precautions

• Use with caution in patients with gastrointestinal disorders
• Monitor for potential allergic reactions

Pregnancy

Cellulase is generally considered safe during pregnancy, but consult a healthcare provider before use.

Breast-feeding

Cellulase is considered safe during breastfeeding, but it is advisable to consult a healthcare provider prior to use.

Storage

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

Formulations

• Tablets
• Powder
• Capsules

Indications

• Constipation
• Dietary fiber supplementation
• Irritable bowel syndrome
• Diverticular disease
• Weight management

Dosage

Children: Refer to appropriate guidelines for specific dosage; generally taken with adequate fluid intake.

Adults: Refer to appropriate guidelines for specific dosage; generally taken with adequate fluid intake.

Mechanism of action

Cellulose acts primarily as a bulk-forming laxative. It absorbs water in the intestines, which increases stool bulk and stimulates peristalsis, thus facilitating bowel movements. Additionally, cellulose is not digestible by human enzymes, leading to fermentation by gut bacteria, which may enhance gut health and alter gut microbiota composition.

Pharmacodynamics

Cellulose increases stool weight and frequency of bowel movements. It works by retaining water in the intestines, leading to softer stools and improved passage through the gastrointestinal tract. The bulking effect of cellulose can help alleviate constipation and promote overall digestive health. It may also play a role in cholesterol reduction and glycemic control through its effects on digestion and absorption of nutrients.

Pharmacokinetics

Cellulose is not absorbed into the bloodstream due to its indigestible nature. Instead, it passes through the gastrointestinal tract, where it adds bulk to the stool. Its fermentation by colonic bacteria produces short-chain fatty acids, which may have beneficial effects on colon health. The onset of action for cellulose as a laxative can vary but is generally within 24 to 72 hours after ingestion.

Adverse effects

• Bloating
• Flatulence
• Diarrhea
• Abdominal discomfort

Precautions

• Use with caution in patients with a history of gastrointestinal disorders.
• Monitor for potential allergic reactions in sensitive individuals.

Pregnancy

Cellulose is generally considered safe during pregnancy as it is a non-toxic, indigestible fiber.

Breast-feeding

Cellulose is also considered safe during breastfeeding; it is excreted in breast milk in negligible amounts.

Storage

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

Formulations

• Powder
• Capsules
• Tablets
• Granules

Indications

• Cerebral edema
• Elevated intracranial pressure

Mechanism of action

Mannitol elevates blood plasma osmolality, enhancing the flow of water from tissues into interstitial fluid and plasma. This effect reduces cerebral edema and intracranial pressure. It is not reabsorbed in the renal tubule, increasing glomerular filtrate osmolality and promoting diuresis. Mannitol aids in the urinary excretion of toxins and serves as a renal function diagnostic aid by allowing measurement of glomerular filtration rate (GFR). In inhaled form, it is thought to create an osmotic gradient across the airway epithelium, although its exact mechanism in cystic fibrosis treatment is unclear.

Pharmacodynamics

Mannitol is a sugar alcohol, structurally similar to other polyols like xylitol and sorbitol. Its solutions can become acidic due to the loss of a hydrogen ion in water. Mannitol is primarily used as a diuretic to increase urine production and to manage conditions associated with fluid retention, including cerebral edema and glaucoma. It is often co-administered with other diuretics and IV fluids. Caution is advised with inhaled mannitol as it may cause bronchospasm and hemoptysis.

Pharmacokinetics

Mannitol is freely filtered by the glomeruli, with less than 10% being reabsorbed in the renal tubules. Its urinary excretion rate can be used to evaluate glomerular filtration rate (GFR). The drug's pharmacokinetics are influenced by its osmotic properties, which dictate its effects on fluid distribution in the body. Mannitol does not undergo significant metabolism and is excreted unchanged in the urine.

