By P. Folleck. Iowa State University. 2019.

Variations in protocol between the studies made comparisons diffcult: just within the core group of four studies 100 ml duphalac mastercard, there were twenty-four dose levels discount duphalac 100 ml on-line, three different schedules of administration, two routes of administration, and four different drug formulations, among other variables. The problem was not that the individual studies presented in the new drug application were fawed. Rachael Berman, noted, each study met its stated goal, but the studies were now being used for purposes other than their original design: ‘The data were looked at using criteria which appear arbitrary and were developed after the studies were completed’. Clearly, impetus to accept surrogate endpoints converged on ddI from many directions, not the least of which was political pressure. The urgency of the disease itself and the need to get additional weapons into the therapeutic arsenal were also clear motivating forces. Moreover, physicians who had used ddI in a clinical setting expressed optimism about the drug. Bush asked Quayle’s Council on Competitiveness to resume the responsibilities of the former Task Force under the original executive order issued by Ronald Reagan. House (1992), including: copies of the executive order and associated memoranda to transfer Task Force functions to the Council on Competitiveness; letters and memoranda to form the Working Group and defne its purpose; the membership list; the fnal report and drafts of interim reports with handwritten comments and corrections. House 1992, 265), David Kessler cited the infuence of the working group as motivation for approving ddI. Department of Health and Human Services, Kessler was paraphrased as saying that ddI’s approval ‘was made possible by the application of several innovative concepts recommended by the working group’; the ‘decision was reached on the basis of surrogate endpoints, without waiting for the completion of the clinical trials’ (U. In the approach to ddI, we witness a continued trend towards moving key decision points to earlier moments in the drug development process (i. Likewise, Subpart E assumed that clinical endpoints would comprise the basis for approval. While there would have to be a plausible scientifc justifcation for believing an endpoint clinically meaningful, the clinical proof of that surrogate marker’s validity, or confrmation of the drug’s clinical beneft, may be pursued in postmarket confrmatory trials. However, these types of differences between drugs can make a substantial difference in the response of the surrogate marker and the interpretation of it. In this way, the promulgation of Subpart H represents not only a continuation of the trend started with Subpart E toward postponing selected data-gathering until postmarketing, but a compounding of it. For drugs intended to treat serious or life-threatening diseases, the pre-market burden of proof continues to be lightened. Feigal noted that while surrogate endpoints have been used as endpoints in trials, ‘this is something that, as a reviewing division, we’ve discouraged in protocols. We think that the surrogate marker changes within trials are very useful, but we would prefer the trials to have clinical endpoints and use the surrogate changes for other purposes’. As we will see in the next section, despite this temporary retreat from surrogate endpoints, the Subpart H provisions for accelerated approval were subsequently written into law. In this way, the former placebo group provided additional evidence for the effcacy approval. According to Cooper, ‘in general there was this sense that one controlled study would be enough’. One example is a famous case of failure of a highly touted, highly anticipated Fast Track drug application. Because the drug was perceived as a potential ‘blockbuster’, the situation led to a media frestorm, including Congressional hearings (U. One could be more confdent that viral protease inhibitors would work and were worth pursuing’. In this paper, I have attempted to trace some of those lines of infuence through time. House (2002) Hearing before the Subcommittee on Oversight and Investigations of the Committee on Energy and Commerce: An Inquiry into the ImClone Cancer Drug Story. Some of the Congresspeople in this hearing criticized the use of surrogate endpoints in the ImClone study, characterizing clinical endpoints as ‘sound science’, seemingly unaware that the use of surrogate endpoints was authorized by their own legislation. The case is mostly famous for resulting in the incarceration of both Martha Stewart and drug company co-founder Dr. Without a successful example of rapid drug development and approval, regulatory and legislative steps towards accelerated approval (if any) would likely have been much more deliberate. The activism movement, as deftly described by Epstein,98 found its voice and energy mainly in demanding access to experimental drugs and demanding modifcations to the traditional approach to clinical trials, both for reasons of ethics and for earlier marketing of important drugs. Militant activists may certainly have pushed for greater funding, a different research agenda, or modifcations to 96 Other examples of this kind of conceptual fexibility can be cited. Young took a position of soft advocacy in which he downplayed the difference between the proposed and reproposed sets of rules. However it seems likely that at least part of the inspiration for their agenda came from the example before their eyes, and that the lack of such an example would necessarily modify the agenda, and very possibly attenuate their stridency, which subsequently might have affected future advocacy movements. More than that, the emphasis on the historical roots of reform is crucial since the foundation for decision-making in any situation must necessarily begin with already-existing experience and ideas.

