VIR 116

Indications

• Vascular health
• Oxidative stress-related conditions
• Anti-aging applications
• Inflammatory disorders

Dosage

Children: Refer to the BNF for Children for pediatric dosing information regarding hydrogen-rich water.

Adults: Refer to the BNF for specific dosages and administration guidelines for hydrogen-rich water.

Mechanism of action

Molecular hydrogen exerts its effects primarily through its antioxidant properties, which involve the activation of the Nrf2 pathway. This pathway regulates the expression of various antioxidant enzymes, thereby reducing oxidative stress and inflammation. In endothelial cells, H2 has been shown to prevent TCDD-induced senescence and promote cellular longevity by maintaining cellular homeostasis and modulating redox status.

Pharmacodynamics

The pharmacodynamics of dihydrogen are characterized by its ability to scavenge free radicals and reduce oxidative stress. It also influences cellular signaling pathways related to inflammation and aging. Specifically, H2 aids in maintaining the balance of NAD+/NADH, which is crucial for cellular metabolism and energy production. The modulation of the Nrf2 pathway leads to enhanced production of endogenous antioxidants, contributing to its protective effects on vascular endothelial cells.

Pharmacokinetics

Dihydrogen is rapidly absorbed and distributed in the body. When administered as hydrogen-rich water, it is absorbed through the gastrointestinal tract. Its concentration decreases over time, becoming nearly undetectable after 12 hours in aqueous solutions. The pharmacokinetic profile indicates that the effects of hydrogen may persist even after the gas has been eliminated, likely due to the activation of protective cellular mechanisms.

Pregnancy

There is insufficient data on the use of dihydrogen during pregnancy. Consult a healthcare provider for guidance.

Breast-feeding

Limited information is available regarding the safety of dihydrogen during breastfeeding. Consult a healthcare provider before use.

Storage

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

Formulations

• Hydrogen-rich water

Indications

• Electrolyte replacement
• Volume expansion in hypovolemic patients
• Management of hyponatremia
• Support in intravenous fluid therapy

Dosage

Children: Refer to the BNF for Children for appropriate dosing in paediatric patients, as dosages may vary based on the formulation and clinical condition.

Adults: Refer to specific product information or clinical guidelines for dosage recommendations, as disodium is often part of combination products.

Mechanism of action

Disodium compounds often function by providing sodium ions that are essential for various physiological processes. Sodium ions play a critical role in maintaining osmotic balance, nerve impulse transmission, and muscle contraction. In the context of intravenous solutions, disodium helps to restore electrolyte balance in patients.

Pharmacodynamics

The pharmacodynamics of disodium is primarily related to its role in electrolyte balance and fluid homeostasis. Sodium ions are vital for the function of excitable tissues, including neurons and muscle cells. Changes in sodium levels can affect blood pressure, hydration status, and overall cellular function.

Pharmacokinetics

The pharmacokinetics of disodium compounds depend on their specific formulation and route of administration. When administered intravenously, disodium is rapidly distributed in the extracellular fluid, where it helps to maintain osmotic pressure. Sodium is primarily excreted by the kidneys, and its levels can be influenced by fluid intake, dietary sodium, and renal function.

Pregnancy

Use with caution. Consult a healthcare provider for specific guidance.

Breast-feeding

Use with caution. Consult a healthcare provider for specific guidance.

Storage

Store at room temperature, away from moisture and direct sunlight.

Indications

• Severe infections caused by Gram-negative bacteria
• Urinary tract infections
• Bacteremia
• Sepsis
• Pneumonia
• Intra-abdominal infections
• Skin and soft tissue infections

Dosage

Adults: The usual dosage for adults is 3 to 5 mg/kg/day divided into 3 doses, given intravenously or intramuscularly. Adjustments should be made based on renal function and severity of infection.

