Joel A. Kaplan, MD, CPE, fa cc

• Professor of Anesthesiology
• University of California, San Diego
• San Diego, California
• Dean Emeritus, School of Medicine
• Former Chancellor, Health Sciences Center
• University of Louisville
• Louisville, Kentucky

An "ideal" adhesive mixture would have both cohesive and adhesive interactions reduced to a minimum fungus gnats gnatrol buy diflucan 100mg without prescription. Such a task can be accomplished using either a coating with material of low adhesion or a coating reducing the particle contact area anti yeast vegetarian diet buy 200 mg diflucan visa, or both antifungal agents mechanisms of action purchase diflucan in india. Magnesium stearate anti fungal additive purchase diflucan 400 mg mastercard, a very common hydrophobic lubricant for oral dosage forms antifungal or antibiotic diflucan 100 mg fast delivery, has been tried extensively for adhesive respiratory blends anti fungal infection medicine order diflucan 100mg otc, typically in concentrations 0. Uniform coatings have been reported for lactose carriers as well as micronized drugs utilizing different high-energy shear mixing (64). Such intensive mechanical treatment also changes the particle surface morphology and possibly the particle size distribution, which need to be taken into account. Other excipients tried as force-controlled agents in blends include leucine and lecithin, which are known for their surface-active properties. Although coatings can improve such formulations, the safety of the hydrophobic excipients. More about different surface-active agents suitable for inhalable engineered particles will be discussed in the next section. Mannitol, a non-reducing sugar alcohol, has been extensively investigated as an alternative carrier, sometimes demonstrating a higher respirable fraction than standard lactose carrier (15) as well as improved physicochemical stability (being more crystalline and less hydroscopic than lactose); thus, it is particularly suitable for blend formulations with biological molecules (66). Ternary mixtures with jet-milled fine mannitol have also been investigated, so all mechanistic principles highlighted above for lactose formulations can also be applied to this carrier. Engineered solid particles the greatest potential to manipulate aerodynamic and dispersive properties lies in formulation of uniform particles with controlled size, shape, density and surface characteristics (rugosity and work of cohesion/adhesion). In parallel, engineering such particles may achieve goals related to their solid-state structural stability; dissolution and drug 20 Physicochemical properties of respiratory particles and formulations release functionality, including fixed-dose drug combination; potential for sustained or controlled release; and site-specific drug targeting. One of the most significant advancements in powder technologies for respiratory drug delivery was the application of spray drying to inhalable forms of insulin conducted in 1990s. Although the marketing strategy for these products failed, extensive physicochemical and manufacturing developments in this area have had a large impact, leading to other opportunities. The fluorocarbon serves as a blowing agent at high temperature to produce porous or hollow structures with a powder tapped density <0. This morphology reduces the effective particle density and aerodynamic diameter with a contribution from the particle shape factor. More information on different lipid formulations and animal and clinical studies can be found in (16). In addition to the optimized aerodynamic diameter combined with a larger geometric diameter, spray-dried particles often exhibit higher particle rugosity (surface asperities), which is also advantageous for reducing the aggregates strength. On the other hand, reduced flowability of such powders compared with the engineered blends has necessitated the use of more advanced filling machines (8,16). Another very important approach is the incorporation of forcecontrol agents into the particle shell, which can be applied to both low-density particles and particles with relatively high density (p > 1 g/cm3) (35). These surfactant molecules tend to accumulate on particle surfaces during spray drying, thus enhancing their surface modification effect. Another extensively studied group of compounds include hydrophobic amino acids, from which leucine has shown an exceptional dispersion enhancing effect for a number of spray-dried pulmonary formulations (15,35). In this work it was also suggested that higher segregation of leucine on the particle surfaces, even for dense particles, may lead to increased particle rugosity. This method can be classified in a group where carriers are produced by crystallization or coacervation in liquid solutions (15). Crystallization in supercritical carbon dioxide with very rapid mixing (13) tends to produce highly crystalline materials of controlled size, which have been extensively studied for small-molecule anti-asthmatic compounds such as salmeterol xinafoate, albuterol sulfate, terbutaline sulfate and fenoterol hydrobromide (14,15,68). The advantages of particle engineering in this case relate mostly to a reduction in specific surface energy, combined with relatively large surface-to-volume shape factor for these single crystals. Considering the high-pressure equipment, there are also restrictions imposed by the manufacturing scale and higher complexity compared to spray drying, which up-to-date has prevented this technology from being used commercially. Nanoaggregates consisting of solid nanoparticles in a format of larger respirable microparticles may possess some advantages, from the perspective of either improved dissolution or modified uptake mechanism in the lungs, when formulated to disintegrate into primary nanoparticles in vivo. Nanoparticles are typically produced by different emulsion-, self-assembly, or homogenization-based methods and showed some promise during in vitro and in animal studies. One of the major obstacles to employing many excipients is their safety profiles, especially for chronic indications. On the other hand, solid lipid nanoparticles (16) offer a higher biocompatibility and lower potential (acute and chronic) toxicity than polymeric nanoparticles or any other synthetic nano-constructs, as well as a relatively streamlined manufacturing process, which ideally is a high-pressure homogenization from low-temperature melts. The actives are usually incorporated within the lipid core matrix but may also be physically or chemically absorbed onto the surface. The challenges with these systems are typically related to their relatively low drug loading capacity (likely <1% w/w relative to the lipid phase) limited by the solubility of most drugs in solid lipids, which may also lead to insufficient drug release characteristics (16). The feasibility of all these systems for sustained/controlled respiratory drug delivery has yet to be proven, however, in clinic trials and on an industrial scale. These natural surfactants form structures varying in size from less than 50 nm for unilamellar liposomes to several microns for multilamellar liposomes. The physicochemical properties of liposomes and their drug release profile can be modified through the liposomal composition, size, membrane thickness, charge and drug loading characteristics, and other factors including osmolarity, pH, and choice of buffer and excipients. Thus, in principle, liposomes represent a versatile drug delivery platform for small molecules, nucleic acids, and peptides, with the rationale of modifying the pharmacokinetic