Professor, Cleveland Clinic Lerner College of Medicine
Metered-Dose inhalers Metering valves are employed when the formulation is a potent medication prostate cancer 60 year old order discount uroxatral online, as in inhalation therapy man health 4 me app buy uroxatral 10mg otc. In these metered valve systems prostate 84 order uroxatral online from canada, the amount of material discharged is regulated by an auxiliary valve chamber by virtue of its capacity or dimensions prostate surgery side effects purchase 10mg uroxatral overnight delivery. A single depression of the actuator causes evacuation of this chamber and delivery of its contents. However, in this position, the chamber is permitted to fill with the contents of the container, to which it is open. Depression of the actuator causes a simultaneous reversal of positions; the chamber becomes open to the atmosphere, releasing its contents, at the same time becoming sealed from the contents of the container. As noted previously, the effectiveness of delivering medication to the lower reaches of the lungs for local or systemic effects depends in part on the particle size of the inhaled drug. Breathing patterns and the depth of respiration also play important roles in the deposition of inhaled aerosols to the lungs. The product contains 200 doses of nitroglycerin in a propellant mixture of dichlorodifluoromethane and dichlorotetrafluoroethane. Filling operations As explained earlier, fluorinated hydrocarbon gases may be liquefied by cooling below their boiling point or by compressing the gas at room temperature. The cooling system may be a mixture of dry ice and acetone or a more elaborate refrigeration system. After the chilled product concentrate has been quantitatively metered into an equally cold aerosol container, the liquefied gas is added. The heavy vapors of the cold liquid propellant generally displace the air in the container. When sufficient propellant has been added, the valve assembly is inserted and crimped into place. Because of the low temperatures required, aqueous systems cannot be filled by this process, because the water turns to ice. For nonaqueous systems, some moisture usually appears in the final product due to the condensation of atmospheric moisture within the cold containers. The desired amount of propellant is allowed to enter the container under its own vapor pressure. When the pressure in the container equals that in the burette, the propellant stops flowing. The trapped air in the package may be ignored if it does not interfere with the quality or stability of the product, or it may be evacuated with a special apparatus. After the container is filled with sufficient propellant, the valve actuator is tested for proper function. This spray testing also rids the dip tube of pure propellant prior to consumer use. It has two advantages over cold filling: There is less danger of moisture contamination of the product, and less propellant is lost in the process. When compressed gases are employed as the propellant in aerosol systems, the gas is transferred from large steel cylinders into the aerosol containers. Prior to filling, the product concentrate is placed in the container, the valve assembly is crimped into place, and the air is evacuated from the container by a vacuum pump. The compressed gas is then passed into the container through a pressure-reducing valve attached to the gas cylinder; when the pressure within the aerosol container is equal to the predetermined and regulated delivery pressure, the gas flow stops, and the aerosol valve is restored to the closed position. Testing the Filled Containers After filling by either method, the aerosol container is tested under various environmental conditions for leaks or weakness in the valve assembly or container. The valve discharge rate is determined by discharging a portion of the contents of a previously weighed aerosol during a period and calculating, by the difference in weight, the grams of contents discharged per unit of time. As is deemed desirable, aerosols may be tested for their spray patterns, for particle size distribution of the spray, and for accuracy and reproducibility of dosage when using metered valves. Packaging, labeling, and storage A unique aspect of pharmaceutical aerosols compared to other dosage forms is that the product is actually packaged as part of the manufacturing process. With most other dosage forms, the product is completely manufactured and then placed in the appropriate container. Most aerosol products have a protective cap or cover that fits snugly over the valve and mounting cup. The cap, which is generally made of plastic or metal, also serves a decorative function. In addition to the usual labeling requirements for pharmaceutical products, aerosols have special requirements for use and storage. For example, for safety, labels must warn users not to puncture pressurized containers, not to use or store them near heat or an open flame, and not to incinerate them. Most medications in aerosol containers are intended for use at ambient room temperatures. Pharmaceutical aerosols are labeled with regard to shaking before use, holding at the proper angle and/or distance from the target; there are special detailed instructions for inhaler devices. Aerosols should be maintained with the protective caps in place to prevent accidental activation of the valve assembly or contamination by dust and other foreign materials. Proper administration and use of Pharmaceutical aerosols the pharmacist should make every attempt to educate the patient about aerosol dosage forms, particularly for oral or nasal Figure 14. To complement verbal instructions, the pharmacist should provide the patient with the written instructions in the product package. It is difficult to predict what percentage of patients will read or understand the printed instruction.