Mechanism of action

Gentamicin acts by binding to the bacterial 30S ribosomal subunit, leading to misreading of mRNA and subsequent production of nonfunctional or toxic peptides. This disrupts protein synthesis and leads to bacterial cell death. The drug enters bacterial cells in a three-phase process: first, ionic binding occurs with the cell membrane, increasing permeability. Second, energy-dependent transport allows the drug to access its intracellular target. Third, concentration-dependent killing is observed as gentamicin accumulates within the cell, amplifying its effects on protein synthesis and membrane integrity.

Pharmacodynamics

Gentamicin exhibits concentration-dependent bactericidal activity, meaning that its efficacy increases with higher concentrations. The pharmacodynamic properties highlight the rapid and delayed bactericidal effects, with membrane disruption occurring immediately followed by impaired protein synthesis. The drug's action is particularly effective against aerobic Gram-negative bacteria, while its effectiveness is significantly reduced in anaerobic conditions.

Pharmacokinetics

Gentamicin is poorly absorbed from the gastrointestinal tract; thus, it is typically administered intravenously or intramuscularly. It has a volume of distribution that reflects extensive tissue penetration, particularly in renal and gastrointestinal tissues. The elimination half-life ranges from 2 to 3 hours in healthy individuals, but it can be prolonged in patients with renal impairment. The drug is primarily eliminated by renal excretion, with dosage adjustments required in cases of renal dysfunction.

Contra-indications

• Hypersensitivity to gentamicin or other aminoglycosides
• Severe renal impairment
• Myasthenia gravis

Adverse effects

• Nephrotoxicity
• Ototoxicity (hearing loss, balance disorders)
• Neuromuscular blockade
• Allergic reactions (rash, pruritus)
• Peripheral neuropathy

Interactions

• Increased risk of nephrotoxicity with other nephrotoxic agents (e.g., cisplatin, vancomycin)
• Increased risk of ototoxicity with loop diuretics (e.g., furosemide)
• Synergistic effects with beta-lactam antibiotics

Precautions

• Monitor renal function during treatment
• Use caution in patients with pre-existing hearing loss
• Adjust dosage in patients with renal impairment
• Consider potential drug interactions

Pregnancy

Gentamicin should be used during pregnancy only if clearly needed, due to potential risk of fetal harm.

Breast-feeding

Gentamicin is excreted in breast milk, but is generally considered safe. Monitor for possible effects on the infant.

Storage

Store in a cool, dry place, away from light. Do not refrigerate or freeze.

Formulations

• Injection (solution for injection)
• Topical ointment
• Eye drops

Indications

• Oxidative stress-related conditions
• Inflammatory conditions
• Potential anti-aging applications
• Vascular health enhancement

Dosage

Children: Refer to specific product formulations and guidelines, as dosing can vary based on the concentration of hydrogen in the product used.

Adults: Refer to specific product formulations and guidelines, as dosing can vary based on the concentration of hydrogen in the product used.

Mechanism of action

Molecular hydrogen acts primarily as an antioxidant and anti-inflammatory agent. It is believed to exert its beneficial effects through the activation of the Nrf2 pathway, which enhances the expression of antioxidant enzymes and protects cells from oxidative stress. Hydrogen-rich environments have been shown to mitigate the harmful effects of various toxins on human umbilical vein endothelial cells, thereby promoting vascular health and longevity.

Pharmacodynamics

Hydrogen's pharmacodynamic properties are linked to its role as a potent antioxidant, which reduces reactive oxygen species (ROS) and modulates inflammation. It has been documented to counteract cellular senescence in endothelial cells, thereby maintaining vascular integrity and promoting overall health. The long-lasting effects of hydrogen exposure can be observed even after its concentration in the medium has decreased, suggesting a sustained activation of protective cellular pathways.

Pharmacokinetics

Hydrogen is a gaseous molecule that diffuses rapidly across biological membranes. Its absorption and distribution in the body are influenced by the method of administration, with hydrogen-rich water being a common delivery form. Once in the bloodstream, hydrogen is quickly utilized by tissues, and its concentration diminishes rapidly, with a half-life that can vary based on conditions. The elimination of hydrogen primarily occurs via exhalation, making it a non-toxic molecule with a favorable safety profile.