Furthermore cheap 100 ml duphalac with visa, this route avoids first-pass effects of degradation in the intestinal wall or the liver buy 100 ml duphalac mastercard, prior to the drug reaching the systemic circulation. Low variability This route has less variability than, for example, the oral route, where factors such as intestinal motility, presence of food and extremes of pH combine to make oral drug delivery highly variable. However, factors such as salivary flow and certain disease states can contribute to a degree of variabiliy associated with this route. Robust The oral mucosa is routinely exposed to a multitude of different foreign compounds and is relatively robust and less prone to irritation than, for example, the nasal mucosa. Prolonged retention Prolonged retention of the drug is possible in the buccal cavity, if the appropriate delivery system is used. Intestinal alternative The buccal cavity is a useful alternative to the intestinal route for drug absorption in situations where the gastrointestinal route is unfeasible. Examples include: • patients with nausea and vomiting; • patients with swallowing difficulties; • drugs that cause gastric irritation; • drugs that are unstable in the gastrointestinal fluids; • drugs that undergo extensive first-pass effects in the gut wall or liver. Zero-order controlled release Buccal drug delivery offers the potential to achieve zero-order controlled release. However, as described above, the oral epithelium is relatively robust and this factor is not as limiting as in other highly sensitive mucosal sites, such as the nasal cavity. Mucus and salivary clearance Mucus and salivary clearance reduces the retention time of drugs within the oral cavity and thus the opportunity for absorption. Mucus barrier Drug diffusion may be limited by the physical barrier of the mucus layer and also the specific or non- specific binding of drugs to the mucus layer. Patient acceptance A buccal patch comprises a relatively novel dosage form, which is placed in an unconventional drug delivery site. As such, there may be difficulties encountered in trying to get patients to accept this route. It can be imagined that patients may be more reluctant to use a buccal patch in comparison to, for example, a transdermal patch, which has become a well-known and well-established dosage form. Commercial Novel approaches, such as the use of buccal adhesive patches for the systemic delivery of large molecular weight drugs, require a huge input of time, effort and money, and are also associated with a large amount of risk. These issues can contribute to significant delay in the development and marketing of a new delivery system and can also make these systems relatively expensive. In sublingual tablet form nitroglycerin is highly effective, usually relieving the pain within 2 min of dissolution. Sublingual tablets are composed of soluble excipients (lactose, mannitol, sucrose) to achieve fast dissolution and thus aid rapid onset of drug action. However, the time taken to dissolve can be variable and prolonged, particularly in the presence of mouth dryness. Furthermore, the tablets have stability 179 problems and extreme care must be taken to avoid their exposure to heat, light, moisture and inappropriate packing material, which leads to a requirement for the tablets to be discarded 8 weeks after opening. Lipid aerosol formulations of nitroglycerin are also available, which are far more stable than the tablets, with a prolonged (3-year) shelf life. Sprayed directly onto the tongue, they produce relief of anginal pain within 2 min with a duration of effect of up to 30 min. However, it has been shown that the use of different aerosol vehicles markedly influences the bioavailability of the drug, which obviously has important therapeutic implications. Fast-dissolving molded tablets consisting of drug and poly(ethyleneglycol) blends with a melting point around the body temperature have also been investigated for the delivery of nitroglycerin and progesterone. Recently, fast-dissolving tablets based on freeze-drying techniques have been developed and are described further below. Oral bioavailability is very low, due to extensive intestinal and hepatic firstpass metabolism. Furthermore, the oral route is impractical in patients with nausea and vestibular disturbance, who have been demonstrated to have impaired gastric emptying. Buccastem tablets are a form of prochlorperazine for buccal administration, containing 3 mg of prochlorperazine in a polysaccharide base. When placed in position the tablet softens over a period of a few minutes to form a gel which adheres to the gum and gradually releases the drug. Prochlorperazine fulfils the criteria for efficient transmucosal delivery; it is a highly lipid soluble base with a pKa of 8. Because first-pass metabolism is avoided, the bioavailability via the buccal route is much higher than via the oral route (Figure 7. By contrast, oral long-acting nitrates have a prolonged but slow onset of action, restricting their use to angina prophylaxis. Sustained release buccal nitroglycerin (Suscard Buccal) was developed to provide both a rapid onset and a prolonged effect, in a single formulation. On contact with the moist mucosa the outer layer of the tablet hydrates and swells, becoming gel-like in consistency. This has the dual effect of: • promoting firm adherence of the tablet to the mucosa; • causing the outer layer of the cellulose meshwork to rupture, immediately releasing some of the drug for absorption. Gradual erosion of the tablet matrix allows slow release of the entrapped active moiety.

