BOSNIB 100

Indications

• Skin disinfection
• Preparation of skin before injections
• Cleansing minor wounds

Dosage

Children: Apply to the skin as required; consult product literature for specific guidance.

Adults: Apply to the skin as required for disinfection.

Mechanism of action

Alcohol exerts its antiseptic effect by denaturing proteins, disrupting cell membranes, and dehydrating microbial cells, leading to cell lysis and death.

Pharmacodynamics

Alcohol has broad-spectrum antimicrobial activity, effective against bacteria, fungi, and viruses. Its efficacy is influenced by concentration, with higher concentrations generally being more effective.

Pharmacokinetics

Alcohol is rapidly absorbed through the skin and mucous membranes. It is metabolized primarily in the liver, with a half-life that varies based on the individual's metabolic rate and the amount consumed.

Contra-indications

• Concomitant use with lithium
• Regular use in neonates
• Patients with severe burns when diathermy has been preceded by application of alcoholic skin disinfectants

Adverse effects

• Eye erythema
• Punctate keratitis
• Cytotoxicity
• Eye discolouration

Interactions

• Increases risk of visual disturbances with antiepileptics
• Increases concentration with methylphenidate
• Increases risk of facial flushing and skin irritation with topical pimecrolimus
• Increases concentration with retinoids
• Increases concentration with acitretin
• Increases risk of facial flushing and skin irritation with topical tacrolimus
• Decreases antidiuretic effect with vasopressin

Precautions

• Avoid regular application to inflamed or broken skin or mucosa
• Avoid broken skin
• Flammable

Pregnancy

Sufficient iodine may be absorbed to affect the fetal thyroid in the second and third trimester.

Breast-feeding

Avoid regular or excessive use.

Storage

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

Formulations

• Betadine 2.5% dry powder spray
• Industrial methylated spirit
• Povidone-Iodine 25 mg per 1 gram

Indications

• Chronic phase Philadelphia chromosome-positive chronic myeloid leukaemia
• Imatinib-resistant CML

Dosage

Adults: 400 mg once daily; consult product literature for specific dosing adjustments based on side effects or treatment response.

Mechanism of action

Bosutinib inhibits the BCR-ABL kinase, which promotes the development of chronic myeloid leukaemia (CML). It effectively inhibits 16 of 18 imatinib-resistant forms of BCR-ABL kinase expressed in murine myeloid cell lines. Additionally, it acts as an inhibitor of Src-family kinases including Src, Lyn, and Hck.

Pharmacodynamics

Clinical studies indicate that higher exposure to bosutinib correlates with a greater likelihood of therapeutic response, although the time course of this pharmacodynamic effect is not fully characterized. Importantly, bosutinib does not significantly prolong the QT interval when administered with ketoconazole, a strong CYP3A inhibitor.

Pharmacokinetics

Bosutinib has a molecular formula of C26H29Cl2N5O3. It undergoes hepatic metabolism and is primarily eliminated via the liver. Dosage adjustments may be necessary in patients with hepatic impairment due to increased drug exposure.

Contra-indications

• Severe hepatic impairment
• History of pancreatitis
• History of QT prolongation

Adverse effects

• Anaemia
• Decreased appetite
• Arthralgia
• Asthenia
• Chest discomfort
• Cough
• Dehydration
• Diarrhea
• Dizziness
• Dyspnea
• Electrolyte imbalance
• Fever
• Gastritis
• Gastrointestinal discomfort
• Hemorrhage
• Headache
• Hepatic disorders
• Skin reactions
• Taste altered
• Vomiting
• Facial paralysis
• Pancreatitis
• Respiratory disorders
• Vision disorders
• Retinal occlusion

Interactions

• Grapefruit juice (severe - increases exposure)
• NNRTIs (severe - decreases exposure)
• St John's Wort (severe - decreases exposure)
• Dronedarone (moderate - increases exposure)
• Belzutifan (moderate - decreases exposure)
• Cenobamate (moderate - decreases exposure)
• Cobicistat (moderate - increases exposure)
• Crizotinib (moderate - increases exposure)
• Idelalisib (moderate - increases exposure)
• Imatinib (moderate - increases exposure)

Precautions

• Monitor liver function before and during treatment
• Assess left ventricular ejection fraction before treatment
• Monitor for visual disturbances
• Monitor blood pressure before and during treatment
• Monitor creatine kinase and creatinine levels monthly during the first 6 months of treatment
• Patients with a history of cardiac disease or hepatitis B infection should be closely monitored

Pregnancy

Manufacturer advises to avoid use due to potential toxicity in animal studies.