Pregnancy

Hydrogen is generally considered safe during pregnancy, but it is advisable to consult a healthcare provider for specific recommendations.

Breast-feeding

Hydrogen is considered safe during breastfeeding, but as with any substance, it is recommended to discuss with a healthcare provider.

Storage

Hydrogen should be stored in a cool, dry place away from direct sunlight and heat sources, in appropriate gas cylinders designed for compressed gases.

Formulations

• Hydrogen gas (H2)
• Hydrogen-rich water

Mechanism of action

Hydrogenphosphate acts as a substrate for various enzymatic reactions where phosphate groups are transferred or incorporated into organic molecules. It is involved in metabolic pathways such as nicotine biosynthesis and NAD/NADH cycling, facilitating biochemical reactions that are vital for cellular function.

Pharmacodynamics

Hydrogenphosphate is crucial for maintaining cellular homeostasis. It regulates acid-base balance and is involved in energy metabolism. The phosphate groups it provides are integral to the structure and function of ATP, which is the primary energy currency of the cell. Additionally, hydrogenphosphate influences signal transduction pathways through phosphorylation and dephosphorylation processes.

Pharmacokinetics

Hydrogenphosphate is readily absorbed in the gastrointestinal tract and distributed throughout the body. Its elimination primarily occurs through renal excretion, where it is filtered and reabsorbed by the kidneys. The balance of hydrogenphosphate levels is tightly regulated by various physiological mechanisms to ensure proper metabolic function.

Pregnancy

There is limited information regarding the safety of hydrogenphosphate in pregnancy. Consult relevant guidelines and consider potential risks versus benefits.

Breast-feeding

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

Storage

Store in a cool, dry place away from direct sunlight. Ensure containers are tightly closed.

Indications

• Nutritional support in malnourished patients
• Post-operative recovery
• Management of malabsorption syndromes
• Support in conditions requiring enhanced protein intake

Dosage

Children: Refer to the BNF for Children for dosing recommendations.

Adults: Refer to specific formulations and BNF guidelines for appropriate dosing.

Mechanism of action

Hydrolysates increase the availability of amino acids and peptides for absorption in the intestines. The smaller size of these molecules compared to whole proteins facilitates their transport across the intestinal wall, allowing for quicker and more effective utilization by the body. This mechanism is particularly beneficial in patients with compromised digestive capabilities.

Pharmacodynamics

The pharmacodynamic effects of hydrolysates involve the supply of essential and non-essential amino acids, which are crucial for various metabolic processes, including protein synthesis, neurotransmitter production, and immune function. The rapid absorption of these peptides can lead to quicker recovery times in malnourished individuals or those undergoing surgical recovery.

Pharmacokinetics

Hydrolysates are rapidly absorbed in the gastrointestinal tract, with peak plasma concentrations occurring shortly after ingestion. The bioavailability of amino acids from hydrolysates is generally higher than that of intact proteins due to their smaller molecular size. The metabolism of amino acids occurs primarily in the liver, where they can be utilized for energy production or incorporated into new proteins. The elimination of amino acids happens through renal pathways, with excess being excreted in urine.

Pregnancy

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

Breast-feeding

It is not known if hydrolysate is excreted in human 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.

Indications

• Nutritional supplementation
• Support for muscle growth and recovery
• Infant nutrition in formulas
• Immune system support

Dosage

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

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

Mechanism of action

Lactalbumin provides essential amino acids that are crucial for protein synthesis in the body. It is rapidly absorbed and utilized by muscle tissues, contributing to muscle repair and growth. The presence of certain bioactive peptides in lactalbumin may also enhance immune response and promote overall health.

Pharmacodynamics

Lactalbumin has been shown to have various beneficial effects on the body, including enhancing muscle protein synthesis, improving recovery from exercise, and supporting immune health. The amino acids, particularly branched-chain amino acids, play a significant role in stimulating muscle protein synthesis and reducing muscle breakdown.

