MEDDOXY

Indications

• Bacterial infections
• Acne
• Destructive (refractory) periodontal disease
• Exacerbations of chronic bronchitis
• Leptospirosis
• Chlamydia infections
• Rickettsial infections
• Mycoplasma infections
• Acute necrotising ulcerative gingivitis

Dosage

Children: For children aged 12–17 years, initially 200 mg daily in 1–2 divided doses for the

Adults: Initially 200 mg daily in 1–2 divided doses for the first day, then maintenance 100 mg daily.

Mechanism of action

Doxycycline exerts its antibacterial effects by binding to the 30S ribosomal subunit of bacterial ribosomes, inhibiting the binding of aminoacyl-tRNA to the mRNA-ribosome complex. This inhibition of protein synthesis is crucial for bacterial growth and is the primary mechanism by which doxycycline exhibits its antimicrobial activity. It also impacts cellular metabolism and has been associated with non-genotoxic carcinogenic effects.

Pharmacodynamics

Doxycycline has a broad spectrum of activity against Gram-positive, Gram-negative bacteria, and some protozoa. Its bacteriostatic action is particularly effective against certain resistant strains, including MRSA. The drug's efficacy may vary based on the sensitivity of the bacteria, and resistance can develop through various mechanisms, such as efflux pumps and ribosomal protection.

Pharmacokinetics

Doxycycline is well absorbed from the gastrointestinal tract, with peak plasma concentrations typically reached within 2 hours after oral administration. It has a high volume of distribution and is approximately 90% protein-bound. The drug is metabolized in the liver and excreted primarily in feces, with a smaller fraction eliminated in urine. The half-life of doxycycline is approximately 18 to 22 hours, allowing for once or twice daily dosing in most cases.

Contra-indications

• Pregnancy
• Breastfeeding
• Hypersensitivity to doxycycline or other tetracyclines
• Myasthenia gravis
• Severe hepatic impairment

Adverse effects

• Photosensitivity
• Dizziness
• Headache
• Nausea
• Vomiting
• Diarrhoea
• Angioedema
• Skin reactions
• Pseudomembranous enterocolitis
• Tooth discolouration
• Intracranial hypertension
• Thrombocytopenia
• Stevens-Johnson syndrome
• Pancreatitis

Interactions

• Fosphenytoin (decreases concentration)
• Rifampicin (decreases exposure)
• Ciclosporin (unknown effect on concentration)
• Antacids containing aluminium or magnesium (reduce absorption)
• Iron supplements (reduce absorption)
• Warfarin (may enhance anticoagulant effect)

Precautions

• Use with caution in renal impairment
• May cause increased intracranial pressure
• Risk of superinfection (e.g., fungal infections)
• Avoid exposure to sunlight or sun lamps
• Monitor liver function in patients receiving prolonged therapy

Pregnancy

Should not be given to pregnant women; effects on skeletal development have been documented in the first trimester in animal studies. Administration during the second or third trimester may cause discoloration of the child's teeth, and maternal hepatotoxicity has been reported with large parenteral doses.

Breast-feeding

Should not be given to women who are breastfeeding; absorption may lead to discoloration of teeth in the infant.

Storage

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

Formulations

• Tablets
• Capsules
• Oral suspension
• Oral solution

Indications

• Low blood volume
• Hypovolemic shock
• Burns
• Cardiopulmonary bypass

Dosage

Children: Initially 10-20 mL per kilogram. Adjust according to the patient's condition and response, using 3.5-4% solution. Use under specialist supervision to mitigate the risk of fluid overload.

Adults: Dose according to requirements, typically administered intravenously. Consult product literature for specific dosing guidance.

Mechanism of action

Gelatin acts as a plasma expander by increasing the oncotic pressure in the vascular compartment, which helps to retain fluid within the bloodstream and restore circulating blood volume. This mechanism aids in maintaining blood pressure and improving tissue perfusion.

Pharmacodynamics

Gelatin solutions increase blood volume and improve hemodynamic stability in patients experiencing hypovolemic conditions. By drawing water into the vascular space, they help to counteract the effects of low blood volume, such as hypotension and compromised organ perfusion.