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The warning stated that “The deaths were due to various causes which could be expected in an elderly population order 100 ml duphalac. Gorman order duphalac 100 ml free shipping, Attainment of treatment goals by people with Alzheimer’s disease receiving galantamine: a randomized control trial. In fact, a recent fnding that clinicians arrive at different impressions of improvement and decline than do their patients, or the patients’ primary carer, suggests this may be contested (Rockwood et al 2006) 92 e. Schmidt, Inger Holmström, The role of drug and therapeutics committees: perception of charirs and information offcers. Initiated in 1977 by the National Institute of Health,93 they are funded by the pharmaceutical companies who sponsor the clinical trials conducted by those same experts. These experts are a familiar group, knowing one another through collaborations, conferences, and as experts at advisory meetings. In the literature, these guidelines become taken for granted and referenced as fact. Often they favour fnal recommendations for standard of care using the drugs they themselves were responsible for studying. The members of these committees do not take their task lightly, but they also come to the meetings with often already decided opinions, and there is seldom an attempt to bring dissenters to the table. Formulary committees have the important task of determining whether to include new drugs, and retain old ones. They sort through often methodologically compromised or incomplete data, decide on the appropriateness of outcomes, determine whether risks and harms have been addressed, and consider potential ethical dilemmas that move the discussion to issues of social justice, utility and community responsibility. Drug companies contract some 60 percent of medical researchers,96 and the pharmaceutical industry spends more on medical research than the National Institutes of Health in the United States. MacLeod, The role of research evidence in pharmaceutical policy making: evidence when necessary but not necessarily evidence. Caulfeld, Globalization, conficts of interest and clinical research: an overview of trends and issues. Clark, Pharmaceutical industry sponsorship and research outcome and quality: systematic review. Dieppe, Relation between agendas of the research community and the research consumer. They have a primary responsibility for their patient’s care and treatment, trusted to “frst do no harm”. Clinical trial research is an experiment that may well pose some threat of risk, harm or benefts. To what extent do regulations that ensure the protection of the fduciary relationship between patient and physician have to be made into laws? The close ties between clinical trial researchers and industry is seen in the remarkable cross-referencing of authors of the studies and membership representation of the expert advisory committees. In 1996, more than three quarters of the expert scientifc advisors to British drug regulatory authorities had personal fnancial interests. The move by some clinicians to an interest in their patients’ life stories and experiences in order to better recognize and target symptoms of decline and improvement seems to counter the technological trend to biomedical platforms, where “physicians no longer rely on narratives of symptoms offered by patients during a medical encounter but turn instead to an expanding collection of diagnostic signs”. But it turns out that the goal of this counter-technology clinical movement is, in fact, simply to award their own impressions with statistical signifcance. The industry enrolls clinician-researchers into clinical trials -multi-sited trials include many physician practices with the aim of recruiting many prescribing physicians; clinicians enroll industry to sponsor their research by conducting these trials; clinicians also enroll patients, and post-marketing, extensive direct-to-physician promotion is followed by direct-to-consumer such a vitriolic attack from the sponsored clinical trial community and national Alzheimer Societies as to be worthy of a special session for refection and wound licking at the 006 Madrid 10th International Conference on Alzheimer’s Disease and Related Disorders. For those interested in such responses, Fujimura (1998) has an excellent analysis of scapegoating activities in the science wars. Potentially valuable data that might provide a far greater profle of individual treatment response and effectiveness remains locked away company vaults as proprietary material. Given the stated and assumed purposes for these trials, by which subjects sign informed consent statements, it might be argued that there is a responsibility to analyse these data. They accept the power of the statistically signifcant results from the industry trials, and while some propose alternative methods to identify symptoms that interpret meaningfulness, there is yet no translation into effectiveness. Conclusion Keating and Cambrosio tell us that the work of standardization (statistics) and clinical interpretation bring the laboratory and the clinic together, and that “technologies of consensus” mediate regulatory layers. Rather, independent scientifc health technology assessments continue to question the judgement and authority of clinical consensus groups whose decisions, nonetheless, get adopted as guidelines for practitioners. Instead, they worked towards changing the measuring stick so that maintenance could be recognized as improvement and more 105 B. To date, the United States and New Zealand are the only countries that permit direct to consumer advertising, although signifcant pressure is being put on other countries to follow suite (Mintzes et al). Less attention, however, has been given to direct-to-physician marketing by drug companies. Some evidence is submitted as “commercial in confdence” to the institutes by the manufacturers and while it is made available to the appraisal committee, it is removed from publicly disseminated versions of the assessment report.