Contra-indications

• Severe renal impairment
• Severe pulmonary congestion
• Anuria
• Cerebral hemorrhage

Adverse effects

• Electrolyte imbalance
• Dehydration
• Hypotension
• Headache
• Nausea
• Vomiting
• Diarrhea
• Thirst
• Pulmonary edema
• Bronchospasm (inhaled form)

Interactions

• May enhance the effects of other diuretics
• Caution with nephrotoxic medications

Precautions

• Monitor renal function during treatment
• Use cautiously in patients with heart failure
• Assess for signs of fluid overload

Pregnancy

Mannitol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is not known whether mannitol is excreted in human milk. Caution should be exercised when administered to a nursing woman.

Storage

Store at room temperature, away from light and moisture. Protect from freezing.

Formulations

• Injectable solution (e.g., 20% mannitol)

Dosage

Children: Refer to specific clinical guidelines for dosing in children, as no standard paediatric dosage is specified in the provided resources.

Adults: Refer to specific clinical guidelines for dosing, as no standard adult dosage is specified in the provided resources.

Mechanism of action

Ethylene glycol toxicity results from its metabolism to glycolic acid and other toxic metabolites. Glycolate accumulates in the body and is eliminated more slowly than ethylene glycol itself. The renal excretion of both compounds plays a crucial role in their elimination, accounting for a significant portion of the administered dose.

Pharmacodynamics

The pharmacodynamics of glycolate are closely tied to its role as a metabolite of ethylene glycol. Its accumulation can lead to metabolic acidosis, although minimal clinical effects have been observed at low doses. The relationship between glycolate and ethylene glycol indicates that glycolate may contribute to the overall toxic effects of ethylene glycol ingestion.

Pharmacokinetics

The pharmacokinetics of glycolate indicate that it reaches peak plasma levels between 4-6 hours after the administration of ethylene glycol. The elimination half-life of ethylene glycol is approximately 1.7 hours in rats and 3.4 hours in dogs. Glycolate is predominantly eliminated through renal excretion, with about 5% of the dose being excreted unchanged.

Pregnancy

There is limited data on the safety of glycolate in pregnancy. Caution is advised.

Breast-feeding

Data on the excretion of glycolate in human milk is not available. Caution is advised.

Storage

Store at room temperature, away from light and moisture.

Indications

• Used as an excipient in tablet formulations
• Used as a bulking agent in capsule formulations
• Used in food products as a thickener or stabilizer

Dosage

Children: Refer to specific product guidelines as dosage will depend on the formulation and the active ingredients.

Adults: Refer to specific product guidelines as dosage will depend on the formulation and the active ingredients.

Mechanism of action

Microcrystalline cellulose acts as a non-digestible filler that enhances the flow properties of powders during the manufacturing of tablets and capsules. It does not have a direct pharmacological action on the body but ensures that the active ingredients are effectively delivered to the patient.

Pharmacodynamics

As a non-active ingredient, microcrystalline cellulose does not exert pharmacodynamic effects typical of active pharmaceutical ingredients. Its primary role is to provide a stable and consistent matrix for the drug, facilitating the release of the active compound once ingested.

Pharmacokinetics

Microcrystalline cellulose is not absorbed in the gastrointestinal tract; it passes through the digestive system largely unchanged. It adds bulk to the stool, which may aid in promoting regular bowel movements. The substance is excreted in feces, where it contributes to dietary fiber intake.

Pregnancy

Data regarding the use of microcrystalline cellulose during pregnancy is limited. It is advisable to consult with healthcare professionals before use.

Breast-feeding

Microcrystalline cellulose is considered safe during breastfeeding, as it is not absorbed systemically.

Storage

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

Indications

• Topical antiseptic for skin disinfection
• Surgical scrubs and hand sanitizers
• Wound care management
• Pharmaceutical excipient in solid and liquid formulations

Dosage

Children: Refer to specific product guidelines for pediatric dosing recommendations, as doses can vary based on formulation and intended use.

Adults: Refer to specific product guidelines for dosing recommendations, as doses can vary based on the formulation and intended use.

Mechanism of action

Povidone acts by forming a complex with iodine when used as an antiseptic, which releases iodine slowly to exert its antimicrobial effect. The iodine disrupts microbial cell walls and interferes with protein synthesis, leading to cell death. Additionally, as a polymer, povidone can enhance drug solubility and stability by forming a hydrophilic matrix.