But whether their pathogenesis differs from that of metastases at other sites is not known man health tonic discount uroxatral 10mg on-line. Permeation of the meninges at the base of the skull and spinal canal is mainly seen in certain types of lymphomas man health food 10mg uroxatral mastercard, though these occasionally produce nodular brain lesions androgen hormone memes safe uroxatral 10mg. Breast cancer is the second most common source of brain metastases prostate oncology letters cheap 10 mg uroxatral visa, being a very common tumor in America; they ultimately develop in 35% of patients with metastatic disease (DiStefano et al. They are not usually symptomatic until late in the course of the disease, after metastases to bone and lung become detectable. The number of metastases per brain in breast cancer patients appears, in some, but not all studies (Delattre et al. But this may be, in part, due to gender; female lung cancer patients have been reported to have more metastases per brain than males (Yawn et al. The incidence of cerebellar metastases is highest in breast cancer patients (Yoshida and Takahashi, 2009), but this does not necessarily indicate a predilection for cerebellar involvement. The incidence of breast metastases in the cerebellum correlates strongly with the total number of brain metastases present (Hengel et al. Most lung cancer patients present with incurable disease, and systemic therapies are only effective in a minority. But the majority of breast cancer patients are potentially curable at presentation, especially with adjuvant therapies. Breast cancer metastases at any site are far more sensitive to systemic chemotherapy than those from lung cancer, and also respond to endocrine therapy in tumors expressing hormone receptors. Such treatments may delay overt progression of micrometastases for years, and 50% of patients with bone and lung metastases may be controlled by systemic therapy for many months. But the drugs used in systemic therapies may not reach the brain, so that metastases there may accumulate while other metastases are suppressed by therapy (Hengel et al. It is rare in acute myeloblastic leukemia, though it occasionally occurs in the monoblastic subsets (M4 and M5). The meninges at the bases of skull and cord are the most frequent sites of involvement. The usual clinical syndrome is that of mononeuritis multiplex, due to entrapment of nerve roots by meningeal growth. Ophthalmoplegias due to cranial nerve involvement are common, as are symptoms of lumbar root involvement. This may be based on experience with primary intracerebral brain tumors, surgical resection of which can result in epileptogenic foci. Although brain imaging is usually performed for brain-related symptoms, it is also indicated in all lung cancer patients regardless of whether symptoms are present (Gore et al. The former are typically sharply circumscribed, though they often display ring enhancement (Barajas and Cha, 2012). It is especially important to rule out apparently localized melanomas, which may metastasize early. Localized primary small cell tumors, whether bronchogenic or arising at other sites, are often found to have metastasized to the brain. Lumbar puncture to reveal neoplastic cells in the cerebrospinal fluid may be specific, but is quite insensitive. Examination of spinal fluid cells is diagnostic in less than 50% of cases, though flow cytometry may increase sensitivity. The presence of, for example, an abducens palsy is sufficient to establish the diagnosis. But their growth is often associated with a local inflammatory, hypervascular reaction around them, denoted as ring enhancing by their appearance on imaging. The resulting edema is usually associated with neurologic deficits, and may lead to midline shift, herniation and sudden death. Cells from most tumors must pass through the pulmonary capillary circulation to reach organs other than the lung itself, which is the commonest site of metastases. Cells from primary lung cancers presumably enter the systemic circulation directly from draining veins. They thus reach the cerebral circulation without the interposition of other small vessels. Yet, specific cellular mechanisms which may facilitate the adhesion and growth of lung cancer cells in the brain still seem probable. Studies in animal melanoma models revealed specific cell lineages from primary melanomas with a strong predilection for spread to the brain. Such cells were shown in vitro to bind to the surface of brain cells and to proliferate in this environment. The assumption was that such tumor cells had gained mutations enabling brain metastases. There is increasing evidence that metastatic cells do not necessarily acquire mutations additional to those in the primary tumors (Jones et al. Tissue from such lesions is usually obtained at post-mortem examinations, in which the metastases are devitalized, so that markers cease to be detectable. Perhaps the best evidence for the existence of such markers is the predilection of specific breast cancer subsets for the brain. Were it possible to characterize brain specific markers in subsets of the cells from any tumors, a pharmacologic approach to inhibiting brain metastases might be possible.