It has been pointed out that the imaging of phase objects at the Scherzer (de)focus maximizes contributions from the “linear or first-order image purchase duphalac 100 ml mastercard,” in which there is a linear relationship between the projected electrostatic potential and the image intensity order duphalac 100 ml on line, and minimizes contribution from the “second- order or quadratic image,” in which the proportionality is quadratic (31). Structure images can, thus, be obtained at the Scherzer (de)focus for crystals that are slightly thicker than weak-phase objects. The instrumental resolution of a transmission electron microscope is for field-emission gun–fitted micro- scopes without a spherical aberration corrector much higher than the Scherzer resolution. The former pat- terns are much less sensitive to the plastic deformation state of the crystals and their real structure content than Kikuchi patterns. For the auto- mated “crystal orientations and structures” mapping of metals and minerals at approximately 30-nm spatial resolution, relative small precession angles of less that 0. Larger precession angles should result in an even better map reliability index, but there may then be a need to include reflections from higher order Laue zones in the analysis. Many older transmission electron microscopes do allow for a hollow cone illu- mination but not for a “proper descanning,” [Figs. While large precession angles reduce multiple scattering more effectively, they may also lead to the excitement of reflections from higher order Laue zones for certain zone axes of crystals with large lattice constants. For silicon in the [110] orientation, 200-kV electrons, and a precession angle of 2. All reflections of the first-order Laue zone are kinematically forbidden by the space group symmetry of silicon. Because the atomic scattering factors fall off quickly for electrons with increasing scat- tering angle, there is typically no measurable reflection intensity for reflections with net plane spacings of a few tens of an A. The maximally obtainable precession angle can for any transmission elec- tron microscope be estimated from the maximally obtainable dark-field tilt angle (57). Precession and descanning distortions will increase the obtainable electron probe sizes. One part of the Lorentz factor should account for the precession diffraction geometry and the other part should depend on the structure and thickness of the crystal(s) in some “Blackman-type” fashion. Different research groups used different approximate formulae for the geometric part of the Lorentz factor, for example, both [d∗(1 −{d∗/ }2)0. Depending on the illumination conditions, an extra term that corrects for the primary beam divergence may be included in the geometric part of the Lorentz factor (78). The structure- and thickness-dependent Lorentz factor should be analo- gous to relation (13) when full integration of the reflections can be achieved. When less than full integration is achieved (because the nanocrystal is, for example, very small so that its shape transform is widely spread out in recip- rocal space and contains several subsidiary maxima or the precession angle is insufficiently small), the mathematical limits of integration of the structure- and thickness-dependent Lorentz factor part need to be modified accordingly. It may become necessary to include an additional Lorentz factor that accounts for Structural Fingerprinting of Nanocrystals in the Transmission Electron Microscope 313 subsequent elastic scattering of electrons that underwent an initial small energy loss. These successes of complementary strategies seem to depend on the particular type of sample. This suggests that more complex forms of Lorentz factors may be appropriate for certain sample types and also illustrates a long- known fact about quasi-kinematic diffraction theory–based electron crystallog- raphy: “As shown in practice, for any formula of transition from I to | | the main features of the structure are revealed on the Fourier synthesis. However, the peaks corresponding to heavy and medium atoms of a given structure in the incorrect transition formula are displaced from the true positions. These programs are part of a comprehensive software suite for electron crystallography, have been developed by Xiaodong Zou, Sven Hovmoller,¨ and coworkers, and can be ordered at http://www. This understanding has generated profound changes in the field, leading to new families of materials, new concepts, and wide-ranging improvements in the mechanical behavior and in all other properties of materials. In our energy-conscious society, materials and structures are required to be more performant, lightweight, and cheap. The best answer to these requirements is often provided through the powerful concept of reinforcement of a “matrix” material with second-phase dispersion (clusters, fibers). It is an interesting fact that many natural forms of reinforcement possess a nanometric dimension, whereas most cur- rent synthetic composites include fibers in the micrometer range. Expected bene- fits of such “miniaturization” would range from a higher intrinsic strength of the reinforcing phase (and thus of the composite) to more efficient stress transfer, to possible new and more flexible ways of designing the mechanical properties of yet even more advanced composites (1). Presently, reinforcement of common materi- als (alloys, polymers) with nanostructures is one of the most promising areas of study. As one of the major factors that determine the quality of reinforcement is the mechanical strength of nanostructures, the studies of elastic properties of nano- materials are of significant importance. Besides reinforcement, investigation of the mechanical properties of nanowires is essential to determine the material strength for practical implementation as electronic or optical interconnects, as components in microelectromechanics, and as active or passive parts in nanosensors. Mechanical failure of those interconnects or building blocks may lead to malfunction, or even fatal failure of the entire device. Mechanical reliability, to some extent, will deter- mine the long-term stability and performance for many of the nanodevices currently being designed and fabricated. When nanowire properties have been adequately explored and understood, their incorporation into solutions of practical problems will become evident more quickly and feasible for active and concerted pursuit. Nanomechanical measurements are a challenge, but remain essential to the fabri- cation, manipulation, and development of nanomaterials and perhaps even more so to our fundamental understanding of nanostructures. For this purpose, various experimental techniques, or methods, have been developed in the last several years, including tensile, resonance, nanoindentation, and bending tests.

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The drugs efficacy was evaluated 3 days after the last treatment of 3 order 100 ml duphalac overnight delivery, 6 generic 100 ml duphalac amex, 9, 12 or 15. Even axenic amastigotes were already validated to be used in drug screening assays exhibiting similar drug-sensitivity as intracellular amastigotes (Callahan et al. Among the several explanations could be the drug difficulty into gain access to all organ infected areas. Further studies containing the drug inside of target delivery systems, such as liposomes, will be useful. Franklim Marques and Barbara Duarte for their support in the haematological parameters determination. Tavares J, Ouaissi A, Santarém N, Sereno D, Vergnes B, Sampaio P, Cordeiro-da-Silva A. Gene 296, 139-50 Vergnes B, Sereno D, Tavares J, Cordeiro-da-Silva A, Vanhille L, Madjidian-Sereno N, Depoix D, Monte- Alegre A, Ouaissi A. In Histone Deacetylases: Transcriptional Regulation and Other Cellular Functions, E. Indeed, the ability to modify the Leishmania genome by introducing or eliminating genes has also been considered a powerful strategy to develop a new generation of +/- vaccines against leishmaniasis. These bi-functional enzymatic activities attributed to parasite enzymes contrast with other Sirtuins already characterized. Indeed, a role in the regulation of mitotic exit in cell-cycle has been attributed to this protein (Dryden et al. The latter is composed mainly of microtubules that are polymers of repeating α/ß tubulin heterodimers, and a variety of minor components known as microtubule-associated proteins. Microtubules play an important role in many cellular processes such as mitosis, cell shape, motility, intracellular vesicle transport and organelle position. Moreover, the protozoan parasite Leishmania, having a digenetic life cycle, exhibits a particular range of cell shapes mostly defined by their internal cytoskeleton. Only a slight difference in the ratio of acetylated tubulin over total α-tubulin between the wild type and single knockout axenic amastigotes was detected. Even though α- tubulin acetylation was already reported a few years ago, its importance in cell biological processes is not yet completely understood. However, the level of tubulin acetylation seems to affect a number of dynamic cellular events, including the correct organization of the immune synapse (Serrador et al. Consequently, the significant presence of this parasite protein in the detergent- soluble fraction of the parasite’s total extract cannot be ignored and could be indicative of the existence of other substrates which might be involved in different biological processes. Indeed, this specificity is due to such differences in the turnover rates of the human and parasite enzymes, that unable the parasite to regenerate enzyme fast enough to survive its irreversible blockade (reviwed in Burri and Brun, 2003). In the search for target specific inhibitors, knowledge of the three-dimensional structure of a protein is of great importance. Fortunately, predictions of protein tertiary structure can be made, even in the absence of crystallographic structures, through the study of sequence–structure–function relationships. Indeed, until now, modelling by homology remains the most reliable method of predicting a protein’s structure. Although, this