Breast-feeding

Manufacturer advises to avoid due to lack of information on safety.

Storage

Store at room temperature, protected from moisture and light.

Formulations

• Tablets: 100 mg
• Tablets: 400 mg

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

• Used as an excipient in solid dosage forms
• Facilitates drug disintegration and dissolution

Dosage

Children: Refer to specific product formulation guidelines as crospovidone is used as an excipient and does not have a direct dosage.

Adults: Refer to specific product formulation guidelines as crospovidone is used as an excipient and does not have a direct dosage.

Mechanism of action

Crospovidone acts by rapidly absorbing water and swelling upon contact with moisture. This action leads to the disintegration of solid dosage forms, thus increasing the surface area of the active ingredients and promoting their dissolution and subsequent absorption in the gastrointestinal tract. It does not affect the pH of the formulation, ensuring that the active ingredients remain stable.

Pharmacodynamics

Crospovidone exhibits properties that enhance the bioavailability of active ingredients in pharmaceutical formulations. Its ability to rapidly disintegrate tablets and capsules leads to quicker release and absorption of the drug into systemic circulation. As a disintegrant, it aids in the effective delivery of drugs that may otherwise be poorly soluble.

Pharmacokinetics

Crospovidone itself is not absorbed systemically when administered orally. It remains in the gastrointestinal tract, where it performs its function as a disintegrant. The pharmacokinetic profile of drugs formulated with crospovidone may be influenced by the enhanced dissolution and absorption rates provided by this excipient.

Pregnancy

Crospovidone is considered to have low toxicity and is generally regarded as safe for use during pregnancy, but specific studies are limited.

Breast-feeding

There is insufficient data on the excretion of crospovidone in human milk, but it is deemed safe for use during breastfeeding.

Storage

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

Formulations

• Powder
• Tablets

Dosage

Children: Dichloromethane is not indicated for pediatric use and does not have established dosing guidelines for children.

Adults: Dichloromethane is used primarily as an industrial solvent and does not have standard dosing recommendations for therapeutic use in adults.

Mechanism of action

The mechanism by which dichloromethane induces mammary adenomas in rats involves an increase in blood prolactin levels, which is similar to the effects of other agents that cause hyperprolactinaemia. This leads to the development of benign neoplasms. The carcinogenic effects observed in mice are associated with the interaction of a glutathione conjugate with DNA, mediated by the class theta glutathione S-transferase T1-1. However, the biological consequences of dichloromethane exposure in humans remain uncertain.

Pharmacodynamics

Dichloromethane acts mainly as a solvent and is absorbed through inhalation and skin contact. Its effects on the body can include central nervous system depression, respiratory irritation, and potential carcinogenic effects due to metabolic conversion in the liver. Its induction of hyperprolactinaemia can lead to specific tumorigenic effects, particularly in rodent models.

Pharmacokinetics

Dichloromethane is rapidly absorbed through the respiratory tract and skin, with peak blood concentrations occurring shortly after exposure. It is metabolized primarily in the liver, with significant conversion to carbon monoxide and other metabolites. The elimination half-life in humans is relatively short, with a rapid exhalation of unchanged dichloromethane. Its distribution in body tissues is influenced by its lipophilicity, leading to accumulation in fatty tissues.

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Use only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is not known whether dichloromethane is excreted in human milk. Caution should be exercised when administering to nursing women.

Storage

Store in a well-closed container at room temperature, away from light and moisture.

Formulations

• Liquid

Indications

• Antiseptic for skin disinfection
• Solvent in pharmaceutical formulations
• Cleaning agent in laboratories and healthcare settings

Dosage

Children: For pediatric use, consult specific guidelines in the BNF for Children, as dosing may vary based on age, weight, and clinical circumstances.

Adults: For skin antisepsis, apply isopropyl alcohol topically in a concentration of 70% to the affected area. Dosage may vary based on clinical indication and setting.

Mechanism of action

Isopropyl alcohol works primarily as an antiseptic by denaturing proteins and disrupting cell membranes of bacteria, viruses, and fungi, leading to cell lysis and death. Its efficacy is enhanced by the presence of water, which facilitates the penetration of the alcohol into microbial cells.

Pharmacodynamics

Isopropyl alcohol exhibits a rapid onset of action against a variety of pathogens, including gram-positive and gram-negative bacteria, fungi, and some viruses. Its antimicrobial activity is concentration-dependent, with higher concentrations generally providing a broader spectrum of activity. It is commonly used in concentrations ranging from 60% to 90%, with 70% being optimal for disinfection due to its ability to penetrate the cell wall effectively.