In general prostate cancer 2016 cheap uroxatral on line, antioxidants act by providing electrons and easily available hydrogen atoms that are accepted more readily by the free radicals than are those of the drug being protected mens health xtreme muscle pro order 10 mg uroxatral overnight delivery. In oleaginous (oily or unctuous) preparations prostate cancer journal articles discount 10mg uroxatral overnight delivery, alpha-tocopherol prostate cancer 67 years of age cheap uroxatral 10 mg fast delivery, butyl hydroxy anisole, and ascorbyl palmitate find application. Sulfites are used as preservatives in many injectable drugs, such as antibiotics and local anesthetics. Some inhalants and ophthalmic preparations also contain sulfites, but relatively few oral drugs contain these chemicals. Sulfite agents covered by the regulations are potassium bisulfite, potassium metabisulfite, sodium bisulfite, sodium metabisulfite, sodium sulfite, and sulfur dioxide. The proper use of antioxidants permits their specific application only after appropriate biomedical and pharmaceutical studies. In certain instances, other pharmaceutical additives can inactivate a given antioxidant. In other cases, certain antioxidants can react chemically with the drugs they were intended to stabilize without a noticeable change in the appearance of the preparation. Because oxygen may adversely affect their stability, certain pharmaceuticals require an oxygen-free atmosphere during preparation and storage. Oxygen may be present in pharmaceutical liquids in the airspace within the container or may be dissolved in the liquid vehicle. To avoid these exposures, oxygensensitive drugs may be prepared in the dry state and packaged in sealed containers with the air replaced by an inert gas such as nitrogen, as may liquid preparations. This is a common practice in commercial production of vials and ampuls of easily oxidizable preparations intended for parenteral use. Trace metals originating in the drug, solvent, container, or stopper are a constant source of difficulty in preparing stable solutions of oxidizable drugs. The rate of formation of color in epinephrine solutions, for instance, is greatly increased by the presence of ferric, ferrous, cupric, and chromic ions. Great care must be taken to eliminate these trace metals from labile preparations by thorough purification of the source of the contaminant or by chemically complexing or binding the metal through the use of specialized agents that make it chemically unavailable for participation in the oxidative process. Light can also act as a catalyst to oxidation reactions, transferring its energy (photons) to drug molecules, making the latter more reactive through increased energy capability. As a precaution against acceleration of oxidation, sensitive preparations are packaged in light-resistant or opaque containers. Because most drug degradations proceed more rapidly as temperature increases, it is also advisable to maintain oxidizable drugs in a cool place. Another factor that can affect the stability of an oxidizable drug in solution is the pH of the preparation. Each drug must be maintained in solution at the pH most favorable to its stability. This varies from preparation to preparation and must be determined on an individual basis for the drug in question. In some instances, the specific agent to employ as a stabilizer is mentioned in the monograph, and in others, the term "suitable stabilizer" is used. Potassium iodide in solution is prone to photocatalyzed oxidation and the release of free iodine, with a resultant yellowto-brown discoloration of the solution. In the event, free iodine is released during storage, and the sodium thiosulfate converts it to colorless and soluble sodium iodide: I 2 + 2Na 2 S 2 O 3 2NaI + Na 2 S 4 O 6 In summary, for easily oxidizable drugs, the formulation pharmacist may stabilize the preparation by the selective exclusion from the system of oxygen, oxidizing agents, trace metals, light, heat, and other chemical catalysts to the oxidation process. Antioxidants, chelating agents, and buffering agents may be added to create and maintain a favorable pH. However, these processes occur less frequently and are peculiar to only small groups of chemical substances. Drug stability is important during preclinical testing and in clinical (human) trials to obtain a true and accurate assessment of the product being evaluated. For a marketed drug product, assurance of stability is vital to its safety and effectiveness during the course of its shelf life and use. It is important for pharmacists to have a basic understanding of pharmaceutical analysis to ensure that valid results are obtained when tests are being conducted. It is important to know (a) when to test, (b) what to test, (c) what method(s) to use, (d) how to interpret the results, (e) the limits of the test, and (f) the importance of analytical testing in the overall quality program in pharmacy. The goal in analytical testing is to produce results as accurately, efficiently, and quickly as possible. Any analytical method used should have accuracy, speed, reproducibility, and specificity. No single analytical method is ideally suited for all drugs; each method has its own strengths and weaknesses, and there are a number of factors that determine the validity and reliability of results. Another consideration involves the physical and chemical characteristics of the analyte, including its solubility, partition coefficient, dissociation constant (pKa), volatility, binding, and the quantity present. One must consider the degree of quantitative measurement in the validation process, for example, accuracy, repeatability/reproducibility, and precision are required; generally, the greater the level that is required, the more sophisticated and expensive the analytical methods that must be used. This is also governed by the types of instrumentation that are on hand or available and the standards available for comparison. The effects of air, such as oxidation of the sample ingredients, the presence of carbon dioxide and the formation of insoluble carbonates, pH changes, free versus bound drug, etc. The sample must be stored at the proper temperature (refrigerated, frozen, or controlled room) prior to shipment and during shipment.