Pharmacodynamics

Povidone has a broad spectrum of antimicrobial activity against bacteria, viruses, and fungi. Its antiseptic properties are primarily due to the release of iodine, which is effective in reducing microbial load and preventing infection. The polymer's ability to bind to various substances allows it to be utilized in formulations that require improved stability and solubility.

Pharmacokinetics

Povidone is not absorbed systemically when applied topically, as it remains localized at the site of application. Its pharmacokinetics are largely dependent on the formulation and route of administration, with the polymer being metabolized by hydrolysis and excreted in urine as low-molecular-weight compounds. The release and activity of iodine are influenced by the concentration of povidone and the presence of organic matter.

Adverse effects

• Local irritation
• Allergic reactions
• Skin rashes
• Hypersensitivity reactions

Precautions

• Use with caution in patients with known allergies to iodine or povidone-iodine
• Avoid use in deep puncture wounds or serious burns

Pregnancy

Povidone is generally considered safe for use during pregnancy, but it is advisable to consult a healthcare professional before use.

Breast-feeding

Povidone is considered safe during breastfeeding, but it is recommended to consult a healthcare professional.

Storage

Store at room temperature, away from moisture and heat. Keep the container tightly closed.

Formulations

• Topical solution
• Ointment
• Surgical scrub
• Gauze impregnated with povidone-iodine

Dosage

Children: Refer to specific drug formulations and product labels as purified substances can vary widely in their use and dosing.

Adults: Refer to specific drug formulations and product labels as purified substances can vary widely in their use and dosing.

Mechanism of action

The mechanism of action for purified compounds varies widely depending on the specific substance. Generally, purified drugs exert their effects by interacting with specific biological targets, such as receptors, enzymes, or ion channels, leading to a desired therapeutic effect. This interaction can involve binding to receptors to activate or inhibit signaling pathways, modulating enzymatic activity, or altering physiological processes.

Pharmacodynamics

Pharmacodynamics describes the effects of a drug on the body and the relationship between drug concentration and effect. For purified drugs, this can involve dose-response relationships and the time course of their action. The purified form often enhances potency and reduces variability in response among patients, which can lead to more predictable therapeutic outcomes. The overall effect is determined by the drug's affinity for its target, the efficacy of the drug-receptor interaction, and the downstream signaling pathways activated as a result of this interaction.

Pharmacokinetics

Pharmacokinetics involves the absorption, distribution, metabolism, and excretion (ADME) of a drug. For purified substances, absorption can be more efficient due to the absence of impurities that may affect solubility or stability. Distribution may also be enhanced, leading to higher bioavailability. Metabolism can be influenced by the structure of the purified compound, as it may be metabolized more readily by liver enzymes. Excretion typically occurs through the kidneys or liver, depending on the molecular characteristics of the purified drug.

Pregnancy

Consult with a healthcare professional, as the safety of purified forms of medications during pregnancy may vary depending on the specific substance.

Breast-feeding

Consult with a healthcare professional, as the safety of purified forms of medications during breastfeeding may vary depending on the specific substance.

Storage

Store in a cool, dry place, away from light and moisture, and keep out of reach of children.

Indications

• Improvement of flow properties in powder formulations
• Preventing clumping in solid dosage forms
• Management of gastrointestinal disorders

Dosage

Children: Refer to specific formulation guidelines as silicified silica is typically used as an excipient and does not have a defined dosage.

Adults: Refer to specific formulation guidelines as silicified silica is typically used as an excipient and does not have a defined dosage.

Mechanism of action

Silicified silica acts by adsorbing moisture and preventing the clumping of powders. It also has the ability to absorb excess gastric acid, which can aid in the management of certain gastrointestinal conditions.

Pharmacodynamics

Silicified silica does not exert a direct pharmacological effect on body systems but improves the physical properties of pharmaceutical formulations. By promoting better flow and preventing caking, it enhances the bioavailability of active pharmaceutical ingredients (APIs).

Pharmacokinetics

Silica is not absorbed in the gastrointestinal tract and is excreted unchanged. Its pharmacokinetic profile is characterized by its inert nature and lack of systemic absorption, which allows it to function primarily at the site of administration.

