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The emulsion formulation also reduced ocular surface irritation caused by indomethacin procyclidine 5 mg. Similar advantages have been shown for a pilocarpine emulsion which produced a prolonged therapeutic effect in comparison with pilocarpine hydrochloride eyedrops in man generic procyclidine 5mg fast delivery. It can be administered only twice a day discount 5 mg procyclidine otc, rather than four times daily for conventional formulation. Other ophthalmic emulsions have been used to formulate prednisolone, piroxicam and amphotericin B emulsion. Although emulsions can produce sustained therapeutic effects and reduced irritancy of drug, their application in ophthalmology have been limited due to problems of stability. Soft contact lenses and ocular inserts The rationale for corneal contact devices has not been fully explored in therapy. In conventional dosing, there is a gradient across the eye caused by lacrimal flow, opposing drag of material above the equatorial axis by the upper lid as illustrated in Figure 12. Thus it is difficult to sustain high drug concentrations in the upper hemisphere unless the eye is bathed or the patient is supine. A corneal device such as a collagen shield or contact lens overcomes this problem by providing a slowly equilibrating reservoir. It is generally accepted that soft contact lenses can act as a reservoir for drugs, providing improved release of the therapeutic agent. The therapeutic value of contact lenses was first demonstrated in a study which showed a significant increase in aqueous humor levels produced by drug-soaked lenses when compared with the conventional eyedrop. The use of Bionite contact lenses for delivery of idoxuridine, polymyxin B and Pilocarpine also showed that instillation of a drug solution onto an unmedicated contact lens was significantly more effective than instillation of a more concentrated drug solution directly to the cornea. However, the soaking of lenses in ophthalmic formulations to incorporate the drug into the lens may cause toxicity to corneal epithelium because preservatives, such as benzalkonium chloride, have a great affinity for the hydrophilic contact lens material and are concentrated in the contact lens. Contact lens for sensitive wearers may also cause foreign-body sensation, blurring and decreased oxygen tension on the corneal surface resulting from occlusion by contact lens. An alternative system, manufactured as a wafer-like insoluble implant, has been developed (Ocusert). The system is preprogrammed to release pilocarpine at a constant rate of 20 or 40 μg/hr for a week to treat chronic glaucoma; however, release from inserts may be incomplete and approximately 20% of all patients treated with the Ocusert lose the device without being aware of the loss. The device also presents problems including foreign-body sensation, expulsion from the eye, and difficulty in handling and insertion. An alternative to the advanced non-erodible systems is an erodible insert for placement in the cul-de-sac. The bioavailability of pilocarpine was shown to be increased sixteen-fold using this system. The system showed considerable promise for prolonged drug delivery since vision is minimally affected by the presence of an insert positioned on the sclera. When the device is placed in the lower fornix, the contact area for the released drug is the sclera and little material is in contact with the cornea. Furthermore, topical application of drugs for the treatment of posterior segment disorders is severely limited by the highly efficient clearance mechanisms and attempts to improve precorneal residence time of the drugs by addition of viscosity enhancing agents, gelling agents, mucoadhesive polymers etc. Moreover, most diseases affecting the posterior segment are chronic in nature and require prolonged drug administration. An intravitreal injection provides therapeutic concentrations of the drug adjacent to the intended site of activity and a much smaller dose is required. Following injection, the drug diffuses through the vitreous gel with little restriction to diffusion. For most drugs the diffusion coefficient through the vitreous humor is close to that through water. Once distributed throughout the vitreous humor, rapid elimination of the drug is observed. Drug loss from the vitreous takes place via two routes: • anteriorly—by simple diffusion to the posterior chamber and followed by removal to the systemic circulation along with the aqueous humor drainage; • posteriorly—across the retina where it is removed by active secretion. Drugs lost primarily by anterior chamber diffusion have a long half-life in the vitreous, usually in the order of 20–30 hours. In contrast, drugs lost via the trans-retinal route, such as the penicillins, have typically 314 much shorter half-lives of 5–10 hours. Ocular inflammation results in the breakdown of blood retinal barrier and increases the elimination of non-transported drugs from the vitreous. In contrast to the elimination of non-transported drugs, drugs that are removed by the active transport systems reside longer in the vitreous following ocular inflammation due to the failure in the transport system. As the majority of the posterior segment disorders are chronic in nature, sustained delivery of medications is highly desirable. Liposomes and microparticulates are such systems designed to release the encapsulated drug gradually and over an extended period of time. For reviews on intra-ocular drug delivery systems see Gregoriadis and Florence (1993), Metrikin and Anand (1994), and Peyman and Ganiban (1995) detailed at the end of this chapter. For example, liposome-encapsulated amphotericin B produced less toxicity than the commercial amphotericin B solution when injected intravitreally. Liposomes have also been used to study the release and distribution of dyes, which in turn reflect the integrity of the retinal vascular constitution. Direct intravitreal injection of liposomal-encapsulated drugs has shown enhanced vitreal levels for extended periods of time in the vitreous of rabbit models. Biodistribution of dexamethasone sodium phosphate has been evaluated following intraocular delivery in rabbits. The liposomes were found to bind to various ocular tissues including the retina, iris, sclera and cornea. Using gold-colloid loaded liposomes, it was demonstrated that retinal bound liposomes were attached to the inner limiting membrane and did not penetrate the inner cells of the retina. Heat-sensitive liposomes containing carboxyfluorescein have also been used to examine the potential of liposomes for targeted drug delivery to selected areas of the retina.