profile in the lung, typically to treat lung diseases (16). These systems have been investigated for their potential as a pulmonary drug delivery vehicle since the mid1980s, with a number of inhaled liposomal formulations for asthma and oncology applications investigated in the clinic; however, the most active areas of current clinical research involve liposomal formulations of the antifungals and antibiotics. However, the industrial processes can be quite sophisticated, involving lipid dissolution and removal of organic solvent, concentration, homogenization or extrusion through a membrane, whereas drug loading can occur during liposome formation, or after formation using a pH or ion gradient for ionizable drugs. The quality control requirements include physicochemical stability of both drug and critical excipients. The lipids are known to undergo degradation via acid or base catalyzed lipid hydrolysis or oxidation reactions. Liposomes must also maintain physical stability to provide the desired drug release characteristics, which include vesicle lamellarity, size distribution and charge/zeta potential, membrane permeability and the drug encapsulation state. These parameters have to be sustained during manufacturing, shelf life (presumably with acceptable stability at least 18 months), and product use, which includes aerosolization and possible reconstitution from lyophilized state. Although significant progress has been achieved, stability still represents an issue for most inhalable formulations. For liquid formulations, more robust to dispersion stresses are small unilamellar liposomes with hydrophobic drugs incorporated into the lipid layer, as was confirmed by experimental studies (16). Several dry powder liposome formulations have been explored for respiratory drug delivery of small molecules and macromolecules (8). In this case, the low velocity is more advantageous for lower mouth-throat deposition but may potentially affect the particle dispersability in suspensions or primary particle size in solution formulations. If the drug is completely dissolved in the formulation, then particle formation may proceed in sequence: propellant atomization-formation of less volatile drops. For suspension formulations, this sequence is: propellant atomization-dispersion of solid drug particles (possibly in combination with carriers/excipients). In the first instance, formation of drug particles occurs in situ by drop evaporation at relatively low temperatures, affected by concentration of the cosolvents and the drug. The droplets may not entirely dry and increase deposition in the mouth and throat. Conversely, the same factors may affect the precipitation mechanism, leading to the structures that are often observed during the spray-drying process such as porous/hollow and amorphous particles (81). The process may also result in significant changes with the solid-state chemistry and dissolution, including formation of different solvates or hydrates dependent on the formulation characteristics, in particular, on the ethanol content and codrugs concentrations. For suspension formulations, the major concerns are related to physicochemical stability of such particles. It is likely that specific surface energy in propellants is reduced compared to that at the particle-air interface, by as much as an order of magnitude judging by the corresponding values for crystals in different media (31), further reducing Conclusions and future perspective 25 propensity for particle aggregation in propellants (see the section called "Particle aggregate strength"). This effect can be pronounced for both solid and porous particles, although perhaps the experimental evidence in this respect is lacking. Several studies have been conducted on use of bulking agents (such as lactose and leucine) to improve suspension stability (and dose uniformity) by employing different grades of micron- and submicron size excipient particles to form drug-excipient coflocculated matrix (17). From a different perspective, advanced carrier-drug mixtures can be beneficial for fixed-dose drug combinations. Such formulations may represent significant challenges for any inhaler type due to chemical incompatibility of drugs, different drug solubilities in a single solvent system but more often because of the difficulty to deliver the required fixed dose as solid particles, for a range of drug loadings, and for individual drugs as required for comparative clinical studies. This problem can be solved in different ways, but one of the most developed approaches consists of using standard micronized drug powders co-suspended with porous lipid microparticles (17,63). These excipient particles provide a bulk dilution for the drug, with the possibility of reducing interparticle interactions between carrier-drug aggregates and increasing physical stability for such suspensions. The principal difference between this type of formulation and those containing standard lactose blends is that porous lipid microparticles may be delivered into the lung together with the drug load, thus eliminating the need to separate them from the carrier surfaces. Measurements of the aggregate strength between drug crystals and porous microparticles in such systems have not been reported, but most likely such associations are reduced compared to the ordered lactose mixtures. More important, the large excess of the surface area available in such formulations physically separate drug crystals from each other so that there is a reduced probability for the drug-to-drug particle interactions. Special emphasis was placed on quantitative description of mechanisms that present challenges or are identified as knowledge gaps in the current development of respiratory drug delivery technology. These topics include particle dispersion and flow rate dependence, interparticle interactions and aggregate strength, the relationship between aerodynamic dispersion and inhaler design, the performance of carrier-based formulations and engineered particles, and fundamental and practically important subjects such as particle dissolution and solidstate stability of amorphous materials. Clearly, understanding physicochemical particle properties is paramount for designing efficient and robust inhalation products. In this relationship, the first-principles systematic approach may represent a more time- and cost-efficient strategy than empirically driven statistical DoE studies, which dominate current research and development. Within the remits of this chapter, the following points are discussed: Particle aerodynamic diameter and Stokes number can be defined a priori for any airflow regime of inhaler device, cascade impactor or mouth-throat deposition using experimentally determined geometric particle diameter, density, surface-to-volume shape factor and drag coefficients (see the section called "Aerodynamic diameter and Stokes number"). Particle aggregate strength, the major parameter of dispersability, can be calculated on the basis of the model proposed, taking into account the aggregates size structure and particle rugosity, but within the limitations imposed by the undefined interparticulate contact area (see the section called "Particle aggregate strength"). In addition, quantitative relationship is established between the inhaler parameters in terms of the device resistance, residence time, characteristic dispersion volume/dimensions and the average rate of energy dissipation which is a fundamental property of turbulence (see the section called "Modeling of dry powder dispersion"). Atomization of droplets for different liquid