Pharmacokinetics

Lactalbumin is absorbed in the gastrointestinal tract following ingestion. The amino acids are then distributed throughout the body and utilized for various metabolic processes, including protein synthesis. The half-life and clearance rates vary depending on the individual's metabolic state and activity levels.

Adverse effects

• Allergic reactions
• Gastrointestinal disturbances
• Nausea
• Vomiting

Precautions

• Use with caution in patients with known allergies to milk or milk products
• Monitor for allergic reactions in sensitive individuals

Pregnancy

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

Breast-feeding

Lactalbumin can be used during breastfeeding; however, any concerns regarding allergies should be discussed with a healthcare provider.

Storage

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

Formulations

• Powder
• Liquid

Indications

• Lactose intolerance
• As a filler or excipient in pharmaceutical formulations

Dosage

Children: Refer to the BNF for Children for specific dosing information based on age and clinical context.

Adults: Refer to the BNF for specific dosing information based on clinical context.

Mechanism of action

Lactose is metabolized in the intestine by the enzyme lactase into its constituent monosaccharides, glucose and galactose. In individuals with lactase deficiency, unabsorbed lactose passes into the colon, where it is fermented by bacteria, leading to gas production and osmotic effects that contribute to diarrhea.

Pharmacodynamics

The pharmacodynamics of lactose are primarily related to its effects on gastrointestinal function. In healthy individuals, lactose is effectively broken down into glucose and galactose, which are absorbed and utilized for energy. In individuals with lactose intolerance, the unabsorbed lactose can cause osmotic diarrhea and colonic fermentation, leading to discomfort and symptoms associated with lactose intolerance.

Pharmacokinetics

Lactose is not absorbed in the gastrointestinal tract until it is hydrolyzed into glucose and galactose by lactase. The absorption of glucose and galactose occurs in the small intestine. The half-life is not applicable as lactose is not typically administered as a medication but is rather ingested as a natural component of food. Its metabolism primarily occurs in the intestine.

Adverse effects

• Bloating
• Diarrhea
• Abdominal pain
• Flatulence

Precautions

• Use with caution in patients with lactose intolerance.
• Consider potential for gastrointestinal upset in sensitive individuals.

Pregnancy

Lactose is generally considered safe for use during pregnancy. However, consult a healthcare professional for individual advice.

Breast-feeding

Lactose is safe to use while breastfeeding, as it is a natural sugar present in breast milk.

Storage

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

Formulations

• Powder
• Granules
• Tablets
• Syrup

Indications

• Type 2 diabetes mellitus
• Management of hyperglycemia in patients with type 2 diabetes
• Weight management in patients with type 2 diabetes

Dosage

Children: Refer to the BNF for Children for appropriate dosing in pediatric patients.

Adults: Refer to specific clinical guidelines or the BNF for tailored dosing information.

Mechanism of action

Lantogenic works by binding to GLP-1 receptors on pancreatic beta cells, which stimulates insulin secretion in a glucose-dependent manner. It also suppresses glucagon release, slows gastric emptying, and promotes satiety, contributing to reduced appetite and caloric intake.

Pharmacodynamics

The pharmacodynamics of lantogenic involve its ability to enhance insulin sensitivity and lower blood glucose levels following meals. It achieves this by increasing insulin secretion and decreasing glucagon levels, which in turn reduces hepatic glucose production. Additionally, it influences gastrointestinal motility, leading to prolonged gastric emptying time, which helps in controlling postprandial glucose spikes.

Pharmacokinetics

Lantogenic is administered subcutaneously and has a relatively long half-life due to its resistance to enzymatic degradation. It is absorbed into the systemic circulation, with peak plasma concentrations occurring approximately 2-4 hours post-injection. The drug is primarily metabolized by proteolytic enzymes, with renal excretion being the main route of elimination. The pharmacokinetic profile allows for once-weekly dosing in many formulations.

Pregnancy

Not enough evidence is available to classify the safety of lantogenic use during pregnancy. Consult healthcare providers for guidance.