However cheap procyclidine 5 mg fast delivery, biotechnologi- • temperature cycling study for drug products cal and biological products have distinguishing characteris- that may be exposed to temperature variations tics to which consideration should be given in any well- above freezing may consist of three cycles of 2 defined testing program designed to confirm their stability days at refrigerated temperature (2°–8°C) fol- during the intended storage period buy discount procyclidine 5 mg line. For such products in lowed by 2 days under accelerated storage con- which the active components are typically proteins or ditions (40°C) order procyclidine 5mg without prescription. The products are particularly sensi- tures may consist of three cycles of 2 days at tive to environmental factors such as temperature changes, freezer temperature (−10° to −20°C) followed oxidation, light, ionic content, and shear. To ensure mainte- by 2 days under accelerated storage conditions nance of biological activity and to avoid degradation, strin- (40°C). With these concerns in mind, the applicant should • Alternatives to these conditions may be accept- develop the proper supporting stability data for a bio- able with appropriate justification. Primary data to support a requested is submitted to the agency, with a commitment to place storage period for either drug substance or drug product the first three manufacturing-scale batches into the long- should be based on long-term, real-time, real-condition term stability program after approval. Thus, the development of a proper long- The quality of the batches of drug substance placed term stability program becomes critical to the successful into the stability program should be representative of the development of a commercial product. The purpose of this quality of the material used in preclinical and clinical document is to give guidance to applicants regarding the studies and of the quality of the material to be made at type of stability studies that should be provided in support manufacturing scale. It is understood that during the material) made at pilot-scale should be produced by a review and evaluation process, continuing updates of ini- process and stored under conditions representative of tial stability data may occur. Containers of The guidance in this section applies to well-characterized reduced size may be acceptable for drug substance stabil- proteins and polypeptides, their derivatives, and products ity testing provided that they are constructed of the same of which they are components and that are isolated from material and use the same type of container and closure tissues, body fluids, or cell cultures or produced using system that is intended to be used during manufacture. Intermediates stability data for products such as cytokines (interferons, During manufacture of biotechnological and biological interleukins, colony-stimulating factors, tumor necrosis products, the quality and control of certain intermediates factors), erythropoietins, plasminogen activators, blood may be critical to the production of the final product. In plasma factors, growth hormones and growth factors, insu- general, the manufacturer should identify intermediates lins, monoclonal antibodies, and vaccines consisting of and generate in-house data and process limits that ensure well-characterized proteins or polypeptides. Drug Product (Final Container Product) Stability information should be provided on at least three 3. However, because manufacturers ble, batches of final container product included in stability of biotechnological and biological products sometimes testing should be derived from different batches of bulk use traditional terminology, traditional terms are specified material. Product Where bulk material is to be stored after manufacture, but expiration dating should be based on the actual data sub- before formulation and final manufacturing, stability data mitted in support of the application. Because dating is should be provided on at least three batches for which based on the real-time/real-temperature data submitted for manufacture and storage are representative of the manu- review, continuing updates of initial stability data should facturing scale of production. The qual- stability data at the time of submission should be submit- ity of the final container product placed on stability studies ted in cases where storage periods greater than 6 months should be representative of the quality of the material used are requested. Data from pilot- of less than 6 months, the minimum amount of stability scale batches of drug product may be provided at the time data in the initial submission should be determined on a the application is submitted to the agency, with a com- case-by-case basis. Data from pilot-scale batches of drug mitment to place the first three manufacturing-scale substance produced at a reduced scale of fermentation and batches into the long-term stability program after approval. Protocol lish the dating for a product, and in the event that the The marketing application should include a detailed pro- product produced at manufacturing scale does not meet tocol for the assessment of the stability of both drug those long-term stability specifications throughout the dat- substance and drug product in support of the proposed ing period or is not representative of the material used in storage conditions and expiration dating periods. Sample Selection ing period including, for example, well-defined specifi- cations and test intervals. When the intended use of a product is linked to a defin- Matrixing—the statistical design of a stability study able and measurable biological activity, testing for in which different fractions of samples are tested at dif- potency should be part of the stability studies. For the ferent sampling points—should be applied only when purpose of stability testing of the products described in appropriate documentation is provided that confirms that this guidance, potency is the specific ability or capacity the stability of the samples tested represents the stability of a product to achieve its intended effect. The differences in the samples for the same the measurement of some attribute of the product and is drug product should be identified as, for example, cover- determined by a suitable in vivo or in vitro quantitative ing different batches, different strengths, different sizes of method. In general, potencies of biotechnological and the same closure, and possibly, in some cases, different biological products tested by different laboratories can container and closure systems. Matrixing should not be be compared in a meaningful way only if they are applied to samples with differences that may affect stabil- expressed in relation to that of an appropriate reference ity, such as different strengths and different containers and material. For that purpose, a reference material calibrated closures, where it cannot be confirmed that the products directly or indirectly against the corresponding national respond similarly under storage conditions. The design of a protocol that incorporates brated, whenever possible, against nationally or interna- bracketing assumes that the stability of the intermediate tionally recognized standards. Where no national or inter- condition samples are represented by those at the national reference standards exist, the assay results may extremes. In certain cases, data may be needed to demon- be reported in in-house derived units using a characterized strate that all samples are properly represented by data reference material. Dissociation of