formulations can be adequately described by the maximum stable droplet size, which can also be linked to the dispersion mechanisms for such formulations and devices (see the section called "Atomization of droplets"). Dissolution of inhalable particles is largely determined by their solid-state properties rather than by solution diffusion or agitation. The dissolution profile in case of immediate release is defined through the particle size distribution, shape factor, surface kinetic coefficient and equilibrium solubility by a cubic polynomial function (see the section called "Drug solubility and mechanism of particle dissolution"). It is proposed that the activation enthalpy and entropy associated with non-cooperative molecular (rotational and translational) motions are the most essential fundamental parameters defining the different types of transitions in amorphous state. The contribution of these activation parameters, together with contributions from supersaturation (or supercooling) and configurational entropy can be assessed in experimental studies, although challenged by the long times required for such measurements below the glass transition temperature (see the section called "Solid-state chemistry of crystalline and amorphous materials"). Such a task can be achieved, in principle, using ternary mixtures with micro- and nanoparticles or surface coatings (see the section called "Lactose carriers and adhesive blends"). Solid engineered particles currently represent the most advanced (and commercially proven) approach to achieving superior aerodynamic characteristics, dose uniformity and potentially drug-release functionality. Liposomes also represent commercially viable and potentially versatile drug delivery systems, when their physicochemical stability can be controlled in the liquid or solid formulation. The optimistic intention here is to show that most issues or limitations can be resolved rationally by using an integral approach to the formulation/ inhaler design and to particle technology, and in relationship to the device-patient interface. Although encouraging, the use of solid engineered particles or liposomes in several currently approved (or close to the marketing authorization) products has to be cautiously considered in the light of over 25 years industrial development in this area. The current products with advanced formulations are based on well-known active ingredients, such as antibiotics or fixed dose combination asthma medicines, rather than new chemical or biological entities. There is also a very little current interest in developing inhalation products for systemic delivery or sustained release. Although there are many potential possibilities in this area, the more delicate biology of the lungs imposes more risks and requires more subtle approaches compared to delivery through the gastrointestinal tract. Thus, it would be premature to say that particle engineering has become an accepted approach to formulation of new drugs, although there are clear and distinct advantages for these particles in terms of high efficiency and dose uniformity. In this connection, it is worthwhile to consider parallels with nanotechnology platforms previously discussed in our review on lipid inhalable formulations (16). Nanomedicine has been one of the most speculative areas after decades of research and development with little practical success until now. The main reason seems to be in the lack of clinical justification for biopharmaceutical mode of action and drug targeting of nanoparticles compared to more traditional formulations, also with uncertainties associated with longterm toxicity or immunogenicity, particularly for formulations using new excipients. These conceptual issues are combined with very significant industrial difficulties in optimizing and controlling physicochemical properties of nanocarriers on a relatively large and complex manufacturing scale, thus creating additional (either psychological or real) hurdles for the industrial development. The major concerns of any pharmaceutical company are finding the fastest, risk-controlled Nomenclature 27 development path to a viable pharmaceutical product and, second, creating its reliable supply to patients. If a new particle formulation or engineering technology cannot offer substantial and clear benefits for ether biopharmaceutics or industrial manufacturing, it is highly unlikely that such a technology can be successful commercially. It is inevitable, however, that an increasing range of sophisticated respiratory drug delivery systems will be available to the patient. One of the driving forces is the shift from traditional crystalline drugs to larger synthetic or biological molecules, which necessitates development of stabilized amorphous formulations and engineered particles. Second, there is an introduction of new classes of potent medicines, or their combinations, specifically tailored for the delivery to the lungs and requiring higher efficiency, reproducibility, and higher therapeutic index achievable with an advanced inhaler-formulation design. An additional aspect of advanced formulation strategies that should not be ignored is the ability to generate novel intellectual property and to withstand generic competition, which is important for progressing such systems into commercial development. Eventually, particles will be designed for sustained and targeted delivery for topical applications, or delivery modes in which excipients play a functional role, for example, enhancing drug stability, adsorption, or residence time in vivo. The idea of systemic delivery is still viable for classes of drugs that require the rapid onset of action or enhanced bioavailability of pulmonary administration. The current state and potential applications of such therapeutics are discussed in the following chapters of this book.

As the clot regresses fungus gnats vermicompost buy diflucan with a mastercard, fibroblasts in the area proliferate to form a loose aggregate of cells fungus gnats egg shells buy diflucan 50 mg line. Small blood vessels grow into the injured area and together with the cells form granulation tissue fungi definition science cheap 150mg diflucan free shipping. During the reparative phase (several days after the fracture) cells from the periosteum and fibroblasts in the granulation tissue differentiate into chondroblasts antifungal cream boots diflucan 50mg fast delivery. Meanwhile fungus gnats baking soda purchase diflucan line, periosteal cells more distal to the injured site differentiate into osteoblasts and begin to form an immature bone tissue called woven bone antifungal horse buy diflucan uk. The combined effects of the osteoblasts and chondroblasts result in formation of a callus; that is, a mass consisting of bone and cartilage. The callus binds together the segments of fractured bone and is gradually replaced by spongy bone. This process involves osteoclasts that destroy the spongy bone and osteoblasts that deposit new compact bone. These cells synthesize and secrete all of the components of the bone matrix; that is, protein fibers. Osteoblasts facilitate the mineralization of the matrix by secreting calcium-binding proteins that create very high extracellular concentrations of calcium, and alkaline phosphatase, an enzyme that promotes formation of phosphate ions. The accumulation of calcium and phosphate results in the formation of hydroxyapatite, which is deposited in the matrix. The side of the cell that makes contact with bone has a ruffled border, whereas the opposite side is smooth. A so-called clear zone is an organelle-free band of cytoplasm