Breast-feeding

Insufficient data exists regarding the excretion of lantogenic in human milk. Caution is advised when administering to breastfeeding women.

Storage

Store at room temperature, away from light and moisture. Ensure the medication is kept out of reach of children.

Indications

• Measles
• Mumps
• Rubella
• Varicella (chickenpox)
• Yellow fever
• Rotavirus
• Intranasal influenza

Dosage

Children: Refer to the BNF for Children for specific dosing information based on age and vaccine type.

Adults: Refer to specific product guidelines for dosing information, as it can vary by vaccine type and brand.

Mechanism of action

Live vaccines work by introducing a weakened or attenuated form of a pathogen into the body. This stimulates the immune system to recognize and respond to the pathogen, leading to the production of antibodies and memory cells that provide long-term protection against future infections by the same pathogen.

Pharmacodynamics

The pharmacodynamics of live vaccines involve the activation of both humoral and cellular immunity. Following vaccination, the immune system generates a robust response, including the production of specific antibodies and the activation of T cells that can recognize and eliminate infected cells. This dual action helps establish long-term immunity.

Pharmacokinetics

The pharmacokinetics of live vaccines vary depending on the specific vaccine. Generally, the vaccine is administered via injection, allowing the live attenuated organisms to enter the bloodstream. The immune response typically begins within days and can last for years, depending on the vaccine. Live vaccines are usually stored under refrigeration to maintain their viability, and they should be administered within their expiration dates.

Interactions

• livevaccines + abrocitinib: Severe (increases risk of generalised infection (possibly life-threatening))
• livevaccines + baricitinib: Severe (increases risk of generalised infection (possibly life-threatening))
• livevaccines + filgotinib: Severe (increases risk of generalised infection (possibly life-threatening))
• livevaccines + dexrazoxane: Severe (increases risk of generalised infection (possibly life-threatening))
• livevaccines + iron chelators: Severe (increases risk of generalised infection (possibly life-threatening))
• livevaccines + ozanimod: Severe (increases risk of generalised infection (possibly life-threatening))
• livevaccines + ponesimod: Severe (increases risk of generalised infection (possibly life-threatening))
• livevaccines + siponimod: Severe (increases risk of generalised infection (possibly life-threatening))
• livevaccines + upadacitinib: Severe (increases risk of generalised infection (possibly life-threatening))
• livevaccines + diroximelfumarate: Moderate (increases risk of generalised infection (possibly life-threatening))

Indications

• Ventricular tachycardia
• Atrial fibrillation
• Atrial flutter
• Supraventricular tachycardia

Dosage

Children: Refer to the BNF for Children for appropriate pediatric dosing recommendations.

Adults: Refer to the BNF for specific dosing guidelines based on the condition being treated.

Mechanism of action

Sotalol acts by blocking beta-adrenergic receptors, which leads to a decrease in heart rate and myocardial contractility. Additionally, it prolongs the cardiac action potential and refractory period through potassium channel blockade, which helps in stabilizing the cardiac rhythm.

Pharmacodynamics

The pharmacodynamics of sotalol involve its dual action as a beta-adrenergic blocker and a potassium channel blocker. This results in decreased conduction velocity in the heart, particularly in the atria and ventricles, which is beneficial in treating arrhythmias. The drug's effects on heart rate and contractility are dose-dependent, and the antiarrhythmic effects may take several hours to manifest after administration.

Pharmacokinetics

Sotalol is well absorbed from the gastrointestinal tract, with approximately 90% bioavailability. It has a long elimination half-life of around 12 hours, allowing for twice-daily dosing. The drug is primarily excreted unchanged in the urine, necessitating dose adjustment in patients with renal impairment. It does not undergo significant hepatic metabolism.

Interactions

• propafenone+sotalol: Unknown (increases risk of cardiovascular adverse effects)
• chloroprocaine+sotalol: Unknown (increases risk of cardiovascular adverse effects)

Indications

• Bacterial infections
• Viral infections
• Epidemiological studies
• Antibiotic resistance monitoring

Dosage

Children: Refer to specific antimicrobial treatment guidelines based on the strain identified and the infection site.