the active ingredient or or parameter that profiles the stability characteristics of a ingredients from the carrier used in conjugates or adju- biotechnological or biological product. As a consequence, vants should be examined in real-time/real-temperature the manufacturer should propose a stability-indicating studies (including conditions encountered during ship- profile that provides assurance that changes in the identity, ment). The assessment of the stability of such products purity, and potency of the product will be detected. The items emphasized in the follow- active compound from the second moiety, in vivo ing subsections are not intended to be all-inclusive, but assays) or the use of an appropriate surrogate test should represent product characteristics that should typically be be considered to overcome the inadequacies of in vitro documented to demonstrate product stability adequately. Purity and Molecular Characterization powders or lyophilized cakes, pH, and moisture For the purpose of stability testing the products described level of powders and lyophilized products. If there is any indi- of stability testing, tests for purity should focus on meth- cation during preliminary stability studies that ods for determination of degradation products. Limits of • The container/closure has the potential to affect acceptable degradation should be derived from the analyt- the product adversely and should be carefully ical profiles of batches of the drug substance and drug evaluated (see following). Temperature comprehensive characterization of the drug substance or drug product (e. As examples, meth- bility studies may be confined to the proposed storage ods that may contribute to this include electrophoresis temperature. Therefore, where it can be demonstrated that the proposed Wherever significant qualitative or quantitative containers (and conditions of storage) afford sufficient changes indicative of degradation product formation are protection against high and low humidity, stability tests at detected during long-term, accelerated, or stress–stability different relative humidities can usually be omitted. Where studies, consideration should be given to potential hazards humidity-protecting containers are not used, appropriate and to the need for characterization and quantification of stability data should be provided. Accelerated and Stress Conditions taking into account the levels observed in material used As previously noted, the expiration dating should be based in preclinical and clinical studies.

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Adjustment of dosage • Kidney disease: Creatinine clearance less than 80 mL/min: usual adult dose; creatinine clearance 50–80 mL/min: ≤2 g q6h; creatinine clearance 25–50 mL/min: up to 1 generic 5mg procyclidine amex. American Academy of Pedi- atrics considers cephalosporins to be compatible with breast- feeding quality 5 mg procyclidine. Contraindications: Hypersensitivity to other cephalosporins or related antibiotics purchase procyclidine 5mg visa, eg, penicillin. Contraindications: Hypersensitivity to statins, active liver disease or unexplained persistent elevations of serum transaminase, preg- nancy, lactation. Editorial comments • It remains to be established whether cerivastatin has a signifi- cant effect on morbidity and mortality from coronary heart dis- ease. Until the safety and effectiveness of higher doses of cerivastatin have been determined, older drugs are preferred. Adjustment of dosage • Kidney disease: Creatinine clearance <31 mL/min: reduce dose to 5 mg/d. Advice to patient • Avoid driving or other activities requiring mental alertness or that are potentially dangerous until response to drug is known. Parameters to monitor: Efficacy of treatment: improvement of symptoms of rhinitis including sneezing, rhinorrhea, itchy/water eyes. Contraindications: Hypersensitivity to chlorambucil or other alkylating agents, patient who did not respond to previous course of therapy. Warnings/precautions • Use with caution in patients with the following conditions: bone marrow depression, history of seizures or head trauma, administration of potential epileptogenic drugs. Avoid full dosage within 4 weeks of radiation therapy because of high risk of bone marrow depression. Advice to patient • Use two forms of birth control including hormonal and barrier methods. Editorial comments • Use latex gloves and safety glasses when handling cytotoxic drugs. Adjustment of dosage • Kidney disease: Adjust dose according to blood levels (see Parameters to Monitor). Plasma drug levels must be monitored carefully in such patients (see Parameters to Monitor). Warnings/precautions • Use with caution in patients with the following conditions: liver or kidney disease, bone marrow depression, other drugs that suppress bone marrow function, glucose-6-phosphate dehydrogenase deficiency, acute intermittent porphyria. Clinically important drug interactions • Drugs that increase effects/toxicity of chloramphenicol: amino- glycosides, polymyxin, nondepolarizing muscle relaxants, suc- cinylcholine, cephalothin. It is essential to monitor blood levels in the newborn to avoid gray baby syndrome. Editorial comments • This drug is to be used only for severe infections that do not respond to other antibiotics or would be expected to respond best to chloramphenicol infections. Detailed knowledge of proper dosing and acute awareness of toxic effects of chlo- ramphenicol are strongly advised prior to clinical use. American Academy of Pediatrics expresses concern about breast- feeding while taking benzodiazepines. Warnings/precautions • Use with caution in patients with the following conditions: his- tory of drug abuse, severe renal and hepatic impairment, elderly, neonates and infants. Advice to patient • Avoid driving and other activities requiring mental alertness or that are potentially dangerous until response to drug is known. If suddenly withdrawn, there may be recurrence of the original anxiety or insomnia. A full-blown withdrawal symptom may occur consisting of vomiting, insomnia, tremor, sweating, muscle spasms. After chronic use, decrease drug dosage slowly, ie, over a period of several weeks at the rate of 25% per week. Parameters to monitor • Signs of chronic toxicity: ataxia, vertigo, slurred speech. Editorial comments • Because of the long half-life of chlordiazepoxide and desmethyl- diazepam (its active metabolite), prolonged sedation may occur. The physician should be thoroughly familiar with the risks involved in using flumazenil, including the possibility of drug-induced seizures. Adjustment of dosage • Kidney disease: For severe kidney failure, 50% of usual adult dose should be used. Contraindications: Porphyria, retinal or visual field impairment, hypersensitivity to other 4-aminoquinolones (eg, hydroxychloro- quine). Advice to patient • Substances (drugs or foods) that increase urinary acidity may increase renal excretion and thereby decrease effectiveness. Clinically important drug interactions • Drugs that decrease effects/toxicity of chloroquine: kaloin, magnesium trisilicate. Monitor for symptoms of retinopathy periodically as this may be irreversible if it occurs. Editorial comments • Used in malaria when chloroquine refractoriness is not a con- cern. Mechanism of action: Inhibits sodium resorption in distal tubule resulting in increased urinary excretion of sodium, potasssium, and water. Contraindications: Anuria, hypersensitivity to thiazides or sul- fonamide-derived drugs. Editorial comments • Chlorpheniramine has antiserotonergic as well as antihista- minic properties.