Pharmacokinetics

Gelatin is administered intravenously, and its effects can be observed relatively quickly. The half-life and the metabolic clearance depend on the formulation and concentration of the solution. Gelatin is gradually metabolized by macrophages and eliminated by the renal system. Close monitoring of fluid balance is essential, particularly in patients with cardiac or renal impairment.

Contra-indications

• Severe liver disease
• History of circulatory disease
• Severe cardiac disease

Adverse effects

• Fever
• Flushing
• Nausea
• Urticaria
• Rare or very rare shock

Interactions

• Calcium salts

Precautions

• Monitor cardiovascular and respiratory function
• Correct dehydration when administering
• Administer slowly to avoid rapid rise in blood pressure and cardiac failure
• Increased capillary permeability

Pregnancy

Consult product literature for specific guidance regarding use in pregnancy.

Breast-feeding

Consult product literature for specific guidance regarding use in breastfeeding.

Storage

Store at controlled room temperature, protect from light. Refer to product-specific storage instructions.

Formulations

• 5% solution for infusion
• 20% solution for infusion
• Concentrated solution (15-25% protein)
• Isotonic solution (3.5-5% protein)

Indications

• Methemoglobinemia
• Urinary tract infections
• Surgical marking
• Treatment of certain types of cyanide poisoning

Dosage

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

Adults: Refer to the relevant clinical guidelines or the BNF for specific dosing recommendations.

Mechanism of action

Methylene blue acts as a reducing agent, converting methemoglobin back to its functional form, hemoglobin. This is primarily achieved through its action as an electron donor, facilitating the reduction of ferric iron (Fe3+) in hemoglobin to ferrous iron (Fe2+), thereby restoring its oxygen-carrying capacity. It also exhibits antimicrobial properties through its ability to generate reactive oxygen species when exposed to light, which can inhibit bacterial growth.

Pharmacodynamics

The pharmacodynamics of methylene blue involve its role in enhancing oxygen delivery in patients suffering from methemoglobinemia. By converting methemoglobin back to hemoglobin, it effectively increases the amount of hemoglobin available for oxygen transport. The drug also shows effects on the vascular system, where it can induce vasodilation and influence blood pressure.

Pharmacokinetics

Methylene blue is rapidly absorbed after intravenous administration, with peak plasma concentrations occurring within 1 to 3 hours. It is extensively distributed in body tissues and fluids, including the liver, kidneys, and lungs. The drug undergoes hepatic metabolism, primarily through the cytochrome P450 system, and is excreted mainly through urine. The half-life ranges from 5 to 24 hours, depending on the dosage and individual patient factors.

Pregnancy

Consult healthcare provider before use, as safety in pregnancy is not established.

Breast-feeding

Consult healthcare provider before use, as safety during breastfeeding is not established.

Storage

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

Indications

• Hypovolemic shock
• Severe burns
• Postoperative fluid replacement
• Sepsis
• Trauma management

Dosage

Children: Refer to established guidelines for specific dosing, as it varies based on the type of colloidal solution used and the clinical condition being treated.

Adults: Refer to established guidelines for specific dosing, as it varies based on the type of colloidal solution used and the clinical condition being treated.

Mechanism of action

Colloidal solutions work by maintaining oncotic pressure in the blood, thus helping to retain fluid within the vascular system. This is primarily due to the large molecular weight of the colloidal particles, which cannot easily pass through capillary walls. The presence of colloids in the blood helps to draw water into the circulation, increasing blood volume and improving tissue perfusion.

Pharmacodynamics

The pharmacodynamics of colloidal solutions are centered on their ability to exert osmotic pressure, which helps maintain blood volume and pressure. This effect is particularly important in conditions such as hypovolemia and shock, where fluid replacement is necessary to restore hemodynamic stability. The efficacy of colloidal solutions can vary depending on the type of colloid used, as well as the underlying clinical condition being treated.

Pharmacokinetics

Colloidal solutions are typically administered intravenously and their pharmacokinetics can vary based on the specific formulation. Generally, colloids are distributed throughout the vascular compartment and have a longer duration of action compared to crystalloids, as they remain in circulation longer. The elimination of colloids is primarily through the reticuloendothelial system, where they are metabolized or eliminated by the liver and spleen. Factors such as particle size and composition can influence their distribution and clearance.