adjacent to the ruffled border. Transport vesicles occupy much of the basolateral region (opposite the ruffled border) of the osteoclast. These vesicles contain components of the resorbed matrix and fuse with the plasma membrane to release this digested material via exocytosis. These remnants enter the interstitial fluid and are subsequently taken up by the blood stream. Hydrochloric acid is created in the extracellular space between the osteoclast and bone matrix. The acid reacts with the hydroxyapatite to produce calcium and phosphate, which enter the surrounding interstitial fluid. Hydrolase is released from lysosomes and causes the degradation of collagen fibers. The calcium and phosphate from the hydroxyapatite and amino acids from collagen are taken up via endocytosis, transported to the basolateral region, and then secreted via exocytosis. It is required for heart function, muscle activity, nerve function, blood clotting, and activity of certain enzymes. Minor imbalances in blood calcium levels can result in life-threatening conditions such as paralysis and heart failure. The mechanisms regulating blood levels of calcium are complex and involve digestive organs, kidneys, and bones. Absorption refers to the process whereby calcium is taken up from the intestine and transported into the blood. Reabsorption refers to the retrieval of calcium that has been previously absorbed. The kidneys produce urine by filtering solutes from blood and by secreting solutes into the filtrate. Note that small changes in blood calcium levels cause large changes in parathyroid hormone levels. We will consider three common bones diseases to reinforce fundamental concepts of bone physiology. One of the major causes of bone problems is a deficiency in calcium and/or vitamin D3, a precursor of calcitriol. A chemical called 7-dehydrocholesterol is a precursor of vitamin D and is stored in skin cells of the stratum basale and stratum spinosum. Cholecalciferol circulates in the blood and is converted to 25-hydroxycholecalciferol as it passes through the liver. In the kidneys, 25-hydroxycholecalciferol is converted to 1,25-dihydroxycholecalciferol, also known as calcitriol, the hormone that is necessary to maintain calcium absorption in the intestine. As noted in the previous section, calcium absorption from the intestine is a major contributor to calcium homeostasis. It is therefore evident that a calcium or calcitriol deficiency can severely disrupt calcium homeostasis. When either of these two conditions occur, bone resorption increases in order to stabilize blood calcium levels. This is the direct result of demineralization; that is, the fibrous component of the bone matrix remains intact, but there is insufficient mineral to make the bones rigid. In adults, demineralization is not associated with bowing of the long bones, but there is increased incidence of bone fractures. One of the most important risk factors is a decrease in sex hormones (estrogen and testosterone). Osteoporosis is more prevalent in postmenopausal women due to the marked, age-related decline in estrogen production by the ovaries. The disease develops from an imbalance between bone resorption and bone formation; that is, the rate of bone destruction by osteoclasts becomes greater than the rate of bone deposition by osteoblasts. The most common sites of fractures include the bones of the wrists, spine, shoulders, and hips. In osteomalacia, the balance between bone resorption and ossification is maintained, so there is no increase in porosity of bones. In contrast, osteoporosis occurs in women with adequate dietary calcium and vitamin D. The disease is the result of improper bone remodeling due to excessive bone resorption. In the past 20 years much has been learned about the mechanisms causing osteoporosis. It appears that development of this disease depends on three major variables: peak bone mass, degree of bone resorption, and degree of new bone formation. After this time there is a gradual loss of spongy bone that appears to be part of the normal aging process. In women estrogen appears to suppress bone resorption, and the decline in estrogen production associated with menopause is a major contributing factor to the age-related loss of bone mass. The most effective way to learn skeletal anatomy is to examine specimens and drawings that depict bones from several perspectives. The text is minimal and limited to only that which is necessary to help you understand diagrams. The axial skeleton consists of bones that are located along the center (axis) of the body, which include the skull, rib cage, hyoid bone, and vertebral column. The appendicular skeleton includes bones of the pectoral girdle, pelvic girdle, upper limbs, and lower limbs. Examination of the skull is facilitated by examination of the external and internal surfaces of these bones. The inferior surface is formed by some of the facial and cranial bones, in addition to the palatine bone and vomer. Surface features of the skull bones include small holes called foramina (singular foramen), canals, protuberances, condyles, crests, and lines. It is located in the anterior side of the cervical region, supports the larynx, and is the site of attachments of the muscles of the tongue, larynx, and pharynx. There are six additional bones that are associated with, but are not part of, the skull. These include three pairs of small bones found in the middle ear cavity; that is, the malleus, incus, and stapes (collectively referred to as the auditory ossicles). Each of the vertebrospinal ("true") ribs connects to the sternum via its own costal cartilage. The vertebrochondral ("false") ribs connect to the sternum by shared costal cartilages, whereas the floating ribs attach to other vertebrae instead of to the sternum. The sternum consists of three bones (manubrium, body, and xiphoid process) and articulates with the ribs and left and right clavicles. Each rib is a flat bone with distinctive features such as a head, neck, and shaft. The spine has four curved sections, named according to the body regions in which they are located. The vertebrae are classified according to the body region in which they reside and are assigned numbers within each group. The distal ends of the radius and ulna articulate with the humerus to form the elbow joint. The trochlea ("pulley") of the humerus connects with the trochlear notch of the ulna, whereas the capitulum of the humerus meets the radial head. They are typically divided into the proximal carpals (scaphoid, lunate, pisiform, triquetrum) and distal carpals (trapezium, trapezoid, capitate, hamate). In your introductory study of skeletal anatomy, it is necessary for you to learn only those that form the carpal tunnel; that is, a space through which the median nerve and blood vessels run between the forearm and hand: scaphoid, lunate, pisiform, and triquetrum. The metacarpals articulate proximally with the metacarpals and distally with the phalanges. They are identified by Roman numerals, beginning with the lateralmost bone; that is, the thumb, or pollex. They, too, are identified by Roman numerals, beginning with the lateralmost digit. Finger I (the thumb, or pollex) consists of only two phalanges, the proximal and distal. Its prominent head articulates with the acetabulum of the hip bone at the proximal end and with the tibia at the distal end. The patella, a small sesamoid bone, forms the kneecap on the anterior side of the joint between the femur and tibia. At the distal end, however, both bones articulate with the tarsal bones to form the ankle. Both sets of bones are identified with Roman