Pharmacokinetics

Isopropyl alcohol is readily absorbed through the skin and mucous membranes. After absorption, it is metabolized primarily in the liver to acetone, which is then further metabolized and excreted, mostly via urine. The elimination half-life of isopropyl alcohol varies but is typically around 2 to 3 hours. Its effects can be influenced by factors such as dosage, route of exposure, and individual metabolic differences.

Pregnancy

Isopropyl alcohol should be used with caution during pregnancy. It is a category C drug, indicating that risk cannot be ruled out.

Breast-feeding

Caution is advised when using isopropyl alcohol during breastfeeding, as it is not known if it is excreted in human milk.

Storage

Isopropyl alcohol should be stored at room temperature, away from heat and flame. Keep the container tightly closed and in a well-ventilated area.

Formulations

• Isopropyl alcohol 70% solution
• Isopropyl alcohol 99% solution

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

• Tablet coating
• Granule coating
• Improvement of drug stability
• Taste masking
• Aesthetic enhancement of pharmaceuticals

Dosage

Children: Dosage will depend on the specific formulation and active ingredients of the medication being coated. Refer to the specific product information for guidance.

Adults: Dosage will depend on the specific formulation and active ingredients of the medication being coated. Refer to the specific product information for guidance.

Mechanism of action

Opadry functions primarily as a coating polymer that adheres to the surface of tablets or granules, creating a protective layer. This layer can control the release of the active ingredient and protect it from environmental factors such as moisture and light. The specific composition of Opadry can vary, but it typically includes film-forming agents, plasticizers, and colorants that work together to achieve the desired coating characteristics.

Pharmacodynamics

The pharmacodynamics of Opadry is largely focused on its physical and chemical properties rather than specific biological interactions. The coating alters the dissolution characteristics of the drug, potentially leading to modified release profiles. This can enhance drug bioavailability or control the release rate of the active ingredient, thereby impacting the therapeutic effect.

Pharmacokinetics

As a coating agent, Opadry itself is not absorbed into the systemic circulation and does not have pharmacokinetic properties related to absorption, distribution, metabolism, or excretion of an active pharmaceutical ingredient. Its impact on pharmacokinetics is indirect, as it affects how the active drug is released and absorbed in the gastrointestinal tract.

Pregnancy

Opadry is a film-coating agent, and specific studies on its effects during pregnancy are not well-documented. Generally, it is advisable to use medications cautiously during pregnancy. Consult a healthcare provider for guidance.

Breast-feeding

Limited data are available regarding the safety of Opadry during breastfeeding. It is recommended to consult a healthcare provider before use.

Storage

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

Formulations

• Opadry OY - a coating system for oral solid dosage forms
• Opadry II - a polymer-based coating system for tablet and capsule applications

Indications

• Topical drug delivery
• Emulsifying agent in pharmaceutical formulations
• Stabilizing agent in aqueous solutions
• Controlled drug release systems

Dosage

Children: Refer to specific product guidelines for dosing, as it varies based on formulation and intended use.

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

Mechanism of action

Poloxamer acts primarily by reducing the surface tension at the interface between different phases, such as oil and water. This property allows it to stabilize emulsions and improve the solubility of poorly soluble drugs. Additionally, poloxamer can form micelles in solution, encapsulating hydrophobic drugs and facilitating their delivery in the body.

Pharmacodynamics

Poloxamer exhibits surfactant properties that can enhance drug absorption and bioavailability by altering the permeability of biological membranes. Its action as a solubilizing agent can improve the pharmacological effects of drugs by ensuring they remain in a bioavailable form longer. The polymeric nature of poloxamer can also lead to sustained release of encapsulated drugs, prolonging their therapeutic effect.

Pharmacokinetics

Poloxamer is poorly absorbed when administered orally and is primarily excreted unchanged in the feces. Its absorption through the skin is minimal, making it more suitable for topical applications. The pharmacokinetics can vary based on the formulation and route of administration, with its action typically being localized rather than systemic.

Adverse effects

• Skin irritation
• Allergic reactions
• Gastrointestinal disturbances
• Headache

Precautions

• Use with caution in patients with known allergies to surfactants
• Assess for skin sensitivity before use
• Monitor for adverse reactions during therapy

Pregnancy

Safety during pregnancy has not been established. Use only if clearly needed and potential benefits justify the risks.

Breast-feeding

It is not known whether poloxamer is excreted in human milk. Caution is advised when administering to nursing mothers.