Pregnancy

There is limited data on the use of silicified in pregnancy. Consult a healthcare provider before use.

Breast-feeding

It is unknown whether silicified is excreted in human milk. Caution is advised when administering to breastfeeding mothers.

Storage

Store in a tightly closed container, protected from moisture and light.

Indications

• Nutritional supplementation
• Energy source in enteral nutrition
• Excipient in pharmaceutical formulations

Dosage

Children: Refer to specific guidelines or product inserts for dosing information, as it can vary based on the context of use.

Adults: Refer to specific guidelines or product inserts for dosing information, as it can vary based on the context of use.

Mechanism of action

Starch is broken down into glucose units by enzymes such as amylase during digestion. The glucose is then absorbed in the intestines and utilized for energy production in the body's cells. This pathway involves hydrolysis of the glycosidic bonds, converting starch into simpler sugars.

Pharmacodynamics

Starch primarily serves as an energy source. Its digestion and absorption lead to an increase in blood glucose levels, which provides energy for metabolic processes. In this context, it plays a crucial role in maintaining energy homeostasis in the body.

Pharmacokinetics

Starch is not absorbed in its polymeric form; it must first be enzymatically hydrolyzed into simpler sugars such as maltose and glucose. The digestion and absorption of starch occur predominantly in the small intestine, with glucose being readily absorbed into the bloodstream. The rate of absorption can vary depending on the type of starch and its physical form.

Adverse effects

• Allergic reactions
• Gastrointestinal discomfort
• Diarrhea
• Constipation

Precautions

• Use with caution in individuals with known allergies to starch or starch derivatives
• Monitor for gastrointestinal symptoms in patients with a history of digestive disorders

Pregnancy

Starch is generally considered safe for use during pregnancy. However, it should be consumed in moderation as part of a balanced diet.

Breast-feeding

Starch is deemed safe for nursing mothers when used in moderation as part of a balanced diet.

Storage

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

Formulations

• Powder
• Granules
• Tablets
• Suspensions

Indications

• Dry skin conditions
• Cosmetic formulations
• Emollient in topical creams and lotions
• Emulsifying agent in pharmaceutical preparations

Dosage

Children: For pediatric use, refer to specific product formulations and guidelines, as dosing may vary based on the formulation and concentration.

Adults: Stearyl alcohol is used topically in various formulations. Specific dosing is typically determined by the formulation and intended use, refer to product guidelines for detailed instructions.

Mechanism of action

Stearyl alcohol functions primarily as an emollient and emulsifier. It aids in the formation of stable emulsions by reducing the surface tension between oil and water phases, allowing for the creation of creams and lotions. Its hydrophobic tail interacts with lipids, while the hydroxyl group can form hydrogen bonds with water, enhancing moisture retention in the skin.

Pharmacodynamics

Stearyl alcohol acts by providing a protective barrier on the skin, reducing transepidermal water loss and enhancing hydration. Its emollient properties make it effective in softening and smoothing the skin, which can alleviate dryness and improve the overall appearance of the skin. Additionally, it can enhance the delivery of other active ingredients in topical formulations.

Pharmacokinetics

Stearyl alcohol is not significantly absorbed systemically when applied topically. Its primary action is local to the site of application, where it exerts its emollient effects. The compound is metabolized in the body to various fatty acids and alcohols, and it is excreted primarily through the skin and gastrointestinal tract, with minimal systemic exposure.

Pregnancy

Stearyl is generally considered safe for use during pregnancy; however, specific formulations should be evaluated for their ingredients.

Breast-feeding

Stearyl can be used while breastfeeding, but it's recommended to consult a healthcare provider for specific concerns regarding topical applications.

Storage

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

Formulations

• Cream
• Ointment
• Lotion

Indications

• Nutritional supplementation
• Antioxidant support
• Heart health
• Anti-inflammatory properties
• Skin health
• Digestive health

Dosage

Children: As strawberries are generally safe and nutritious, they can be introduced to children as part of a healthy diet. Portion sizes should be age-appropriate, and whole strawberries should be cut to prevent choking hazards in younger children.