Adults: Refer to specific antimicrobial treatment guidelines based on the strain identified and the infection site.

Mechanism of action

The mechanism of action for a strain depends on the type of microorganism it represents. For pathogenic bacteria, the strain may produce toxins, evade the host's immune response, or possess resistance mechanisms that allow it to survive in the presence of antibiotics. For viruses, strains may exhibit mutations that alter their ability to infect host cells or evade antiviral therapies.

Pharmacodynamics

Pharmacodynamics in the context of strains involves the interaction between the strain and the host's immune system, as well as the effects of specific antimicrobial agents on the strain. These interactions can influence the efficacy of treatments and the development of resistance.

Pharmacokinetics

Pharmacokinetics is not directly applicable to strains themselves but rather to the drugs used to treat infections caused by specific strains. Factors such as absorption, distribution, metabolism, and excretion of antimicrobial agents can vary depending on the strain's characteristics and the site of infection.

Pregnancy

There is limited information on the safety of strain in pregnancy. It is advisable to consult healthcare professionals for guidance.

Breast-feeding

Safety during breastfeeding is not well established. It is recommended to seek medical advice before use.

Storage

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

Mechanism of action

Substantial evidence indicates that molecular hydrogen (H2) has beneficial vascular effects because of its antioxidant and/or anti-inflammatory effects. Thus, hydrogen-rich water may prove to be an effective anti-aging drink. This study examined the effects of H2 on endothelial senescence and clarified the mechanisms involved. Hydrogen-rich medium was produced by a high-purity hydrogen gas generator. Human umbilical vein endothelial cells (HUVECs) were incubated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for various time periods in normal or hydrogen-rich medium. The baseline H2concentration in hydrogen-rich medium was 0.55 +/- 0.07 mmol/L. This concentration gradually decreased, and H2 was almost undetectable in medium after 12 hr. At 24 hr after TCDD exposure, HUVECs treated with TCDD exhibited increased 8OHdG and acetyl-p53 expression, decreased nicotinamide adenine dinucleotide (NAD(+))/NADH ratio, impaired Sirt1 activity, and enhanced senescence-associated beta-galactosidase. However, HUVECs incubated in hydrogen-rich medium did not exhibit these TCDD-induced changes accompanying Nrf2 activation, which was observed even after H2 was undetectable in the medium. Chrysin, an inhibitor of Nrf2, abolished the protective effects of H2 on HUVECs. H2 has long-lasting antioxidant and anti-aging effects on vascular endothelial cells through the Nrf2 pathway, even after transient exposure to H2. Hydrogen-rich water may thus be a functional drink that increases longevity. /Hydrogen-rich water/ Amyloid beta (Abeta) peptides are identified /as a/ cause of neurodegenerative diseases such as Alzheimer's disease (AD). Previous evidence suggests Abeta-induced neurotoxicity is linked to the stimulation of reactive oxygen species (ROS) production. The accumulation of Abeta-induced ROS leads to increased mitochondrial dysfunction and triggers apoptotic cell death. This suggests antioxidant therapies may be beneficial for preventing ROS-related diseases such as AD. Recently, hydrogen-rich water (HRW) has been proven effective in treating oxidative stress-induced disorders because of its ROS-scavenging abilities. However, the precise molecular mechanisms whereby HRW prevents neuronal death are still unclear. In the present study, we evaluated the putative pathways by which HRW protects against Abeta-induced cytotoxicity /in SK-N-MC cells/. Our results indicated that HRW directly counteracts oxidative damage by neutralizing excessive ROS, leading to the alleviation of Abeta-induced cell death. In addition, HRW also stimulated AMP-activated protein kinase (AMPK) in a sirtuin 1 (Sirt1)-dependent pathway, which upregulates forkhead box protein O3a (FoxO3a) downstream antioxidant response and diminishes Abeta-induced mitochondrial potential loss and oxidative stress. Taken together, our findings suggest that HRW may have potential therapeutic value to inhibit Abeta-induced neurotoxicity. /Hydrogen-rich water/ The NLRP3 inflammasome, an intracellular multi-protein complex controlling the maturation of cytokine interleukin-1beta, plays an important role in lipopolysaccharide (LPS)-induced inflammatory cascades. Recently, the production of mitochondrial reactive oxygen species (mtROS) in macrophages stimulated with LPS has been suggested to act as a trigger during the process of NLRP3 inflammasome activation that can be blocked by some mitochondria-targeted antioxidants. Known as a ROS scavenger, molecular hydrogen (H2) has been shown to possess therapeutic benefit on LPS-induced inflammatory damage in many animal experiments. Due to the unique molecular structure, H2 can easily target the mitochondria, suggesting that H2 is a potential antagonist of mtROS-dependent NLRP3 inflammasome activation. Here we have showed that, in mouse macrophages, H2 exhibited substantial inhibitory activity against LPS-initiated NLRP3 inflammasome activation by scavenging mtROS. Moreover, the elimination of mtROS by H2 resultantly inhibited mtROS-mediated NLRP3 deubi