strategy failed to identify a truly potent and selective lead compound, it was effective in identifying N-(2- fluorophenyl) nicotinamide (molecule 56), which can be used for lead designing. Belonging to the hydroxamate, benzamide, aliphatic acids and cyclic peptides chemical classes, a number of derived molecules have reached clinical trials as anticancers (review in Xu et al. In comparison, normal cells are quite more resistant to cell death induced by these compounds (review in Xu et al. Two of them were described as essential, and one required for normal cell cycle progression (Ingram and Horn, 2002). However, the two enzymes’ binding mode differs considerably, which explains their different potencies. Suramin and several related adenosine receptor antagonists inhibit sirtuins as well (Howitz et al. Moreover, a recent study has identified several new lead structures for Sirtuin inhibitors by searching a library of kinase and phosphatase inhibitors (Trapp et al. Indeed, polyamine biosynthesis is one area of parasite biology that has attracted attention in terms of drug development (Muller et al. The natural polyamines spermidine and spermine, and their precursor diamine putrescine, are present in most eukaryotic cells, playing pivotal roles in several cellular processes including protein/nucleic acid synthesis as well as cell proliferation/differentiation, and have been implicated in the development of certain cancers (reviewed in Gerner and Meyskins, 2004). Furthermore, in trypanosomatid protozoan parasites, polyamines have an additional role, since spermidine is used in the synthesis of trypanothione, a glutathione-spermidine dithiol conjugate that plays a central role in several detoxification processes and supplies reducing equivalents used in nucleic acid synthesis (Fairlamb et al. As this thiol is both unique and essential to trypanosomatids, any process involving trypanothione is considered a potential target for drug intervention. Furthermore, the intracellular concentrations of polyamines in mammalian cells are regulated by feedback mechanisms involving multiple routes of synthesis and interconversion that differ from the parasite pathway (reviewed in Muller, 2001). Furthermore, the anticancer drug cisplatin has also exerted antileishmanial activity in vitro, being more effective in the reduction of the parasite’s vertebrate stage growth. Therefore, both studies suggest that the mechanisms leading to the parasite’s growth arrest are different according to the parasite’s stage.

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This was the case discount duphalac 100 ml overnight delivery, for instance discount duphalac 100 ml online, with the prescription of estrogens to reduce the sufferings of the menopausal transition, a practice many gynecologists contested. Based on these industrially defned guidelines, Schering’s regulation of prescription combined a palette of initiatives that included package design, trademark choice, the writing of package inserts, the dissemination of leafets and brochures providing examples of successful treatments, as well as standards of use. In the 1930s, these discussions, at the boundary between research, clinical standardization, and promotion diversifed into an authentic system of “scientifc marketing. Besides the organization of small conferences with “opinion leaders” in various medical specialties interested in a given type of products that enlarged the circle of “core” collaborators, a critical change was also the decision to launch Medizinische Miteilungen, a publication mimicking academic journals but juxtaposing direct advertisement and research reports originating either in Schering’s laboratory or in the collaborating clinical services, all of this supplemented with articles on the frm’s products directly reprinted from the medical press. Judging from the resonance obtained in the medical press by some of the therapeutic regimens promoted by Schering – such as the combined administration of estrogens and progesterone to create an artifcial reproductive cycle and cure amenorrhea – it was far from negligible. Conclusion Contemporary France has the reputation of being a country that invented a unique alliance between private industrial frms and state administration. Labeled as “Colbertism,” this 51 J-P Gaudillière, “Genesis and Development of a Biomedical Object: Styles of Thought, Styles of Work and the History of the Sex Steroids”, Studies in History and Philosophy of the Biological and the Biomedical Sciences, 2003, 34 : 32-55. During the twentieth century, it supposedly led French high-ranking civil servants trained in the country’s major engineering schools such as the École des Mines or the École Polytechnique, which staffed the state’s technical bodies, to work in close connection with private capitalistic entrepreneurs in order to further industrial investments, scale up production, protect the national markets, and rescue, if needed, threatened strategic enterprises or banks. Echoing previous work showing the slow transformation of the French pharmaceutical frms