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View Online Drug Discovery Approaches for Rare Neuromuscular Diseases 283 premature stop codon buy procyclidine 5 mg cheap, vide infra); both of these latter concerns would be circumvented by the use of orally available small-molecule drugs discount 5mg procyclidine with mastercard. Compounds that were able to promote read- through of this premature stop codon would therefore result in an increased amount of luciferase expression discount procyclidine 5 mg on-line, and more luminescence. The result of this screen was identication of a series of hit compounds based on an oxadiazole core, which were subsequently optimised further using conventional library- based medicinal chemistry synthesis techniques. All in all, following the high-throughput screen, approximately 3500 compounds were synthesised and evaluated in follow-up biological tests. Given the putative mode of action of the compound, it might be antici- pated that any compounds discovered using this paradigm would similarly have the potential to nd utility as a therapeutic agent for use in other diseases caused by premature stop codons. In terms of target plasma concentration for efficacy, detailed information on the plasma levels required to see a therapeutic effect were not available, but the pre-clinical efficacy models used had suggested that maintaining plasma À1 concentrations between 2 and 10 mgmL would prove efficacious. Accord- ingly, these were the trough levels targeted during the clinical studies for the compound. In addition, a qualitative assessment of drug taste (palatability) of the orally delivered liquid suspension was included in the trial design, again to cater for the intended paediatric patients. Based on the dose dependence of these events, the investigators concluded that the occurrences were linked to Cmax plasma levels of drug. In line with the investigators’ expectations, no toxicological issues were encountered. Critically, given the compound mode of action, analysis of blood samples for evidence of non- selective read-through of stop codons was also undertaken by looking for extended length marker proteins. Although the drug was well tolerated and this latter result was encouraging, it was not statisti- cally signicant, and the study was discontinued. Further- more, the confounding activity in the rey luciferase assay was conrmed. The assay protocol was validated using ataxia-telangiectasia as a disease model, and in separate experiments also established that the treatment of mdx cells with the compounds resulted in the restoration of dystrophin expression. Although a detailed evaluation of the compound’s pharmacokinetics was not reported, bioanalysis of 11. Interestingly no parent compound was detectable in plasma at any time point following intraperi- toneal injection, although levels up to around 3 mM were detected in most muscles sampled, including the heart. This observation is of particular relevance for a muscular dystrophy therapeutic where cardiac muscle has historically proven difficult to target with drugs. Based on the in vitro cellular data, compound levels of between 2 and 10 mM would be predicted to increase dystrophin levels by around 1–3%, and indeed this is what was Figure 11. View Online Drug Discovery Approaches for Rare Neuromuscular Diseases 287 observed when various types of muscle were analysed for dystrophin-positive bres. More importantly, these positive histological data translated to functional benet following treatment with 11. Although these data are clearly encouraging, it is important to place this project in context. A more detailed analysis of the compound/class pharmacokinetics will be essential, as well as concomitant delineation of structure–activity relationships in order to translate the intraperitoneal dosing regimen into (ideally) an orally delivered agent. There are also functional groups within the compound that may raise concern, for example the nitrophenyl motif, as well as the iminothiazolone ring, because these types of functionalities have been commonly associated with both assay interference and poor drug proles in the past, and so appropriate replacements and/or safety assessments will be critical. For reasons that are not yet clear, utrophin expression decreases signicantly with maturity during foetal development, and is replaced almost exclusively by dystrophin. As well as having structural similarity, utrophin has been established as playing a functionally equivalent role to dystrophin, this having been conclusively demonstrated by Davies et al. Although the proof-of-concept murine experiments were conducted using transgenes, alternative strategies using pharmacological approaches can be envisaged, and are potentially attractive as a small-molecule drug can in principle be delivered orally, would be relatively inexpensive compared to a biologic agent, and should be systemi- cally available, thereby having the potential for treating all muscles, including the difficult to target cardiac tissue. The potential of both biologics and low molecular weight biochemicals to upregulate the production of utrophin has good precedent, with agents such as heregulin128 and L-arginine129 having been shown to ameliorate the dystrophic phenotype when dosed to mdx mice. Heregulin is thought to work by activation of the utrophin A promoter, with the mode of action of L-arginine being postulated as being through activation of the nitric oxide pathway, indirectly activating utrophin. Although providing a critical proof-of-concept