Adverse effects

• Allergic reactions
• Injection site reactions
• Nausea
• Vomiting
• Headache
• Fever

Precautions

• Use with caution in patients with known allergies to any component of the formulation
• Monitor for signs of hypersensitivity during administration
• Consider volume overload in patients with cardiac or renal impairment

Pregnancy

The safety of colloidal solutions 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 whether colloidal solutions are excreted in human milk. Caution should be exercised when administering to breastfeeding mothers.

Storage

Store at room temperature, protect from light, and do not freeze. Keep out of reach of children.

Formulations

• Colloidal silver
• Colloidal gold
• Colloidal iron
• Other metal colloids

Mechanism of action

The precise mechanism of action is not well-documented in the provided resources. However, compounds with similar molecular structures often interact with biological pathways through modulation of neurotransmitter systems or receptor activity.

Pharmacodynamics

Pharmacodynamics for compounds like Colour typically involve interactions at the cellular level, influencing physiological responses through receptor binding and modulation of signaling pathways. The specific effects and potency would depend on the context of use and formulation.

Pharmacokinetics

Information on the pharmacokinetics of Colour, including absorption, distribution, metabolism, and excretion, is not provided in the available resources. Generally, pharmacokinetic properties will vary significantly based on formulation and route of administration.

Pregnancy

Safety in pregnancy has not been established. Use only if the benefits outweigh the risks.

Breast-feeding

Caution is advised. There are no adequate studies in breastfeeding women.

Storage

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

Indications

• Chronic hepatitis C virus infection
• Genotype 1 HCV infection

Dosage

Children: Refer to BNF for Children for specific dosing information tailored to paediatric patients.

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

Mechanism of action

Paritaprevir inhibits the NS3/4A serine protease of the Hepatitis C Virus (HCV). This enzyme is responsible for cleaving the viral polypeptide into essential structural and nonstructural proteins necessary for the assembly of mature virus. By inhibiting NS3/4A, paritaprevir prevents viral replication and function.

Pharmacodynamics

At concentrations significantly above therapeutic levels, paritaprevir and its combination with ombitasvir do not prolong the QTc interval to a clinically relevant extent. This suggests a favorable safety profile concerning cardiac effects at therapeutic doses.

Pharmacokinetics

Paritaprevir is absorbed effectively after oral administration, with its pharmacokinetic profile characterized by a peak plasma concentration occurring within a few hours post-dose. It is extensively metabolized in the liver, primarily via CYP3A4, and is eliminated mainly through fecal excretion. The half-life of paritaprevir allows for once-daily dosing when used in combination therapies.

Pregnancy

The safety of paritaprevir in pregnancy has not been established. Use only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is unknown if paritaprevir is excreted in human milk. Caution is advised when administered to breastfeeding women.

Storage

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

Dosage

Children: Refer to specific pediatric dosing guidelines based on the identified drug, as 'hard' does not provide sufficient information.

Adults: Refer to specific drug information for dosing guidelines, as 'hard' does not specify a particular medication.

Mechanism of action

The mechanism of action for drugs termed 'hard' must be specified for accurate information, as this phrase does not designate a specific compound. Mechanisms may involve receptor interaction, enzyme inhibition, or modulation of biochemical pathways, depending on the drug in question. For example, opioid analgesics work primarily by binding to mu-opioid receptors in the central nervous system, leading to analgesic effects.

Pharmacodynamics

Pharmacodynamics refers to the effects of a drug on the body and its mechanisms of action. The pharmacodynamics of any drug classified as 'hard' would depend on its specific pharmacological profile, including its efficacy, potency, and the nature of its therapeutic effects. For instance, in the case of opioids, pharmacodynamic effects include pain relief, sedation, and potential respiratory depression.

Pharmacokinetics

Pharmacokinetics involves the absorption, distribution, metabolism, and excretion (ADME) of a drug. The pharmacokinetics of a substance termed 'hard' would vary significantly based on the specific drug. For many medications, absorption may occur via oral or parenteral routes, distribution may involve binding to plasma proteins, metabolism may occur in the liver, and excretion is typically renal. Each of these parameters is critical for understanding the drug's action and potential side effects.

Pregnancy

Consult a healthcare professional before use, as safety has not been established.

Breast-feeding

Consult a healthcare professional before use, as safety has not been established.