numerals as with the bones of the hand. The degree of movement (range of motion) is a function of the structure of the joint. Angular movements are those in which the two axes of a joint are moved together or apart; that is, the angle between the adjoining bones changes. Elevation and depression movements are those that involve movements above or below the horizontal plane. Movement of the sole of the foot away from the median plane Movement that decreases the angle between adjoining bones. Synarthrotic joints permit little to no movement, whereas diarthrotic joints allow free movement between bones. Amphiarthrotic joints allow a greater range of motion than synarthrotic joints but are much stronger and less movable than diarthrotic joints. The subclassification of synovial joints is based largely on the shapes of the articulated bones at their junction points as well as the types of movements they permit. This capsule consists of a superficial articular capsule (connective tissue) that is continuous with the periosteum of the adjoined bones. The synovial membrane connects with sheets of hyaline cartilage (articular cartilage) that cover the surfaces of the articulating bones. Together these membranes form the joint cavity that is filled with synovial fluid, an aqueous solution produced by cells of the synovial membrane. The synovial fluid and articular cartilages reduce friction between the articulating bones. Some of the synovial joints also include fluid-filled pouches called bursae (singular bursa). These are located between tendons or ligaments and underlying tissues and seem to reduce friction and/or act as shock absorbers. The structures of three synovial joints are described in the next sections: shoulder, hip, and knee. It is stabilized by five ligaments, and several bursae reduce friction in locations where muscles and tendons pass over the joint capsule. Although the range of motion is not as great as that of the shoulder joint, it is still quite flexible and allows flexion, extension, adduction, abduction, circumduction, and rotation of the lower limbs. A fat pad and fibrous cartilage pad line the acetabulum, and the ligamentum teres originates from an acetabular ligament and attaches at the fovea capitis of the femoral head. Three ligaments reinforce this attachment: pubofemoral, iliofemoral, and ischiofemoral. The anterior surface of the joint is covered by a tendon from the rectus femoris muscle. This tendon engulfs the patella and divides into left and right halves before attaching to the anterior surface of the tibia. The medial and lateral menisci (singular meniscus) line the superior surface of the tibia. The fibular and tibial collateral ligaments run along the lateral and medial aspects of the joint. The anterior cruciate ligament and posterior cruciate ligament attach to the condyles of the femur and the intercondylar area of the tibia. They quickly became friends and discovered that they had a lot in common, including the fact that neither one of them had ever done much exercise. They were required to enroll in a physical education class, and the only one available was in basic strength training.

Theoretical and experimental approaches to modeling human lung deposition of pharmaceutical aerosols have a high probability of accurately and reproducibly predicting the lung dose antifungal cream for dogs buy 150 mg diflucan. However antifungal lotion prescription generic 50 mg diflucan fast delivery, more work is required to refine experimental models sufficiently to predict regional deposition antifungal oral thrush order diflucan 100mg fast delivery, but theoretical models generate good approximations fungus gnats soap cheap diflucan 400 mg on-line. Of course antifungal hair shampoo diflucan 150mg generic, each person exhibits unique deposition based on anatomy and physiology antifungal lip balm cheap 100mg diflucan visa, and all models are, at some level, averaging their results to make population predictions. This source of variation will be overcome only if a personalized medicine approach appears in the coming years. The major clearance mechanisms are absorption and mucociliary and cell-mediated transport. The site of deposition dictates the combination of clearance mechanisms that prevail and other local phenomena that may influence disposition (35,38). In the tracheobronchial region, transport to the bronchial circulation occurs (43). Transport to the pulmonary blood supply, which is in intimate association with the alveoli to support gaseous exchange, happens in the periphery (43). The large surface area and short distance from airways to vasculature resulting from local cell structure in the periphery makes this the target for rapid uptake to treat systemic rather than local disease. For materials that exhibit delayed dissolution for whatever reason (low solubility, impeded dissolution due to the presence of additives) that deposit in the tracheobronchial airways, mucociliary transport will influence disposition. The region from which transport or translocation to the local site of action occurs requires presentation of the 402 Ensuring effectiveness and reproducibility of inhaled drug treatment drug in the molecular state. To illustrate the importance of this mechanism, two situations can be considered while recognizing that a range of intermediate phenomena may occur. Highly soluble materials are available for absorption/action at the site of deposition, and they are only influenced by local permeability; poorly soluble materials present at each site where they are cleared by a combination of dissolution and mucociliary transport rates and local permeability. Materials that exhibit delayed dissolution in the periphery, and depending on their geometric particle size characteristics, are taken up by alveolar macrophages that may act as a depot for release or degrade the drug depending on its composition. As indicated earlier, the extent of the influence of this mechanism depends on the local solubility of the drug and the rate at which it dissolves. So far, the biological disposition of the drug has been considered at large spatial scales of scrutiny: the whole and regional disposition in the lungs and systemic disposition, through the vascular circulation. It should also be acknowledged that, at a molecular scale, there are further barriers to be overcome at each of the sites of deposition. The thickness and composition of airway lining fluid varies throughout the respiratory tract. In the periphery, a layer of surfactant is the only barrier to penetration to the epithelium (47). The extent and nature of transport and metabolism depends on the chemical structure of the drug and is usually influenced by its similarity to endogenous substances. A great deal of progress has been made in understanding and controlling the drug product and aerosol performance characteristics. An effort is underway to translate that into a prediction of the biological disposition and development of appropriate tools to evaluate disposition both in terms of pharmacokinetics and pharmacodynamics, and perhaps to develop an inhaled biopharmaceutical classification system (29,51,52). However, more scientific research into the biology of drug disposition from the lungs is required to define the limits to predictive modeling. Control may be exercised through practices of QbD in product development and through training and adherence to therapy of the patient. The anatomical, pathophysiological, and pharmacological variability within and between patients mediate between the uniformity of the product and anticipated therapeutic