for the approach, none of these agents represents a viable drug therapy at this stage, because many questions remain unanswered, particularly how an appropriate dosing regimen can be established, as well as whether or not there are any longer- term compound-associated toxicological consequences. A number of companies, including large pharmaceutical organisations as well as biotechnology companies, are seeking to develop small-molecule upregulators of utrophin, including BioFocus and Summit plc, and the View Online Drug Discovery Approaches for Rare Neuromuscular Diseases 289 therapeutic approach has been reviewed recently by Khurana et al. It was discovered during a collaborative programme with scientists from the University of Oxford’s Chemistry, Physiology, Anatomy and Genetics Departments. The medicinal chemistry hit discovery and lead optimisation work for this project has been published recently. Following hit conrmation, a more straightforward lead optimisation approach was undertaken, based on evaluating the structure–activity relationships of a series of hit compounds. The initial assay used for primary screening of the compound libraries was conducted in H2K cells, which had been engineered to express the utrophin A promoter linked to a luciferase reporter construct. Accordingly, any compounds that interacted with and activated the respective utrophin promoter would be easily detected and quantied using a luminescent readout. Since that time additional utrophin promoters have been identied, and therefore it is possible that this screen would not necessarily identify all compounds that are potentially able to upregulate the production of utrophin using this or a related mechanism. View Online 290 Chapter 11 considerable optimisation, because they were described as suffering from rapid metabolism in mouse liver microsomes and having poor physico- chemical properties. Moreover, both contained functional groups that were felt to be unsuitable for progressing the compounds further, including anilines and phenols. The aniline motif contained within both examples was felt to be a particular liability, because it is known to be a potent toxicophore in some cases. The latter liability was conrmed in vivo when preliminary assessment of exposure levels was made by dosing lead molecules orally in mice, and plasma levels of compound were found to be very low. A schematic representation of the strategy used to explore the structure–activity relationships carried out is illustrated in Figure 11. Alkyl amides were found to be active, particularly when located at the 6- and 7-positions of the benzoxazole core, and with a clear size dependence, although they were also found to suffer from poor metabolic stability, a problem that was further apparent following in vivo dosing.

However cheap procyclidine 5 mg on-line, a major limitation of these systems is their inability to cross intact endothelial barriers and leave the general circulation buy procyclidine 5mg with mastercard. However generic procyclidine 5 mg visa, sterically stabilized particulate carriers have extended circulation times and can remain in the blood, either acting as circulating drug reservoirs, or they may slowly escape from the blood pool at pathological sites with increased vascular permeability. Intra-arterially administered particles with dimensions exceeding 7 µm will be trapped in the closest organ located upstream; for example, administration into the mesenteric artery leads to entrapment in the gut, into the renal artery leads to entrapment in the kidney etc. This approach is under investigation to improve the treatment of diseases in the liver. Active targeting strategies for particulate systems are similar to those discussed for soluble macromolecular systems (see Table 5. The lipid molecules are usually phospholipids, amphipathic moieties with a hydrophilic head group and two hydrophobic chains (“tails”). Such moieties spontaneously orientate in water to give the most thermodynamically stable conformation, in which the hydrophilic head-group faces out into the aqueous environment and the lipidic chains orientate inwards avoiding the water phase; this gives rise to bilayer structures. In order to reduce exposure at the edges, the bilayers self-close into one or more concentric compartments around a central discrete aqueous phase. Dependent on the preparation protocol used, liposome diameters can vary between 0. Depending on the physico-chemical nature of the drug, it can either: • be captured in the encapsulated aqueous phase (i. Thus liposomes can serve as carriers for both water-soluble and lipid-soluble drugs. The liposomal encapsulation of a wide variety of drugs, including antitumor and antimicrobial agents, chelating agents, peptides, proteins and genetic material have all been described. Bilayer composition can be almost infinitely varied by choice of the constituent lipids. Liposomal bilayers may also accommodate sterols, glycolipids, organic acids and bases, hydrophilic polymers, antibodies and other agents, depending on the type of vesicle required. The rigidity and permeability of the bilayer strongly depend on the type and quality of lipids used. The alkyl-chain length and degree of unsaturation play a major role For example, a C18 saturated alkyl chain produces rigid bilayers with low permeability at room temperature. Such systems are more stable and can retain the entrapped drug for relatively longer periods, whereas more “fluid” bilayer systems can be prepared if a more rapid release is required. As phospholipid