Storage

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

Indications

• Motion sickness
• Nausea and vomiting
• Gastrointestinal spasms
• Preoperative sedation

Dosage

Children: Refer to the BNF for Children for specific dosing recommendations based on the child's age, weight, and condition being treated.

Adults: Refer to the appropriate clinical guidelines or BNF for specific dosing recommendations based on the condition being treated and patient factors.

Mechanism of action

Hyclate exerts its effects by antagonizing muscarinic acetylcholine receptors, which are found throughout the central and peripheral nervous systems. This inhibition leads to a decrease in acetylcholine-induced effects, particularly in the gastrointestinal system and vestibular apparatus, thus alleviating symptoms of nausea and motion sickness.

Pharmacodynamics

The pharmacodynamic effects of hyoscine include reduced gastrointestinal motility, decreased secretions, and a sedative effect on the central nervous system. Its antimuscarinic activity can result in side effects such as dry mouth, blurred vision, constipation, and drowsiness, depending on the dose and individual patient response.

Pharmacokinetics

Hyclate is well-absorbed from the gastrointestinal tract, and its peak plasma concentrations are typically reached within 2 hours after oral administration. The drug is widely distributed throughout the body, including the central nervous system where it crosses the blood-brain barrier. Hyoscine is metabolized in the liver and excreted primarily through the urine. The half-life of hyoscine is approximately 3 to 5 hours, but this can vary based on the formulation and route of administration.

Contra-indications

• Hypersensitivity to hyoscyamine or any of the excipients
• Glaucoma
• Myasthenia gravis
• Severe ulcerative colitis
• Tachycardia

Adverse effects

• Dry mouth
• Blurred vision
• Constipation
• Urinary retention
• Dizziness
• Confusion
• Nausea
• Vomiting

Interactions

• Anticholinergic agents may enhance effects
• Opioids may increase risk of constipation
• Antidepressants may increase anticholinergic effects
• Antihistamines may have additive sedative effects

Precautions

• Use with caution in patients with prostate enlargement
• May exacerbate conditions like heart disease or hypertension
• Caution in elderly patients due to increased sensitivity

Pregnancy

Consult the prescribing information; safety during pregnancy is not established.

Breast-feeding

Consult a healthcare provider; may inhibit lactation.

Storage

Store at room temperature, away from moisture and heat.

Formulations

• Oral tablets
• Injection solution
• Extended-release capsules

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

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

• Drug delivery
• Controlled release of medications
• Protection of sensitive compounds

Dosage

Children: Dosage for paediatric patients is also dependent on the specific active ingredient within the shell. Refer to the BNF for Children for appropriate dosing information.

Adults: Dosage depends on the specific formulation and active ingredient contained within the shell. Refer to the specific drug monograph for dosing recommendations.

Mechanism of action

The mechanism of action of shells depends on the specific active ingredients they contain. Typically, the shell serves as a barrier that controls the release of the drug, enabling it to reach the desired site of action. This can involve various pathways, including diffusion through the shell material, enzymatic degradation, or dissolution in the gastrointestinal tract.

Pharmacodynamics

Pharmacodynamics of shell formulations is related to their ability to modulate the release profile of the encapsulated drug. This can result in altered onset of action, duration of effect, and therapeutic efficacy. The properties of the shell material can influence these dynamics, including factors such as thickness, permeability, and solubility in biological fluids.

Pharmacokinetics

Pharmacokinetics of shell-based drug formulations involves the absorption, distribution, metabolism, and excretion of the active ingredient following its release from the shell. The release rate can be affected by the shell's composition and the physicochemical properties of the drug. Typically, the drug is absorbed in the gastrointestinal tract, distributed throughout the body, metabolized primarily by the liver, and excreted via urine or feces.

Pregnancy

Not enough information available to assess safety in pregnancy. Consult healthcare provider.

Breast-feeding

Not enough information available to assess safety during breastfeeding. Consult healthcare provider.