Mechanism of action

There are 3 key phases of aminoglycoside entry into cells. The first “ionic binding phase” occurs when polycationic aminoglycosides bind electrostatically to negatively charged components of bacterial cell membranes including with lipopolysaccharides and phospholipids within the outer membrane of Gram-negative bacteria and to teichoic acids and phospholipids within the cell membrane of Gram-positive bacteria. This binding results in displacement of divalent cations and increased membrane permeability, allowing for aminoglycoside entry. The second “energy-dependent phase I” of aminoglycoside entry into the cytoplasm relies on the proton-motive force and allows a limited amount of aminoglycoside access to its primary intracellular target - the bacterial 30S ribosome. This ultimately results in the mistranslation of proteins and disruption of the cytoplasmic membrane. Finally, in the “energy-dependent phase II” stage, concentration-dependent bacterial killing is observed. Aminoglycoside rapidly accumulates in the cell due to the damaged cytoplasmic membrane, and protein mistranslation and synthesis inhibition is amplified. The necessity of oxygen-dependent active transport explains why aminoglycosides are ineffective against anaerobic bacteria. Hence, aminoglycosides have both immediate bactericidal effects through membrane disruption and delayed bactericidal effects through impaired protein synthesis; observed experimental data and mathematical modeling support this two-mechanism model. Inhibition of protein synthesis is a key component of aminoglycoside efficacy. Structural and cell biological studies suggest that aminoglycosides bind to the 16S rRNA in helix 44 (h44), near the A site of the 30S ribosomal subunit, altering interactions between h44 and h45. This binding also displaces two important residues, A1492 and A1493, from h44, mimicking normal conformational changes that occur with successful codon-anticodon pairing in the A site. Overall, aminoglycoside binding has several negative effects including inhibition of translation, initiation, elongation, and ribosome recycling. Recent evidence suggests that the latter effect is due to a cryptic second binding site situated in h69 of the 23S rRNA of the 50S ribosomal subunit. Also, by stabilizing a conformation that mimics correct codon-anticodon pairing, aminoglycosides promote error-prone translation. Mistranslated proteins can incorporate into the cell membrane, inducing the damage discussed above. Aminoglycosides are usually bactericidal in action. Although the exact mechanism of action has not been fully elucidated, the drugs appear to inhibit protein synthesis in susceptible bacteria by irreversibly binding to 30S ribosomal subunits. /Aminoglycosides/ ... Aminoglycosides are aminocyclitols that kill bacteria by inhibiting protein synthesis as they bind to the 16S rRNA and by disrupting the integrity of bacterial cell membrane. Aminoglycoside resistance mechanisms include: (a) the deactivation of aminoglycosides by N-acetylation, adenylylation or O-phosphorylation, (b) the reduction of the intracellular concentration of aminoglycosides by changes in outer membrane permeability, decreased inner membrane transport, active efflux, and drug trapping, (c) the alteration of the 30S ribosomal subunit target by mutation, and (d) methylation of the aminoglycoside binding site. ... /Aminoglycosides/