bilayers form spontaneously when water is added, the important challenge in liposome preparation is not the assembly of simple bilayers (which happens automatically), but in causing the bilayers to form stable vesicles of the desired size, structure and physicochemical properties, with a high drug encapsulation efficiency. There are many different approaches to the preparation of liposomes; however, they all have in common that they are based on the hydration of lipids: Liposomes represent highly versatile drug carriers, offering almost infinite possibilities to alter structural and physicochemical characteristics. This feature of versatility enables the formulation scientist to modify liposomal behaviour in vivo and to tailor liposomal formulations to specific therapeutic needs. It has taken two decades to develop the liposome carrier concept to a pharmaceutical product level, but commercial preparations are now available in important disease areas and many more formulations are currently undergoing clinical trials. Examples of the different applications and commercial products of various types of liposomal systems are given below. Most of the early work on liposomes as a drug-carrier system employed this liposomal type. Conventional liposomes have also been used for antigen delivery and a liposomal hepatitis-A vaccine has received marketing approval in Switzerland. A commercial product based on conventional liposomes has been introduced for the parenteral delivery of the anti-fungal drug, amphotericin B, which is poorly tolerated in conventional formulations. Two other lipid-based formulations of amphotericin B have also recently been commercially introduced: • Abelcet consists of ribbon-like structures having a diameter in the 2–5 µm range. In spite of the large differences in structural features (a further example of “liposomal” versatility), all formulations have been shown to greatly reduce the toxicity of amphotericin B, allowing higher doses to be given and thereby improving clinical efficacy. DaunoXome liposomes are also long circulating liposomes, in this case encapsulating the cytostatic daunorubicin. Although a non-stealth system, long circulation times are attained by using a particularly rigid bilayer composition, in combination with a relatively small liposome size. The encapsulation of these anthracycline cytostatics in liposomes effects a modified biodistribution of the drug; the drug is distributed away from the heart, where it can exert considerable toxic effects, and is preferentially taken up by solid tumor tissue. The primary focus of their use has been in the targeted delivery of anticancer agents. The stability of these micelles depends on the nature of the hydrophilic and hydrophobic effects. Micellar systems based on amphipathic block-copolymers have gained most attention as intravenously administered drug carrier systems over the years. These block-copolymers form micelles in aqueous solution with spherical core/shell structures and diameters around 20–40 nm (Figure 5. The hydrophobic core of these micelles can be loaded with a hydrophobic drug such as doxorubicin. After intravenous administration the micelles tend to accumulate at tumor sites and release the entrapped drug there. Polymeric micelles loaded with doxorubicin have shown strongly increased antitumor activity in animal models. Work in progress to optimize the performance of polymeric micelles includes varying the copolymer characteristics, drug pay load, covalent binding strategies and using other types of drugs. Drug loading efficiency varies widely between different drugs, monomers and reaction conditions. Poor drug loading is therefore generally achieved for alkaline drugs because the polymerization reaction takes place under acidic conditions. Poly(butyl cyanoacrylate) nanoparticles are degraded fairly rapidly (1 day), whereas poly(hexyl cyanoacrylate) nanoparticles take a number of days to degrade.

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Concomitant therapy with cimetidine may increase altretamine’s half-life buy generic procyclidine 5 mg online, increasing the risk of altretamine toxicity procyclidine 5 mg amex. Metabolism and excretion Bone marrow Paclitaxel is metabolized primarily in the liver with a small suppression is also amount excreted unchanged in urine generic procyclidine 5mg with visa. Pharmacodynamics When other treatments fail, don’t Paclitaxel and docetaxel exert their chemotherapeutic effect by give up! Try paclitaxel disrupting the microtubule network essential for mitosis and oth- to treat metastatic er vital cellular functions. Pharmacotherapeutics Paclitaxel is used when first-line or subsequent chemotherapy has failed in treating metastatic ovarian cancer as well as metastatic breast cancer. Head, neck, and below The taxanes may also be used for treating head and neck cancer, prostate cancer, and non–small-cell lung cancer. Cultural considerations with docetaxel use Adverse reactions to Clinical trials of docetaxel in Japanese and Other results showed fewer incidences of American patients with breast cancer re- fluid retention, neurosensory effects, muscle paclitaxel and vealed significant differences in the incidence pain, infection, and development of anemia in docetaxel of adverse effects between the two cultures. The study also indicat- During clinical trials, ed that Japanese patients are more likely to The results 25% or higher of patients develop fatigue and weakness than are Ameri- Japanese women were more likely to develop experienced these ad- can