Storage

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

Indications

• Silicosis
• Chronic obstructive pulmonary disease (COPD)
• Lung cancer associated with silica exposure

Dosage

Adults: Silica is not administered as a drug, but rather

Mechanism of action

Silica, particularly crystalline forms like quartz and cristobalite, can induce cytotoxicity and morphological transformation in cells. The cytotoxic effects are attributed to the presence of silanol groups and trace iron on the silica surface, which can generate reactive oxygen species. These interactions lead to cellular damage and transformation, suggesting multiple molecular mechanisms underlying silica's biological effects. The activity is sensitive to the silica's surface structure and composition, indicating that the biological response is a phenomenon originating from the silica's surface characteristics.

Pharmacodynamics

Silica's pharmacodynamic effects are largely related to its cytotoxic and transforming properties, particularly in lung tissue. The inhalation of crystalline silica can lead to the activation of inflammatory pathways, oxidative stress, and apoptosis in alveolar macrophages and epithelial cells. This can result in chronic inflammation, fibrosis, and ultimately, diseases such as silicosis and lung cancer. The degree of these effects varies based on the type of silica, its crystalline structure, and the presence of surface modifications.

Pharmacokinetics

The pharmacokinetics of silica is complex as it is not absorbed systemically when inhaled or ingested. Instead, inhaled silica particles can deposit in the alveolar region of the lungs, where they may persist for long periods. The body responds to silica exposure through inflammatory processes, and macrophages attempt to phagocytize silica particles. However, the persistence of these particles can lead to chronic lung conditions. Clearance mechanisms are inefficient, leading to prolonged retention in lung tissue.

Adverse effects

• Cytotoxicity
• Morphological transformation of cells
• Respiratory issues
• Silicosis
• Lung cancer

Precautions

• Use caution in occupational settings with silica dust exposure
• Regular monitoring of lung function in exposed individuals

Pregnancy

There is insufficient data on the effects of silica on pregnancy. It is advised to minimize exposure.

Breast-feeding

Limited data available; caution is advised due to potential respiratory effects.

Storage

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

Formulations

• Crystalline silica
• Amorphous silica (diatomaceous earth)
• Silica gel

Dosage

Children: Refer to the specific drug's prescribing information for paediatric dosing guidelines.

Adults: Refer to the specific drug's prescribing information for adult dosing guidelines.

Mechanism of action

The mechanism of action would depend on the specific drug referred to by 'size'. Generally, drugs exert their effects through interaction with biological targets such as receptors, enzymes, or ion channels, leading to a physiological response.

Pharmacodynamics

Pharmacodynamics refers to the effects of the drug on the body, including the relationship between drug concentration and effect. This can involve receptor binding, signal transduction, and the resulting biological effects. Specific dynamics would vary based on the drug in question.

Pharmacokinetics

Pharmacokinetics describes the absorption, distribution, metabolism, and excretion (ADME) of a drug. Factors such as bioavailability, volume of distribution, half-life, and clearance would vary significantly based on the specific drug being considered.

Pregnancy

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

Breast-feeding

Use with caution, as it is not known whether it is excreted in human milk.

Storage

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

Indications

• Used as an excipient in drug formulations
• Pleurodesis for the management of recurrent pleural effusions

Dosage

Children: Refer to specific guidelines for paediatric use, as dosing may differ based on age and clinical condition.

Adults: Refer to specific guidelines for the appropriate dosage in pleurodesis and other applications, as it may vary based on clinical context.

Mechanism of action

Talc exhibits very good absorptive properties, allowing it to absorb moisture and other substances effectively. This characteristic is particularly useful in pharmaceutical formulations, where it may enhance the stability and texture of the drug product.

Pharmacodynamics

Talc's primary pharmacodynamic effect is its ability to act as an inert filler and bulking agent in pharmaceutical preparations. It does not have any intrinsic pharmacological activity but serves to improve the physical properties of formulations, such as flowability and compressibility.

Pharmacokinetics

Talc is not absorbed systemically when used as an excipient or in medical procedures. Its effects are local, and it remains in the site of application, where it functions primarily as a mechanical agent. The pharmacokinetics of talc in the context of its use in pleurodesis involves its ability to promote adhesion of the pleural surfaces, thereby preventing fluid accumulation.

Pregnancy

Talc is classified as a substance with minimal systemic absorption, but safety during pregnancy has not been well established. Consult relevant guidelines.

Breast-feeding

Talc is not expected to be absorbed in significant amounts; however, caution is advised and consult guidelines.