Mechanism of action

Substantial evidence indicates that molecular hydrogen (H2) has beneficial vascular effects because of its antioxidant and/or anti-inflammatory effects. Thus, hydrogen-rich water may prove to be an effective anti-aging drink. This study examined the effects of H2 on endothelial senescence and clarified the mechanisms involved. Hydrogen-rich medium was produced by a high-purity hydrogen gas generator. Human umbilical vein endothelial cells (HUVECs) were incubated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for various time periods in normal or hydrogen-rich medium. The baseline H2concentration in hydrogen-rich medium was 0.55 +/- 0.07 mmol/L. This concentration gradually decreased, and H2 was almost undetectable in medium after 12 hr. At 24 hr after TCDD exposure, HUVECs treated with TCDD exhibited increased 8OHdG and acetyl-p53 expression, decreased nicotinamide adenine dinucleotide (NAD(+))/NADH ratio, impaired Sirt1 activity, and enhanced senescence-associated beta-galactosidase. However, HUVECs incubated in hydrogen-rich medium did not exhibit these TCDD-induced changes accompanying Nrf2 activation, which was observed even after H2 was undetectable in the medium. Chrysin, an inhibitor of Nrf2, abolished the protective effects of H2 on HUVECs. H2 has long-lasting antioxidant and anti-aging effects on vascular endothelial cells through the Nrf2 pathway, even after transient exposure to H2. Hydrogen-rich water may thus be a functional drink that increases longevity. /Hydrogen-rich water/ Amyloid beta (Abeta) peptides are identified /as a/ cause of neurodegenerative diseases such as Alzheimer's disease (AD). Previous evidence suggests Abeta-induced neurotoxicity is linked to the stimulation of reactive oxygen species (ROS) production. The accumulation of Abeta-induced ROS leads to increased mitochondrial dysfunction and triggers apoptotic cell death. This suggests antioxidant therapies may be beneficial for preventing ROS-related diseases such as AD. Recently, hydrogen-rich water (HRW) has been proven effective in treating oxidative stress-induced disorders because of its ROS-scavenging abilities. However, the precise molecular mechanisms whereby HRW prevents neuronal death are still unclear. In the present study, we evaluated the putative pathways by which HRW protects against Abeta-induced cytotoxicity /in SK-N-MC cells/. Our results indicated that HRW directly counteracts oxidative damage by neutralizing excessive ROS, leading to the alleviation of Abeta-induced cell death. In addition, HRW also stimulated AMP-activated protein kinase (AMPK) in a sirtuin 1 (Sirt1)-dependent pathway, which upregulates forkhead box protein O3a (FoxO3a) downstream antioxidant response and diminishes Abeta-induced mitochondrial potential loss and oxidative stress. Taken together, our findings suggest that HRW may have potential therapeutic value to inhibit Abeta-induced neurotoxicity. /Hydrogen-rich water/ The NLRP3 inflammasome, an intracellular multi-protein complex controlling the maturation of cytokine interleukin-1beta, plays an important role in lipopolysaccharide (LPS)-induced inflammatory cascades. Recently, the production of mitochondrial reactive oxygen species (mtROS) in macrophages stimulated with LPS has been suggested to act as a trigger during the process of NLRP3 inflammasome activation that can be blocked by some mitochondria-targeted antioxidants. Known as a ROS scavenger, molecular hydrogen (H2) has been shown to possess therapeutic benefit on LPS-induced inflammatory damage in many animal experiments. Due to the unique molecular structure, H2 can easily target the mitochondria, suggesting that H2 is a potential antagonist of mtROS-dependent NLRP3 inflammasome activation. Here we have showed that, in mouse macrophages, H2 exhibited substantial inhibitory activity against LPS-initiated NLRP3 inflammasome activation by scavenging mtROS. Moreover, the elimination of mtROS by H2 resultantly inhibited mtROS-mediated NLRP3 deubi