Adults: Strawberries can be consumed as part of a balanced diet. Recommended servings vary, but a common suggestion is about one cup of fresh strawberries daily to obtain health benefits.

Mechanism of action

The health benefits of strawberries can be attributed to their high content of polyphenols, particularly anthocyanins, which have antioxidant properties. These compounds may help reduce oxidative stress and inflammation in the body, potentially lowering the risk of chronic diseases. The vitamins and minerals present in strawberries, such as vitamin C and manganese, also play essential roles in various metabolic processes.

Pharmacodynamics

Strawberries exhibit multiple pharmacodynamic effects. The antioxidants in strawberries help neutralize free radicals, which can prevent cellular damage and reduce the risk of chronic diseases. Additionally, the fiber content aids in digestive health and may help regulate blood sugar levels, while the anti-inflammatory properties can support cardiovascular health and contribute to overall wellness.

Pharmacokinetics

The bioavailability of nutrients from strawberries can vary based on factors like preparation and individual metabolism. Vitamins such as vitamin C are readily absorbed in the gastrointestinal tract. The various phytonutrients, including flavonoids, are metabolized in the liver, where they can exert their beneficial effects on health. The absorption and metabolism of these compounds can be influenced by factors such as the presence of other foods and individual digestive health.

Adverse effects

• Allergic reactions (e.g., skin rash, itching)
• Gastrointestinal upset (e.g., diarrhea, nausea)

Precautions

• Monitor for allergic reactions in individuals with known sensitivities to strawberries
• Use with caution in individuals with oxalate kidney stones due to high oxalate content

Pregnancy

Strawberries are generally considered safe to consume during pregnancy as they provide essential nutrients and hydration.

Breast-feeding

Strawberries can be consumed during breastfeeding. However, monitor for any signs of allergy in the infant, especially if there is a family history of food allergies.

Storage

Store strawberries in a cool, dry place. Refrigeration can help extend freshness, ideally in a breathable container to prevent mold.

Formulations

• Fresh strawberries
• Frozen strawberries
• Strawberry puree
• Strawberry juice
• Strawberry jams and preserves

Indications

• Caloric reduction in food and beverages
• Management of diabetes
• Weight management

Dosage

Children: Refer to the BNF for Children for specific guidelines on the use of sucralose in pediatric populations.

Adults: Sucralose is typically used in food and beverage products as a sweetener. There are no specific dosage recommendations for adults, as it is used according to taste preference and product formulation.

Mechanism of action

Sucralose acts as a positive allosteric modulator of the human sweet taste receptor. It interacts with the T1R taste receptor family, particularly enhancing the sweetness perception by binding to the hinge region of the receptor. This interaction induces a conformational change that stabilizes the active state of the receptor, increasing its responsiveness to sweet stimuli. This mechanism allows sucralose to mimic the taste of sugar without the associated caloric intake.

Pharmacodynamics

As a non-nutritive sweetener, sucralose does not undergo metabolic processing in the body, which means it does not contribute to energy intake. It provides intense sweetness at low concentrations, stimulating the sweetness receptors in the taste buds. The pharmacodynamic profile indicates minimal physiological effects beyond taste perception, making it suitable for dietary use without impacting blood glucose levels.

Pharmacokinetics

Sucralose is poorly absorbed in the gastrointestinal tract, with an estimated absorption rate of less than 15%. The majority of ingested sucralose is excreted unchanged in the urine. The elimination half-life is not well defined due to its minimal absorption, but it is generally considered to have a rapid clearance from the body. The pharmacokinetic properties support its use as a safe alternative to sugar for those managing caloric intake.

Pregnancy

Sucralose is generally considered safe during pregnancy, but it is recommended to consult a healthcare provider.

Breast-feeding

Sucralose is also considered safe during breastfeeding, although it is advisable to seek medical advice.