into large corporations, this paper actually documents a different pattern, linking a scattered economic landscape with diversifed forms of industrialization and innovation. Two features of the twentieth-century regulatory landscape are hence worth emphasizing. Strong professional regulation resulted in the absence (until the 1941 establishment of the visa system) of any form of pre-marketing evaluation organized under the authority of the state. As many observers of French medicine have noticed, the central state health administration was anemic and without much power. The trajectories of plant extracts and organ therapy discussed here confrm what has been documented when comparing the regulation of sera in France and Germany. True, biological therapies, due to their novelty in the pharmacopoeia, their variability, and their potency, were granted a special status. Even when sera or hormones were considered, however, this special status was limited to a system of preliminary authorization – with or without inspection – of the production facility. Rather than being a means for drug surveillance, this control refected the current understanding of professional autonomy. When acting as experts, physicians and pharmacists were left alone to decide what drugs were worth producing and prescribing, whereas when acting as producers, their legal responsibility was the same as that of any industrialist, i. A second, less expected dimension of this professional regulation focuses on the type of knowledge associated with the critical function granted to the pharmacopoeia. The assumed consequence is then that a chemical paradigm centered on the purifcation, the structural description, and – when possible – the synthesis of therapeutic substances dominated the culture in parallel with the pharmacological model of the relationship between doses and effects mentioned in the introduction to this volume. In contrast to this assumed connection, the cases analyzed here suggest that until late in the twentieth century, chemical entities barely played a role in the pharmacists’ world of preparation. Up to the 1920s, the receipts of the Codex did not favor making pure, molecular entities, but rather making stable, reliable compositions of medical matters, a majority of which originated in living (mostly plant) bodies. A pharmacists’ culture of preparation that owed little to the model of purifcation and synthesis dominated the early industrialization of drugs. This form of innovation placed value on the art of combining or the art of presenting known – and often complex – substances. As shown by the case of Dausse, such industrialization mobilized chemical tools as a means for concentration, control, and standardization, as well as marginally as a source of isolated substances. Complexes seemed especially valuable and important to preserve when plant extracts came under consideration. The industrialization of plant and organ extracts therefore relied on mechanics on the one hand and physiology on the other. The model of professional regulation advanced in our introductory chapter should therefore be amended to take into account this diversity of know-how, beyond the mere mobilization of pharmacological modeling. As illustrated here, biological testing systems were not just important elements in the industrial practice of standardization and quality control. In parallel, academic pharmacists used them to perform physiological functions and make them manifest, meaning that they became tools to explore and signal the synergies and complexities that remained central to the culture of preparations. If there is a caricature of German history to parallel the image of the French industrial state, it is the idea of a rapidly growing chemical industry that colonized the entire pharmaceutical sector after the 1890s. One major interest of the history of plant extracts is to show the importance of these practices, which made a subset among German frms comparable to their French counterparts living off of the exploitation of specialties registered in the pharmacopoeia. The history of Madaus thus reveals a culture of preparation that shares many aspects with the practices at Dausse, including the organization of plant collection and breeding, mechanical innovations, a deep interest in physiological tools, and research. The social and intellectual landscape within which the frm blossomed was not the French professional order, but a rare combination of industry and alternative medicine. Madaus’s holistic approach of the living, which nurtured a system of correspondences among plants, animals, and human beings, than the integration of alternative medical practices – homeopathy, as well as the use of plants and organ extracts – into the industrial regulatory order and its values of productivity, standardization, and homogeneity, all of which were taken as synonymous of quality and effectiveness. The consequences were not only the prominent role attributed to mechanics and processing, but the mobilization of pharmacology and chemistry 63 Jean-Paul Gaudillière for quality control.