outcomes. The recent focus on patient feedback and breath control systems are steps toward greater physiological reproducibility. The challenge is to extend knowledge sufficiently to define the absolute limit to the ability to predict drug disposition and to effect maximum control over pharmacological performance. Gantt charts revisited: A critical analysis of its roots and implications to the management of projects today. Manufacture, characterization, and pharmacodynamic evaluation of engineered ipratropium bromide particles. Aerodynamic and electrostatic properties of model dry powder aerosols: A comprehensive study of formulation factors. Bowles N, Cahill E, Haberlin B, Jones C, Mett I, Mitchell J, Muller-Walz R, et al. Emerging technology: A key enabler for modernizing pharmaceutical manufacturing and advancing product quality. A review of the use of process analytical technology for the understanding and optimization of production batch crystallization processes. In vitro testing for orally inhaled products: Developments in science-based regulatory approaches. A comparison of dry powder inhaler dose delivery characteristics using a power criterion. Deposition and retention models for internal dosimetry of the human respiratory tract. Mitchell J, Nagel M, Doyle C, Ali R, Avvakoumova V, Christopher J, Quiroz J, Strickland H, Tougas T, Lyapustina S. Aerodynamic characterstics of a dry powder inhaler at low flows using a mixing inlet with an Andersen Cascade Impactor. Validation of a general in vitro approach for prediction of total lung deposition in healthy adults for pharmaceutical inhalation products. Surfactant: A review of its functions and relevance in adult respiratory distress disorders. Ehrhardt C, Backman P, Couet W, Edwards C, Forbes B, Friden M, Gumbleton M, et al. Current progress toward a better understanding of drug disposition within the lungs: Summary proceedings of the first workshop on drug transporters in the lungs. Olsson B, Bondesson E, Borgstrom L, Edsbacker S, Eirefelt S, Ekelund K, Gustavsson L, HegelundMyrback T. The I-neb adaptive aerosol delivery system enhances delivery of alpha1antitrypsin with controlled inhalation. Novel devices for individualized controlled inhalation can optimize aerosol therapy in efficacy, patient care and power of clincial trials. The foundation of scientific and technical principles on which inhaled therapy is based was established over a period of approximately 50 years and continues to be elaborated as new approaches emerge. There are a large number of introductory and specialized texts on the topics of inhaled medicines, pharmaceutical aerosols, and pulmonary drug delivery. The intent in this text has been to adopt a structure that relates directly to clinical translation. An overview of the physical chemistry, aerosol physics, biology of drug disposition, and device and product considerations was considered a necessary introduction and reference for the remainder of the text. Subsequent chapters focused on specific diseases and their aerosol treatment, highlighting the specific barriers that need to be overcome and the solutions adopted from the range of options available. The necessarily diverse discussion arising from each of these diseases has been placed in two integrated contexts. Dosage form and disease general observations may be useful to consider during product development. In addition, their influence on quality, safety, and efficacy should be elements of the overarching development framework. The development of a target product profile draws on many of the points that have been emphasized throughout this text. Items that should be considered are dose, aerodynamic particle size distribution, and other measures such as aerosol delivery and dissolution rates. Genotypic and phenotypic differences may also play a role, and the best current examples are cystic fibrosis and drug-resistant microorganisms. There are a number of ways to consider dose, each of which reflects the efficiency of transitioning through delivery of the drug aerosol. Unlike oral drug delivery, where the dose is clear in the sense that the nominal dose in the tablet or capsule is ingested by the patient and there is no equivocation about the amount of drug that is delivered. Inhaled therapy involved multiple steps in which the dose delivered is a function of intervening events. It was noted over two decades ago that the contribution of each of these elements of delivery contributes, through compound functions, to the therapeutic dose (1). The next major limitation on dose is the proportion of the aerosol that is respirable, that is, the fraction that can pass the oropharynx and enter the lungs. Two terms are often used interchangeably that have completely different definitions and absolute values. The term fine particle dose (or fine particle fraction if expressed as a percentage of nominal or emitted dose) is a quality measure of particles in a size range that statistically have a high probability of entering the lungs. In contrast, the respirable dose (or respirable fraction) is based on known lung deposition and is a composite term made up of probabilities of all particles below 10 m depositing in the lungs where smaller particles have a higher probability than larger ones. This approach has significance for determining risk and was first developed by organizations such as the American Conference on Government and Industrial Hygienists (3). The reduction in dose to the target site up to the point described in the previous paragraph is defined clearly, and all steps are subject to measurement from which quality of performance can be translated into lung delivery. Unfortunately, the last step, defining the therapeutic dose, is not currently subjected to the same level of scrutiny. The location of certain receptors in the lungs or the likely site of infection can be defined, but the drug availability at the specific site of action is limited by the dissolution of particles and the residence time (as dictated by clearance mechanisms). The instantaneous amount of drug present to act depends on competing kinetic phenomena that are subject only to measurement in in vitro models or by inference from the pharmacokinetics of systemic appearance. Consequently, the last step does not allow a formal definition of the therapeutic dose. As a result, bioequivalence testing is currently constrained to a combination of tests that give approximations that have yet to be fully accepted as predictors of performance (4,5). While considerable research has been conducted on the influence of aerodynamic diameter on lung delivery using both monodisperse and polydisperse aerosols, there is no consensus on the ideal particular size distribution. Generally speaking, it is acknowledged that there is sufficient control of aerosol particle delivery to achieve predominantly central or peripheral deposition by adjusting the median diameter between 1 and 5 m. However, it is not clear that deposition at a specific level of branching within the lungs is either feasible or desirable. Moreover, the desired target for therapeutic agents for specific diseases has not been localized to specific airway generations. First, the aerosol delivery rate relating to the point at which the aerosol is introduced on the inspiratory flow has an impact on the site of deposition (6,7). Nebulizers are not affected by this phenomenon because the aerosol is inhaled from a near steady-state dispersion. For highly soluble, rapidly dissolving drugs, this step is presumably not a barrier to bioavailability. However, given the limited airway lining fluid