Storage

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

Formulations

• Poloxamer 188 (used as a surfactant in various formulations)
• Poloxamer 407 (used in pharmaceutical formulations and drug delivery systems)

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.

Pregnancy

No specific data available, consult a healthcare professional.

Breast-feeding

No specific data available, consult a healthcare professional.

Storage

Store in a cool, dry place away from light.

Mechanism of action

Ethanol affects the brain’s neurons in several ways. It alters their membranes as well as their ion channels, enzymes, and receptors. Alcohol also binds directly to the receptors for acetylcholine, serotonin, GABA, and the NMDA receptors for glutamate. The sedative effects of ethanol are mediated through binding to GABA receptors and glycine receptors (alpha 1 and alpha 2 subunits). It also inhibits NMDA receptor functioning. In its role as an anti-infective, ethanol acts as an osmolyte or dehydrating agent that disrupts the osmotic balance across cell membranes. ... Ethanol is known to affect a large number of membrane proteins that participate in signaling pathways such as neurotransmitter receptors, enzymes, and ion channels, and there is extensive evidence that ethanol interacts with a variety of neurotransmitters. The major actions of ethanol involve enhancing the inhibitory effects of gamma-aminobutyric acid (GABA) at GABAa receptors and blockade of the N-methyl-D-aspartate (NMDA) subtype of glutamate, an excitatory amine acid (EAA) receptor. Animal studies indicate that the acute effects of ethanol result from competitive inhibition of glycine binding to NMDA receptor and disruption of glutamatergic neurotransmission by inhibiting the response of the NMDA receptor. Persistent glycine antagonism and attenuation of glutamatergic neurotransmission by chronic ethanol exposure results in tolerance to ethanol by enhancing EAA neurotransmission and NMDA receptor upregulation. The latter appears to involve selective increases in NMDA R2B subunit concentrations and other molecular changes in specific brain loci. The abrupt withdrawal of ethanol thus produces a hyperexcitable state that leads to the ethanol withdrawal syndrome and excitotoxic neuronal death. GABA-mediated inhibition, which normally acts to limit excitation, is eliminated during ethanol withdrawal syndrome and further intensifies this excitation. In addition, NMDA receptors function to inhibit the release of dopamine in the nucleus accumbens and mesolimbic structures, which modulate the reinforcing action of addictive xenobiotics such as ethanol. By inhibiting NMDA receptor activity, ethanol could increase dopamine release from the nucleus accumbens and ventral tegmental area and could thus create dependence. Chronic ethanol administration also results in tolerance, dependence, and an ethanol withdrawal syndrome, mediated, in part, by desensitization and or downregulation of GABAa receptors. The development of alcoholic ketoacidosis (AKA) requires that a combination of physical and physiologic events occur. The normal response to starvation and depletion of hepatic glycogen stores is for amino acids to be converted to pyruvate. Pyruvate can serve as a substrate for gluconeogenesis, be converted to acetyl-CoA, which can enter the Krebs cycle or can be utilized in various biosynthetic pathways (eg, fatty acid, ketone bodies, cholesterol, and acetylcholine) ... Ethanol metabolism generates NADH, resulting in an excess of reducing potential. This high redox state favors the conversion of pyruvate to lactate, diverting pyruvate from being a substrate for gluconeogenesis. To compensate for the lack of normal metabolic substrates, the body mobilizes fat from adipose tissue and increased fatty acid metabolism as an alternative source of energy. This response is mediated by a decrease in insulin and an increased secretion of glucagon, catecholamines, growth hormone, and cortisol. Fatty acid metabolism results in the formation of acetyl-CoA and it combines with the excess acetate that is generated from ethanol metabolism to form acetoacetate. Most of the acetoacetate is reduced to beta-hydroxybutyrate due to the excess reducing potential or high redox state of the cell. Volume depletion interferes with the renal elimination of acetoacetate and beta-hydroxybutyrate, and contributes to the acidosis. An elevated lactate concentration may result from shunting from pyruvate or

Pharmacodynamics

Alcohol produces injury to cells by dehydration and precipitation of the cytoplasm or protoplasm. This accounts for its bacteriocidal and antifungal action. When alcohol is injected in close proximity to nerve tissues, it produces neuritis and nerve degeneration (neurolysis). Ninety to 98% of ethanol that enters the body is completely oxidized. Ethanol is also used as a cosolvent to dissolve many insoluble drugs and to serve as a mild sedative in some medicinal formulations. Ethanol also binds to GABA, glycine, NMDA receptors and modulates their effects. Ethanol is also metabolised by the hepatic enzyme alcohol dehydrogenase.