women. How- verse reactions to pacli- ever, the Japanese women in this study were Putting it into a plan taxel: less likely than the American patients (6% ver- These results are important to consider when • bone marrow suppres- sus 29. Docetaxel Adverse reactions to do- Quick quiz cetaxel include: • hypersensitivity reac- tions 1. What’s the major adverse reaction that’s common to all alky- • fluid retention lating drugs? Bone marrow suppression is a common adverse re- • numbness and tingling action to all alkylating drugs. The drug likely to be administered with methotrexate to mini- mize its adverse effects is: A. Leucovorin is typically administered in conjunction with methotrexate to minimize adverse effects. Before administering bleomycin to a patient, why should you administer an antihistamine and an antipyretic? An antihistamine and an antipyretic may be adminis- tered before bleomycin to prevent fever and chills. For cases of smallpox, institute airborne precautions for the duration of the illness and until all scabs fall off. For pneumonic plague cases, institute droplet precautions for 72 hours after initiation of effective therapy. In the event of chemical agent exposure, follow standard precautions and decontamination protocols, such as removing cloth- ing and sealing it in plastic bags, irrigating the eyes, washing skin and hair using copious water, treating waste water as needed, and decontaminating the health care facility according to the specific agent involved. Chemical agent Treatment Antidote Chemical agent Treatment Antidote Nerve agents • Supportive • Atropine I. Phosgene intubation and zures Sulfur dioxide mechanical ventilation with Cyanides • Supportive • Amyl nitrite via positive-end Cyanogen chloride care inhalation expiratory Hydrogen cyanide • 100% oxygen • Sodium nitrite pressure by face mask; I. Herbal medicine Common uses Special considerations Aloe Oral • The laxative actions of aloe may take up to 10 hours after ingestion to • Constipation be effective. Ginseng • Fatigue • Ginseng may cause severe adverse reactions when taken in large • Improve concentration doses (more than 3 g per day for 2 years), such as increased motor and • Treat atherosclerosis cognitive activity with significant diarrhea, nervousness, insomnia, hy- • Also believed to strengthen pertension, edema, and skin eruptions. John’s wort • Mild to moderate depression • Effects may take several weeks; however, if no improvement occurs • Anxiety after 4 to 6 weeks, consider alternative therapy. John’s wort shouldn’t be used in combination with prescription • Viral infections antidepressants or antianxiety medications. Therapies for Glaucoma,” Expert Opinion on Emerg- ing Drugs 10(1):109-18 February 2005. Philadel- cine in an Outpatient Oncology Center,” Clinical phia: Lippincott Williams & Wilkins, 2007. Introductory Clinical Pharma- out Parathyroid Glands,” Endocrinology 146(2):544- cology, 8th ed. Clinical Geriatric Psychopharmacology, 4th physiologic Basis of Drug Therapy, 2nd ed. Adrenergic blocking drugs, 40-47 Aminophylline, 183-185 Anticholinergic drugs, 27-32, 60-62, topical, 416t Amiodarone, 131-132 177-178 Adrenergic drugs, 32-39 Amitriptyline, 322-325 Anticholinesterase drugs, 24-27 classifying, 32 Amlodipine, 138-140 differentiating toxic response to, mechanism of action of, 33i Ammonium chloride, 368-369 from myasthenic crisis, 24 Adsorbent drugs, 204-205 Amobarbital, 316-317 mechanism of action of, 22i Adverse drug reactions, 17-19 Amoxapine, 322-325 Anticoagulant drugs, 161-171 dose-related, 17-18 Amoxicillin, 196-197, 241-243 Anticonvulsant drugs, 68-85 patient sensitivity–related, 18-19 Amphetamine salts, mixed, 336-337 Antidepressants, 320-329 Agonist, 12 Amphotericin B, 280-283, 418t risks of, 322 Albuterol, 37-39, 176-177 Ampicillin, 241-243 Antidiabetic drugs, 339-345 Alclometasone, 419t Amprenavir, 272-275 Antidiarrheal drugs, 208-210 Aldesleukin, 408-409 Amylase, 206 Antidiuretic hormone, 350-352 Aldosterone, 301 Amyl nitrite, 135-136 Antiemetics, 216-219 Alemtuzumab, 398-399 Anakinra, 302-306 Antiestrogens, 388-390 Alfuzosin, 40-43 Anastrozole, 387-388 Antiflatulent drugs, 205 Alkalinizing drugs, 366-368 Androgens, 390-391 Antifungal drugs, 280-289 Alkylating drugs, 371-379 Anesthetic drugs, 108-115 dermatologic, 418t mechanism of action of, 373i ophthalmic, 414t Antigout drugs, 306-309 otic, 417t Antihistamines, 216-219, 294-297 i refers to an illustration; t refers to a table. Carboplatin, 378-379 Atazanavir, 272-275 Biperiden, 60-62 Carboxamides, 80-81 Atenolol, 43-47, 137-138 Bisacodyl, 214-215 Carboxylic acid derivatives, 76-78 Atorvastatin, 149-150 Bisoprolol, 43-47 Cardiac glycosides, 120-122 Atracurium, 56-58 Bistriazole antimycotic drug, 285-287 Cardiovascular drugs, 119-152 Atropine, 27-32, 30i, 416t Bitolterol, 37-39 Carisoprodol, 50-52 Atypical antipsychotics, 331-332 Bivalirudin, 169-170 Carmustine, 375-376 Autonomic nervous system drugs, Bleomycin, 385-386 Carteolol, 43-47, 416t 21-47 Boric acid, 417t Carvedilol, 43-47, 141-142 Azaspirodecanedione derivatives, 319 Bortezomib, 400-402 Caspofungin, 287-288 Azatadine, 294-295, 297 Brimonidine, 416t Castor oil, 214-215 Azathioprine, 302-306 Brinzolamide, 416t Catecholamines, 33-37 i refers to an illustration; t refers to a table. See also inhibitors, 66-68 mechanism of action of, 22i Nonsteroidal anti-inflammatory Cefaclor, 243-246 Choline salicylate, 94-96 drugs. See Dactinomycin, 385-386 Centrally acting skeletal muscle relax- also Calcium channel blockers. Dalteparin, 161-164 ants, 50-52 Clemastine, 294-295, 297 