for dissolution if a substance with low solubility and slow dissolution dissolves, this may well become a significant barrier to bioavailability and therapeutic effect. This may well be explained by the temporal effect of the dosing regimen controlling the symptoms and underlying cause of disease such that the impact of a single dose and its pharmacokinetics are mitigated. Steroid therapy of asthma, for example, takes days or weeks to control the disease and the performance of a single dose is not likely to influence the outcome. Nevertheless, dissolution rate may well be the cause of some variability in response. Further study is required to establish the extent to which dissolution is a valuable measure of quality, safety, and efficacy. Disease Clearly, factors that influence the anatomy of physiology of the lungs will affect lung deposition and potentially therapeutic outcome (see Chapters 2 and 25). However, the most significant influence derives from the disease and its influence on the normal lung structure. The disease influences the deposition of the aerosol but, more significantly, it may change the nature of the drug target. For example, where microorganisms are located in granulomas or bronchiectatic regions, the nature of the final step in drug delivery following deposition remains unknown since these are not ventilated parts of the lungs and require an extra transport step through tissue. At the cellular level, certain infectious organisms are capable of producing biofilms that present another barrier to the delivery of the drug for which specific strategies may be required if therapy is to be achieved. The inability to generalize the factors influencing the anatomy and physiology of diseased airways may require a complete change in the approach to therapy if the intention is to predict the response from first principles. It may be possible to predict outcomes of drug delivery only from specific pharmaceutical aerosol dosage forms by acquiring data on individual airway structure and function. Therapy would then be approached as personalized medicine designed to match the performance of high-quality, controlled drug delivery systems to the unique biological conditions of the individual patient (11,12). The intent of this text is to be foundational when it comes to the translation of inhaled aerosol therapy to specific clinical applications. The initial summary of the fundamentals of inhaled aerosols will be useful to those who are not immersed in the field. The majority of the text addresses the prominent clinical applications and the optimal approaches to aerosol treatment. Finally, lessons are drawn from the experience of therapy to generalize on dosage form design and the best approaches to overcoming particular disease barriers as a guide to first step when considering the most valuable approach for a specific application.

As mentioned earlier in this section antifungal youtube buy generic diflucan 100 mg online, the first menstrual cycles often fail to produce ovulations fungus in sinus cheap diflucan 100mg overnight delivery. In these cases fungus structure buy cheap diflucan 100 mg line, gonadotropin surges induce luteinization of a follicle but not ovulation antifungal indications discount 50mg diflucan. The process begins with stem cells that contain a diploid (full complement) number of chromosomes fungus gnats control uk 400mg diflucan visa. These cells undergo mitotic divisions to increase numbers of potential gametes called primary spermatocytes or primary oocytes antifungal fluconazole buy diflucan line. The primary spermatocytes then undergo meiosis to generate numerous haploid spermatids in males. During this phase, chromosomes have condensed, replicated, and assumed the form consisting of chromatids and a centromere. The major event during this period is the migration of homologous chromosomes in opposite directions away from the equatorial region. The first meiotic division concludes with telophase I, a phase that results in two secondary spermatocytes in males. In females this step produces only one secondary oocyte and a small cell called the first polar body. Each of these cells has a nuclear membrane and a nucleus housing one member of each homologous chromosome pair. Briefly, chromosomes in each offspring cell align in the equatorial regions, and each chromosome splits. The halves of each chromosome migrate to opposite sides, and in males, each cell divides to produce a total of four spermatids, each containing half the number of chromosomes present in the original stem cell. By the end of pregnancy, all of these cells have begun meiosis, but this process is arrested during prophase. At this point, the cells are called primary oocytes, and they are housed in various types of follicles ranging from primordial to tertiary. Follicle development begins at about the same time the oogonia begin meiotic prophase. As noted in the previous section, this cell division does not result in two functional cells. The result of meiosis I is a secondary oocyte and the first polar body, a nonviable cell with almost no cytoplasm. The ovum and the two polar bodies are all enveloped by the zona pellucida and degenerate by the time of ovulation. Newly produced sperm leave the testes and accumulate in the tail of the epididymis, where they are stored until ejaculation. Spermatogenesis occurs at a rate that ranges between 300 and 600 sperm per gram of testis per second! Two functional characteristics of the seminiferous tubules are responsible for this continual production. First, stem cells undergo mitosis on a periodic basis, thereby giving rise to new generations of sperm-producing cells. As noted in the previous paragraph the process begins with stem cells known as type A0 spermatogonia. These cells undergo a series of mitotic divisions, each of which gives rise to morphologically distinct types of spermatogonia. Some of these types can revert back to A0 spermatogonia in order to replenish and sustain the pool of stem cells. Each primary spermatocyte undergoes meiosis I, resulting in production of two secondary spermatocytes. During the differentiation phase, the round spermatids undergo dramatic morphological changes to produce elongated spermatids and finally spermatozoa. Changes in ovarian structures are associated with changes in function of the ovaries. Of particular importance are changes in patterns of reproductive hormones that cause changes in the structures and functions of their target tissues. One of the more familiar changes is menstruation (menses), or the sloughing of the uterine lining with bleeding. Menses lasts between three and five days and occurs at approximately 28-day intervals. The purpose of ovarian cycles is to facilitate timing between fertilization of an oocyte and preparation of the uterus for pregnancy. The menstrual cycle is typically divided into the follicular and luteal phases, based on the ovarian structures that are prevalent at those times. The follicular phase is between days 0 and14, whereas the luteal phase is between days 14 and 28. The follicular and luteal phases are also known as the estrogen and progesterone phases, based on the type of ovarian steroid that is dominant in each phase, or the proliferative and secretory phases, based on activity of the uterine mucosal epithelium. Having established the basic characteristics of the menstrual cycle, it is now possible to explore its physiology; specifically, the functional changes in the female reproductive system that occur in each of the phases of the menstrual cycle. The first half of the menstrual cycle is called the