The film covering the stratum corneum varies in composition androgen hormone with pcos generic uroxatral 10mg with mastercard, thickness prostate 20 quality 10 mg uroxatral, and continuity as a result of differences in the proportion of sebum and sweat produced and the extent of their removal through washing and sweat evaporation androgen hormone 15 buy uroxatral toronto. Hair follicles and gland ducts can provide entry for drug molecules prostate 60 grams buy cheap uroxatral 10mg line, but because their relative surface area is so minute compared to the total epidermis, they are minor factors in drug absorption. The stratum corneum, being keratinized tissue, behaves as a semipermeable membrane, and drug molecules can penetrate by passive diffusion. The rate of drug movement across this skin layer depends on the drug concentration in the vehicle, its aqueous Duct of sweat gland Hair shaft Epidermis Horny layer Cellular layer Sebaceous gland Muscle that erects hair shaft Dermis Subcutaneous tissue Sweat gland Nerve Artery Vein Hair follicle FigUre 10. Substances with both aqueous and lipid solubility characteristics are good candidates for diffusion through the stratum corneum. If the drug reaches the vascularized dermal layer, it becomes available for absorption into the general circulation. Whereas drug blood levels achieved by transdermal delivery systems may be measured and equated against desired therapeutic effects, the same is not true for topical nonsystemic dermatologic products. For topical products, the therapeutically effective drug concentration in the skin is not known, so treatment is based on qualitative measures, with clinical efficacy often varying between patients and products. Differences in emollient and occlusive effects and ease of application and removal between products are factors of the base used and product type. As noted earlier, oleaginous bases provide greater occlusion and emollient effects than do hydrophilic or water-washable bases. Pastes offer even greater occlusion and are more effective than ointments at absorbing serous discharge. Creams, usually oil-inwater emulsions, spread more easily than ointments and are easier to remove. Unless otherwise directed, before applying a dermatologic product, the patient should thoroughly clean the affected area with soap and water and dry by patting with a soft cloth. In most instances, a thin layer of medication should be applied to the affected area and spread evenly using gentle pressure with the fingertips. Typically, about 1 to 3 mg of ointment or cream is applied per square centimeter of skin (1). Unless there is a specified need for an occlusive dressing to protect the area from excessive contact or contaminants, a bandage should not be used. The patient should be advised if symptoms persist or irritation develops, use of the product should be discontinued, and a physician or pharmacist consulted. It is fairly common for patients to have an allergic response, such as a skin rash, to a topical product as a result of sensitivity to the medicinal agent or pharmaceutic ingredient. An alternative product that does not contain the suspected offending agent may be substituted to solve the problem. Other ophthalmic dosage forms used topically include solutions, suspensions, and inserts, discussed elsewhere in this text. Systemic therapy also may be undertaken, as in the use of diuretics in the adjunctive treatment of glaucoma. The application of medication to the eye or conjunctival sac affects the surface of the eye and underlying tissues as the drug penetrates. For drugs that are poorly absorbed by the cornea, the conjunctiva and sclera provide an alternate route (12). The cornea is a threelayered structure with a lipophilic epithelial layer, a hydrophilic stromal layer, and a less lipophilic endothelial layer on the inside (12). Compared with ophthalmic solutions, ophthalmic ointments and gels provide extended residence time on the surface of the eye, increasing the duration of their surface effects and bioavailability for absorption into the ocular tissues. The ointment base selected for an ophthalmic ointment must not be irritating to the eye and must permit the diffusion of the medicinal substance throughout the secretions bathing the eye. Ointment bases used for ophthalmics should have a softening point close to body temperature, both for comfort and for drug release. Most often, mixtures of white petrolatum and liquid petrolatum (mineral oil) are used as the base in medicated and unmedicated (lubricating) ophthalmic ointments. Medicinal agents are added to an ointment base either as a solution or as a finely micronized powder. Rendering an ophthalmic ointment sterile requires special technique and processing. For a number of reasons, the terminal sterilization of a finished ointment by standard methods may be problematic. Steam sterilization or ethylene oxide methods are ineffective because neither is capable of penetrating the ointment base. Although dry heat sterilization can penetrate the ointment base, the high heat required may pose a threat to the stability of the drug substance and introduces the possibility of separating the ointment base from the other components (15). Because of these difficulties, terminal sterilization generally is not undertaken. Rather, strict methods of aseptic processing are employed as each drug and nondrug component is rendered sterile and then aseptically weighed and incorporated in a final product that meets the sterility requirement (15). When an antimicrobial preservative is needed, among those used are methylparaben (0. Detected metal particles are counted and measured by a calibrated eyepiece micrometer disk. The requirements are met if the total number of particles 50 mm or larger from ten product tubes does not exceed 50 and if not more than one tube contains more than eight such particles (2). These tubes have an elongated narrow tip to facilitate application of a narrow band of ointment to the eye. Then the ointment tube is held between the thumb and forefinger and the tip placed near the eyelid without touching it. The tip of the ointment tube should be held slightly above the inside portion of the sack between the lower eyelid and eyeball.