Dantrolene, 52-53 Central nerve block, 113i Clindamycin, 248-249, 418t, 420t Darbepoetin alfa, 160-161 Cephalexin, 243-246 Clioquinol, 281 Darifenacin, 230-231 Cephalosporins, 243-246 Clobetasol, 419t Darunavir, 272-275 mechanism of action of, 245i Clocortolone, 419t Daunorubicin, 385-386 Cerumenolytics, 417t Clomipramine, 322-325 Decongestants, 191-193 Cetirizine, 294-295, 297 Clonazepam, 74-76, 312-313, 314i, 315 Delavirdine, 270-271 Cevimeline, 21-24 Clonidine, 141-142 Demecarium, 24-27 Chamomile, 423t Clopidogrel, 165-169 Demeclocycline, 247-248 Chemical weapons exposure, treat- Clorazepate, 74-76, 312-313, 314i, 315 Depolarizing blocking drugs, 58-59 ment and antidotes for, 422t Clotrimazole, 281, 418t Dermatologic drugs, 418-420t Chloral hydrate, 317-318 Clove oil, 114-115 Desflurane, 109-110 Chlorambucil, 372-374 Clozapine, 331-332 Desipramine, 322-325 Chloramphenicol, 417t, 421t Cocaine, 112-115 Desloratadine, 294-295, 297 Chlordiazepoxide, 312-313, 314i, 315 Codeine, 102-105, 188-189 Desmopressin, 350-352 Chloroprocaine, 112-114 Colchicine, 307-309 Desonide, 419t Chlorothiazide, 224-225 Colesevelam, 147-148 Desoximetasone, 419t Chlorpheniramine, 294-295, 296i, 297 Colestipol, 147-148 Dexamethasone, 298-300, 415t, Chlorpromazine, 216-219, 333-336 Colistin sulfate, 417t 417t, 419t Chlorpropamide, 342-345 Competitive drugs, 56-58 Dexchlorpheniramine, 294-295, 297 Chlorthalidone, 224-225 Competitive inhibition, 107 Dextroamphetamine, 336-337 Chlorzoxazone, 50-52 Corticosteroids, 178-180, 297-301 Dextromethorphan, 188-189 Cholesterol absorption inhibitors, 152 special population concerns Diazepam, 53-55, 74-76, 312-313, 314i, Cholestyramine, 147-148 and, 179 315, 422t Choline magnesium trisalicylate, 94-96 Corticotropin, 349-350 Diazoxide, 142-143 Cholinergic agonists, 21-24 Corticotropin repository, 349-350 Dibucaine, 114-115 mechanism of action of, 22i Cortisone, 298-300 Diclofenac, 98-100, 415t Cholinergic blocking drugs, 27-32, Cosyntropin, 349-350 Dicloxacillin, 241-243 60-62, 177-178 Co-trimoxazole, 257-259 Dicyclomine, 27-32 i refers to an illustration; t refers to a table. Pirbuterol, 37-39, 176-177 Psyllium hydrophilic mucilloid, 212-213 Paromomycin, 238-240 Piroxicam, 98-100 Purine analogues, 383-384 Paroxetine, 320-322 Pituitary drugs, 348-352 Pyrazinamide, 276-280 Partial agonists, 44 Plants as drug sources, 3 Pyridostigmine, 24-27 Passive transport, 7 Podophyllotoxins, 396-397 Pyrimidine analogues, 381-383 Pathogen resistance, preventing, Polycarbophil, 212-213 mechanism of action of, 382 237-238 Polyenes, 280-283 Pyrophosphate analogues, 264 Patient sensitivity–related reactions, Polyethylene glycol, 211-212 Pyrrolidines, 84-85 18-19 Polymyxin B sulfate, 417t Patient’s response to drug, factors that Polythiazide, 224-225 Q affect, 15 Polyvinyl alcohol, 415t Quazepam, 312-313, 314i, 315 Peak concentration, 11-12 Positive inotropic effect, 119-120 Quetiapine, 331-332 Pediculicides, 420t Posterior pituitary drugs, 350-352 Quinapril, 144-145 Pegaspargase, 404 Potassium replacement, 360-361 Quinidine, 124-125 Penbutolol, 43-47 Potassium-sparing diuretics, 227-228 Penciclovir, 418t R Potentiation, 16 Penicillin-binding proteins, 241-242 Rabeprazole, 201-202 Pramipexole, 62-66 Penicillins, 241-243, 421t Radioactive iodine, 355-356 Pramoxine, 114-115 Pentazocine, 105-107 Ramelton, 317-318 Pravastatin, 149-150 Pentobarbital, 316-317 Ramipril, 144-145 Prazosin, 40-43, 141-142 Pentostatin, 383-384 Ranitidine, 199, 200i, 201 Prednisolone, 178-180, 298-300, 415t Peptic ulcer drugs, 195-203 Rasagiline, 62-66 Prednisone, 178-180, 298-300 Peripheral vascular resistance, 136 Recombinant human activated protein Prilocaine, 112-114 Permethrin, 420t C, 289-290 Primidone, 70-72 Perphenazine, 216-219, 333-336 Rectal route of administration, 5 Probenecid, 306-307 Pharmacodynamics, 12-13, 14i Remifentanil, 102-105 Procainamide, 124-125 Pharmacokinetics, 7-12 Repaglinide, 342-345 Procaine, 112-114 Pharmacologic class, 2 Replacement therapy, 15 Procarbazine, 405 Pharmacotherapeutics, 14-15 Reserpine, 141-142 Prochlorperazine, 216-219 Phenazopyridine hydrochloride, Respiratory drugs, 175-193 Procyclidine, 60-62 100-101 Respiratory route of administration, 5 Prodrug, 10 Progestins, 392-393 i refers to an illustration; t refers to a table. Yohimbine, 424t Triptorelin, 393-395 Tromethamine, 366-368 Z Tropicamide, 416t Zafirlukast, 180-182 Trospium, 230-231 Zaleplon, 317-318 Tuberculosis Zidovudine, 266-270, 268i directly observable therapy for, 276 Zileuton, 180-182 drug regimens for treating, 276-280 Ziprasidone, 331-332 Typical antipsychotics, 333-336 Zolmitriptan, 86-88 i refers to an illustration; t refers to a table. Professor and Executive Dean, South Carolina College of Pharmacy, The University of South Carolina, Columbia, Medical University of South Carolina, Charleston, South Carolina William J. Professor and Dean, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina Jane M. The information presented herein reflects the opinions of the contributors and reviewers. Drug information and its applications are constantly evolving because of ongoing research and clinical experience and are often subject to professional judgment and interpretation by the practitioner and to the uniqueness of a clinical situation. However, the reader is advised that the publisher, author, contributors, editors, and reviewers cannot be responsible for the continued currency or accuracy of the information, for any errors or omissions, and/or for any consequences arising from the use of the information in the clinical setting.