Storage

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

Formulations

• Granulated sucralose
• Liquid sucralose
• Tablets

Mechanism of action

Dolutegravir is an HIV-1 antiviral agent. It inhibits HIV integrase by binding to the active site and blocking the strand transfer step of retroviral DNA integration in the host cell. The strand transfer step is essential in the HIV replication cycle and results in the inhibition of viral activity. Dolutegravir has a mean EC50 value of 0.5 nM (0.21 ng/mL) to 2.1 nM (0.85 ng/mL) in peripheral blood mononuclear cells (PBMCs) and MT-4 cells. Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral deoxyribonucleic acid (DNA) integration which is essential for the HIV replication cycle. Strand transfer biochemical assays using purified HIV-1 integrase and pre-processed substrate DNA resulted in IC50 values of 2.7 nM and 12.6 nM.

Pharmacodynamics

HIV-1 infected subjects on dolutegravir monotherapy demonstrated rapid and dose-dependent reduction of antiviral activity with declines of HIV-1 RNA copies per ml. The antiviral response was maintained for 3 to 4 days after the last dose. The sustained response obtained in clinical trials indicates that dolutegravir has a tight binding and longer dissociative half-life providing it a high barrier to resistance. The combination therapy (ripivirine and dolutegravir) presented the same viral suppression found in previous three-drug therapies without integrase strand transfer inhibitor mutations or rilpivirine resistance.

Mechanism of action

Mannitol is an osmotic diuretic that is metabolically inert in humans and occurs naturally, as a sugar or sugar alcohol, in fruits and vegetables. Mannitol elevates blood plasma osmolality, resulting in enhanced flow of water from tissues, including the brain and cerebrospinal fluid, into interstitial fluid and plasma. As a result, cerebral edema, elevated intracranial pressure, and cerebrospinal fluid volume and pressure may be reduced. As a diurectic mannitol induces diuresis because it is not reabsorbed in the renal tubule, thereby increasing the osmolality of the glomerular filtrate, facilitating excretion of water, and inhibiting the renal tubular reabsorption of sodium, chloride, and other solutes. Mannitol promotes the urinary excretion of toxic materials and protects against nephrotoxicity by preventing the concentration of toxic substances in the tubular fluid. As an Antiglaucoma agent mannitol levates blood plasma osmolarity, resulting in enhanced flow of water from the eye into plasma and a consequent reduction in intraocular pressure. As a renal function diagnostic aid mannitol is freely filtered by the glomeruli with less than 10% tubular reabsorption. Therefore, its urinary excretion rate may serve as a measurement of glomerular filtration rate (GFR). The exact mechanism of action of inhaled mannitol in the symptomatic maintenance treatment of cystic fibrosis remains unclear. It is hypothesized that mannitol produces an osmotic gradient across the airway epithelium that draws fluid into the extracellular space and alters the properties of the airway surface mucus layer, allowing easier mucociliary clearance. MANNITOL IS.../USED/ IN PROPHYLAXIS OF ACUTE RENAL FAILURE. IT IS USED FOR THIS PURPOSE IN CONDITIONS AS DIVERSE AS CARDIOVASCULAR OPERATIONS, SEVERE TRAUMATIC INJURY, OPERATIONS IN THE PRESENCE OF SEVERE JAUNDICE, AND MGMNT OF HEMOLYTIC TRANSFUSION REACTIONS. IN EACH OF THESE CONDITIONS, A PRECIPITOUS FALL IN THE FLOW OF URINE MAY BE ANTICIPATED EITHER AS THE RESULT OF AN ACUTELY REDUCED FILTRATION RATE OR FROM ACUTE CHANGES IN TUBULAR PERMEABILITY. THE LATTER MAY BE CONSEQUENCE OF THE PRESENCE OF NOXIOUS AGENT WITHIN THE TUBULAR FLUID IN EXCESSIVELY HIGH CONCN, IN SOME INSTANCES SUFFICIENT TO RESULT IN ACTUAL PRECIPITATION. IN THESE SITUATIONS, MANNITOL EXERTS OSMOTIC EFFECT WITHIN THE TUBULAR FLUID, INHIBITS WATER REABSORPTION, & MAINTAINS THE RATE OF URINE FLOW. ...CONCN OF TOXIC AGENT WITHIN TUBULAR FLUID DOES NOT REACH EXCESSIVELY HIGH LEVELS THAT OTHERWISE WOULD HAVE BEEN ACHIEVED BY MORE COMPLETE REABSORPTION OF WATER. ...EVEN THOUGH /GLOMERULAR/ FILTRATION RATE IS REDUCED, MANNITOL IS STILL FILTERED @ GLOMERULUS. THE TUBULAR IMPERMEABILITY TO MANNITOL IS NOT ALTERED BY ACUTE RENAL ISCHEMIA OF SHORT DURATION. HENCE, THE MANNITOL THAT IS FILTERED IS ALSO EXCRETED IN THE VOIDED URINE. UNREABSORBED SOLUTE LIMITS BACK DIFFUSION OF WATER. ...URINE VOL CAN BE MAINTAINED EVEN IN PRESENCE OF DECR GLOMERULAR FILTRATION.