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Both utilize premetered doses packed into hard gelatin capsules although different mechanisms of powder delivery are employed: • The Spinhaler contains pins for perforating the capsule buy 100 ml duphalac free shipping, the cap of which fits into an impeller which rotates as the patient inhales through the device order 100 ml duphalac with mastercard. The powder mass empties from the capsule body by the forces imparted by the inhaled airsteam and the drug particles subsequently enter the airways of the lung. The first device employing a multidose reservoir was the Turbuhaler, designed to deliver 200×1 mg doses of terbutaline sulphate devoid of any carrier (Figure 10. The inhaled airstream dislodges the drug from the cavities and dispersion continues in the inhalation channels which are helical to induce turbulent flow. A desiccant is employed to ensure that the powder reservoir remains dry during the shelf life of the inhaler. The Diskhaler, also a multi-dose system, employs individual doses contained within blisters on a disk. On actuation, a needle pierces the upper and lower surfaces of one of the blisters. As the patient inhales, the contents of the blister are dispersed into the airstream, the drug particles dissociate from the carrier and a fraction is delivered to the lung. On re-priming the device, the disk rotates to expose the next blister to the piercing needle. Some of the recent patented devices incorporate an additional energy source to supplement the inspiratory force of the patient, in order to aerosolize the drug particles into the inhaled airstream. Biopharmaceuticals under investigation for potential pulmonary delivery include those for local, and systemic, effects (Table 10. For example, The Inhale device system effectively disperses fine particles (which require a dispersion force far stronger than can be generated by a patient’s inspiration); it also creates a stationary cloud to Table 10. Preliminary results for the systemic delivery of insulin using this device have been reported. By employing a colloidal carrier in which drug is dispersed, it is possible to control: • the duration of local drug activity, or • the plasma levels of systemically active agents. A number of novel drug delivery systems have been identified as potential systems for controlling drug- release within the lung and include: • liposomes; • bioerodible microspheres composed of polymers such as polyesters (e. Tracheobronchial deposition of such carriers may not be desirable as clearance on the mucociliary escalator will occur in a relatively short time providing insufficient time for release from these controlled- release systems. Alveolar deposition will, in contrast, result in extended clearance times which are dependent on the nature of the carrier particle and may therefore be a better option for the effective use of such carrier systems for pulmonary drug delivery. It is therefore possible to select liposome compositions displaying minimal interaction with these cells and thereby function as controlled-release systems for entrapped solutes. For example, liposomes composed of dipalmitoylphosphatidylcholine and cholesterol and containing entrapped sodium cromoglycate will provide sustained delivery of the drug for over 24 hours. Conversely other liposome compositions could be utilized for enhanced epithelial interaction and transport of the drug (e. For liposomes, size and composition are important in maintaining liposome integrity and hence entrapped drug during the nebulization process. The major challenge that remains is to find enhancers that will reversibly increase membrane permeability without causing toxicity during long-term use. Various surfactants and protease inhibitors have been reported to increase the pulmonary absorption of peptides and proteins on an experimental basis but their clinical use is not established and the current general consensus seems to be against their inclusion in pulmonary formulations. The future will undoubtedly see products for inhalation on the market which contain systemically-acting drugs. Based on the published literature, it is likely that we will witness new designs in devices and formulations to achieve greater bioavailability and control in the pulmonary delivery of both conventional drugs (small organic molecules) and the increasing number of proteins, nucleotides and biotechnology compounds which require a mucosal transport route to the systemic circulation. Describe the factors affecting the absorption and metabolism of drugs in the airways. Describe the three principal categories of aerosol generator employed in inhalation therapy. Outline the rationale for the development of “new technologies” for pulmonary drug delivery. Preparations for local delivery include: Anti-infectives These include antibacterial, antifungal, antiprotozoal, antichlamydial and antiviral agents. Symptoms include vaginal discharge, offensive odor, itching, and vaginal irritation. Three etiologies account for over 90% of the cases: trichomonas (25%), Candida (Candida albicans, yeast) (25%), and bacterial vaginosis (40%). Metronidazole and other 5-nitroimidazoles (tinidazole, ornidazole) are used in the treatment of trichomonas. Vaginal yeast infections (candida) are treated primarily with antifungal imidazole drugs (clotrimazole, econazole, isoconazole and miconazole). The preparations, which are available over the counter, generally comprise pessaries or creams inserted high into the vagina. Oral or intravaginal metronidazole is effective in the treatment of bacterial vaginosis. Intravaginal administration of metronidazole results in much lower systemic levels than oral administration, thus side-effects such as nausea, alcohol intolerance and peripheral neuropathy, as well as the risk of possible teratogenic effects, are reduced with vaginal treatment.