follicular phase because the dominant structure on the ovaries is a large tertiary follicle that is destined to ovulate. This particular follicle emerged from a pool of primordial follicles and began its developmental journey approximately five months earlier. Throughout the remaining portion of the follicular phase, the selected follicle becomes the dominant follicle, meaning it grows rapidly, and releases increasing amounts of estradiol. By the late follicular phase (mid-cycle), the follicle attains its maximum size, and its estradiol secretion reaches a peak level. The high levels of estradiol observed during the follicular phase exerts important effects on the female reproductive tract. Third, this steroid causes the cervix to secrete a clear mucus with low viscosity. This type of mucus facilitates transport of sperm through the cervix into the uterus. The mechanism of ovulation involves release of proteolytic enzymes from the germinal epithelium and follicular cells. These enzymes digest the follicle wall and create a small opening (stigma) through which the oocyte can escape. As the follicle releases its oocyte, it begins a remarkable transformation in both its structure and function to eventually become a corpus luteum. Much of the basement membrane of the follicle remains after rupture of the follicle, allowing the granulosa and theca cells to remain separated. The granulosa cells become granulosa-lutein (large luteal) cells, and theca cells become theca-lutein (small luteal) cells. As the corpus luteum develops, it undergoes a 16-fold increase in size due to hypertrophy and hyperplasia of the cells. The structure also becomes highly vascularized due to development of an extensive capillary plexus. The major functional change of this structure is the type of steroid hormone it produces. As the follicular cells are transformed into luteal cells, they lose their ability to synthesize testosterone (theca) and estradiol (granulosa) and produce mostly progesterone with some estradiol. As the structure grows, it produces increasing amounts of progesterone and estradiol. The increase in progesterone secretion seen during the luteal phase induces development and secretory activity of uterine endometrial glands. These structures develop under the influence of estradiol during the follicular phase and then become functional when progesterone secretion increases. These effects help create a uterine environment that will support implantation of an embryo and sustain pregnancy. In the cervix, progesterone induces production of a thick, viscous mucus that creates a protective barrier and discourages transport of sperm. Cells begin to disappear due to apoptosis, and as a consequence, blood levels of progesterone decline rapidly. Within 48 hrs the corpus luteum has disappeared and its tissue replaced with scar tissue. The decline in progesterone that marks the end of the luteal phase results in menses. As luteal cells die and lose their ability to produce progesterone and estradiol, levels of these steroids fall, and this induces release of prostaglandins from endometrial cells. The prostaglandins induce constriction of spiral arteries that carry blood to the endometrium. Loss of blood flow to this tissue causes it to become necrotic and then to slough off. Perhaps most obvious is the fact that viable sperm must be available to interact with the oocyte. The next several sections describe the most important mechanisms required for pregnancy to be established and maintained. This discussion does not include a detailed description of how humans interact sexually to ensure that a sperm and oocyte meet. Suffice it to say that humans typically engage in sexual intercourse throughout the menstrual cycle. Oocytes survive for little more than 24 hrs in the female reproductive tract, but sperm can survive for up to one week. This means that the probability that copulation will result in pregnancy varies among days of the menstrual cycle. As you might expect, the greatest chance is near the time of ovulation; specifically, between four days before and one day after ovulation. The probability of copulation resulting in pregnancy during this period varies between 20 and 30%. This may seem rather low, but variables other than the mere presence of sperm determine the likelihood of pregnancy; for example, viability of gametes, transport of sperm and the oocyte, and condition of the female reproductive tract. These variables determine the probability of fertilization as well as survival of a conceptus. Approximately 25% of human pregnancies fail during the first several weeks of pregnancy. The next several sections describe some of the major processes that are necessary for pregnancy. A tightly coordinated sequence of physiologic events is necessary for a successful pregnancy. The first necessary step in establishing pregnancy is insemination; that is, the introduction of sperm into the female reproductive tract. In sexually reproducing animals, a repertoire of behaviors known as sexual behaviors are necessary for ensuring that insemination occurs. Copulation (sexual intercourse) provides the means for this in humans and many other animal species. This act involves a variety of physiologic and behavioral responses to sexual arousal, collectively referred to as the sexual response cycle. Our main concern is with the behavioral reflexes that are directly involved with insemination. During sexual excitement blood flow to the external genitalia increases in both men and women, causing the erectile tissues of the penis and clitoris to engorge with blood. Penile erection has been studied to greater extent than clitoral erection and therefore offers a better example for analysis. Recall that a large portion of the penis is comprised of erectile tissue consisting of the corpus spongiosum and the two corpora cavernosa. When the penis is flaccid, the arterioles that supply blood to the erectile tissue are in a state of tonic constriction, thereby limiting rate of blood flow to that which is sufficient for providing nutrients and gas exchange. During sexual arousal, the arterioles dilate, causing blood to flow more rapidly into the erectile tissue. Expansion of this tissue compresses the venous plexuses, draining the tissue, leading to a buildup of blood in the cavernous tissues. Penile erection is an important reflex in natural insemination because it is tightly coupled to ejaculation; that is, the release of semen from the male reproductive tract. During the flaccid state, smooth muscle tissue of these arterioles is slightly contracted due to mild sympathetic impulses. This maintains the blood vessels in a constricted state that limits blood flow to the erectile tissue. This lowers intracellular calcium levels and promotes vasodilation by inducing relaxation of these muscle cells. During the past 20 years, several drugs have been developed to treat erectile dysfunction in men. Fertilization occurs in the oviduct, at the junction between the ampulla and isthmus. In order for sperm to meet an oocyte in this location, both the oocyte and sperm must be transported away from the gonads. Following ovulation, the oocyte is captured by fimbriae (the lace-like border of the fallopian tube near the ovary) and directed into the lumen of the oviduct, where it then migrates to the site of fertilization. On the other hand, sperm are ejaculated into the vagina and journey to the oviduct. Appearance of fluid in the urethra triggers the expulsion reflex; that is, propulsion of seminal fluid out of the urethra into the exterior.

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