Mechanism of action

Bosutinib is a tyrosine kinase inhibitor. Bosutinib inhibits the BCR-ABL kinase that promotes CML; it is also an inhibitor of Src-family kinases including Src, Lyn, and Hck. Bosutinib inhibited 16 of 18 imatinib-resistant forms of BCR-ABL kinase expressed in murine myeloid cell lines. Bosutinib did not inhibit the T315I and V299L mutant cells.

Pharmacodynamics

A greater likelihood of response and a greater likelihood of safety events were observed with higher bosutinib exposure in clinical studies. The time course of bosutinib pharmacodynamic response has not been fully characterized. At a single oral dose of 500 mg bosutinib with ketoconazole (a strong CYP3A inhibitor), bosutinib does not prolong the QT interval to any clinically relevant extent.

Mechanism of action

The mechanism by which methylene chloride induces mammary adenomas in the rat is important for human hazard assessment. Female Sprague- Dawley rats receiving methylene chloride have a high blood level of prolactin. In common with the response to other agents which act via hyperprolactinaemia, the methylene chloride-induced response is of benign neoplasms only. There is no evidence for the binding of methylene chloride to the DNA of other tissues and hence it seems unlikely that it will bind to mammary tissue when the primary site of metabolism is the liver. It seems most likely, therefore, that the increased incidence of mammary adenomas is the result of an indirect mechanism operating via hyperprolactinaemia. Dichloromethane (DCM) is a hepatic and pulmonary carcinogen in mice exposed to high doses by inhalation. It has been shown previously that the incidence of liver and lung tumors does not increase in rats or hamsters exposed to the dihaloalkane under conditions similar to those that produced tumors in mice. The biological consequences of DCM exposure to humans is therefore uncertain. The carcinogenic effects of DCM in the mouse are caused by the interaction with DNA of a glutathione (GSH) conjugate that is produced by the class theta glutathione S-transferase T1-1 (GST T1-1). The species specificity is thought to be due to the greater amount of transferase activity in mouse target organs and specific nuclear localization of GST T1-1 in target cells. This paper directly compares the relative capacity and locality of DCM activation in mouse and human tissues. The results show that mouse GST T1-1 is more efficient in catalyzing the conjugation of DCM with GSH than the orthologous human enzyme. In addition, the mouse expresses higher levels of the transferase than humans in hepatic tissue. Histochemical analysis confirmed the presence of GST T1-1 in the nucleus of mouse liver cells. However, in human liver GST T1-1 was detected in bile duct epithelial cells and hepatocyte nuclei but was also present in the cytoplasm. Taking this information into account, it is unlikely that humans have a sufficiently high capacity to activate DCM for this compound to be considered to represent a carcinogenic risk. Dichloromethane (DCM) is considered a probable human carcinogen. Laboratory studies have shown an increased incidence of lung and liver cancer in mice but not in rats or hamsters. Despite the correlation between metabolism of DCM by the glutathione-S-transferase (GST) pathway and the occurrence of tumors in different species, the mechanism of tumor induction by DCM metabolites produced through the GST pathway remains unclear. In this study a V79 cell line stably transfected with the murine GST theta 1 gene (mGSTT1) was compared to the parent cell line (MZ) to determine how the construct affects DCM metabolism and the sensitivity of the cell line to DNA damage and cytotoxicity. V79 cells were treated with DCM (2.5-10mM) or formaldehyde (150-600muM) for 2hr. Also, formaldehyde produced by V79 cytosol metabolism of DCM was measured spectrophotometrically. DNA damage and DNA-protein crosslinks were measured by the standard and proteinase K-modified alkaline single cell gel electrophoresis (SCG) assays. Cytotoxicity was assessed by trypan blue stain exclusion, the Live/Dead((R)) cell viability/cytotoxicity kit for animal cells, and the neutral red assay. After DCM treatment a significant concentration-dependent increase in tail moment in the V79 MZ cells was observed compared to a significant concentration-dependent decrease in tail moment in the V79 mGSTT1 cells. Post-incubation with proteinase K significantly increased DNA migrations in DCM-treated V79 mGSTT1 cells. DCM formed significantly higher levels of formaldehyde in the cytosol of the V79 mGSTT1 cells than in the cytosol of the V79 MZ cells. Results using the cytotoxicity assays were comparable using the trypan blue and Live/Dead((R)) assays, neither showing a difference in resp