Storage

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

Mechanism of action

Paritaprevir is a potent inhibitor of the NS3/4A serine protease of Hepatitis C Virus (HCV). Following viral replication of HCV genetic material and translation into a single polypeptide, Nonstructural Protein 3 (NS3) and its activating cofactor Nonstructural Protein 4A (NS4A) are responsible for cleaving it into the following structural and nonstructural proteins required for assembly into mature virus: NS3, NS4A, NS4B, NS5A, and NS5B. By inhibiting viral protease NS3/4A, paritaprevir therefore prevents viral replication and function.

Pharmacodynamics

At concentrations approximately 6 and 1.8 times the therapeutic concentrations of paritaprevir and ombitasvir, the combination did not prolong QTc to any clinically relevant extent.

Mechanism of action

...Some quartz and cristobalite dusts (crystalline) as well as the diatomaceous earths (amorphous), but not the pyrogenic amorphous silica, were cytotoxic and induced morphological transformation of SHE cells in a concentration-dependent manner. The ranking in cytotoxicity was different from that in transforming potency, suggesting two separate molecular mechanisms for the two effects. The cytotoxic and transforming potencies were different from one dust to another, even among the same structural silicas. The type of crystalline structure (quartz vs cristobalite) and the crystalline vs biogenic amorphous form did not correlate with cytotoxic or transforming potency of silica dusts. Comparison of cellular effects induced by original and surface modified samples revealed that several surface functionalities modulate cytotoxic and transforming potencies. The cytotoxic effects appeared to be related to the distribution and abundance of silanol groups and to the presence of trace amounts of iron on the silica surface. Silica particles with fractured surfaces and/or iron-active sites, able to generate reactive oxygen species, induced SHE cell transformation. The results show that the activity of silica at the cellular level is sensitive to the composition and structure of surface functionalities and confirm that the biological response to silica is a surface originated phenomenon. In vivo exposure of rat lungs to crystalline silica either by intratracheal instillation or by inhalation results in an increase in mRNA levels for inducible nitric oxide synthase (iNOS) in bronchoalveolar lavage cells (BALC), elevated nitric oxide (.NO) production by BALC, and an increase in .NO-dependent chemiluminescence (CL) from alveolar macrophages (AM). Induction of iNOS message occurs in both AM and polymorphonuclear leukocytes (PMN) harvested from silica-exposed lungs but is not significantly elevated in lavaged lung tissue. This review presents characteristics of simple and complicated coal workers' pneumoconiosis (CWP) as well as pathologic indices of acute and chronic silicosis by summarizing results of in vitro, animal, and human investigations. These results support four basic mechanisms in the etiology of CWP and silicosis: a) direct cytotoxicity of coal dust or silica, resulting in lung cell damage, release of lipases and proteases, and eventual lung scarring; b) activation of oxidant production by pulmonary phagocytes, which overwhelms the antioxidant defenses and leads to lipid peroxidation, protein nitrosation, cell injury, and lung scarring; c) activation of mediator release from alveolar macrophages and epithelial cells, which leads to recruitment of polymorphonuclear leukocytes and macrophages, resulting in the production of proinflammatory cytokines and reactive species and in further lung injury and scarring; d) secretion of growth factors from alveolar macrophages and epithelial cells, stimulating fibroblast proliferation and eventual scarring. Results of in vitro and animal studies provide a basis for proposing these mechanisms for the initiation and progression of pneumoconiosis. Data obtained from exposed workers lend support to these mechanisms. /The authors/ reported previously that freshly fractured silica (FFSi) induces activator protein-1 (AP-1) activation through extracellular signal-regulated protein kinases (ERKs) and p38 kinase pathways. In the present study, the biologic activities of FFSi and aged silica (ASi) were compared by measuring their effects on the AP-1 activation and phosphorylation of ERKs and p38 kinase. The roles of reactive oxygen species (ROS) in this silica-induced AP-1 activation were also investigated. FFSi-induced AP-1 activation was four times higher than that of ASi in JB6 cells. FFSi also caused greater phosphorylation of ERKs and p38 kinase than ASi. FFSi generated more ROS than ASi when incubated with the cells as measured by electron spin resonance (ESR). Studies using ROS-sensitive dyes and

Mechanism of action

It has very good absorptive properties.