Pharmacodynamics

Chemically, mannitol is an alcohol and a sugar, or a polyol; it is similar to xylitol or sorbitol. However, mannitol has a tendency to lose a hydrogen ion in aqueous solutions, which causes the solution to become acidic. For this reason, it is not uncommon to add a substance to adjust its pH, such as sodium bicarbonate. Mannitol is commonly used to increase urine production (diuretic). It is also used to treat or prevent medical conditions that are caused by an increase in body fluids/water (e.g., cerebral edema, glaucoma, kidney failure). Mannitol is frequently given along with other diuretics (e.g., furosemide, chlorothiazide) and/or IV fluid replacement. Inhaled mannitol has the possibility to cause bronchospasm and hemoptysis; the occurrence of either should lead to discontinuation of inhaled mannitol.

Mechanism of action

Ethylene glycol toxicity results from its metabolism to glycolic acid and other toxic metabolites. The accumulation of glycolate and the elimination kinetics of ethylene glycol and its metabolites are not well understood, so studies with male Sprague-Dawley rats and mixed breed dogs have been carried out. Ethylene glycol was administered by gavage to rats and dogs which were placed in metabolic cages for urine and blood sample collection at timed intervals. The peak plasma level of ethylene glycol occurred at 2 hr after dosing and that of glycolate between 4-6 hr. The rate of ethylene glycol elimination was somewhat faster in rats with a half-life of 1.7 hr compared to 3.4 hr in dogs. The maximum plasma level of glycolate was greater in rats although the pattern of accumulation was similar to that in dogs. Glycolate disappeared from the plasma at the same time as ethylene glycol, suggesting a slower rate of elimination of the metabolite than that of ethylene glycol. Renal excretion of ethylene glycol was an important route for its elimination accounting for 20-30% of the dose. Renal excretion of glycolate represented about 5% of the dose. Ethylene glycol induced an immediate, but short lived diuresis compared to that in control rats. Minimal clinical effects (mild acidosis with no sedation) were noted at these doses of ethylene glycol (1-2 g/kg) in both rats and dogs. The results indicate that the toxicokinetics of ethylene glycol and glycolate were similar in both species. The effect of 0.35 to 0.8 mmol/kg glycolic acid and 1.0 to 4.4 mmol/kg sodium glycolate on cyclopropane-epinephrine induced cardiac arrhythmias was examined using dogs. Doses of 0.35 to 0.5 mmol/kg glycolic acid increased the duration of arrhythmias in the 13 dogs tested, whereas doses >0.5 mmol/kg decreased or totally eliminated the arrhythmias in each of 11 dogs. Depression was observed for many of the dogs at higher doses. Sodium glycolate was much less effective in decreasing the arrhythmias, with 3 mmol/kg being required and its action being transient.

Mechanism of action

Positive allosteric modulators of the human sweet taste receptor ...developed as a new way of reducing dietary sugar intake .../can be used as/ ...valuable tool molecules to study the general mechanism of positive allosteric modulations of T1R taste receptors. Using chimeric receptors, mutagenesis, and molecular modeling, .../the study/ reveal how ...sweet enhancers follow a similar mechanism as the natural umami taste enhancer molecules. Whereas the sweeteners bind to the hinge region and induce the closure of the Venus flytrap domain of T1R2, the enhancers bind close to the opening and further stabilize the closed and active conformation of the receptor.