By K. Barrack. Carroll College, Helena, MT.

A good example of the consequences of this legal regulation of property on the standards of production is the “turn” toward a cholesterol-based partial synthesis of the three sex hormones (estrogens discount avalide 162.5 mg with visa, progesterone purchase 162.5 mg avalide overnight delivery, and testosterone) that Schering sold and was implemented during the war buy 162.5 mg avalide free shipping. A second approach typical of Schering’s industrial regulation linked questions of drug quality and safety of clinical uses with the control of highly variable biological raw materials. Defning consensual biological assays for hormone preparations was seen as a very important step in the company, since animal rather than human testing was considered indispensable to evaluate the potency of hormone charges in the production setting, the composition of which was complex, variable, and badly known. Until the late 1930s, direct measurement of one or a few carefully recorded physiological effects remained the only way to assess the presence of an active substance within these charges and to quantify it. In other words, the industrial standardization of hormone preparations was a problem of Wertbestimmung (valuation). As had been the case in the production of sera after 1895, biological assays played a critical role in measuring the potency of every single batch of the processed material. The characterization of each batch with a reference number of “male” or “female” biological units was the frst and mandatory step in the defnition of the pharmacological dosages to be employed by doctors. As a consequence, clinicians’ prescription practices relied on the same sort of bioassays as those of engineers. Legally defned professional responsibility of the pharmacist as drug manufacturer – biological or not – made the pharmacist liable if the composition of the products did not correspond to claims and if use under normal dosage and circumstances led to injuries. Standardized preparations were thought to be better and more reliable drugs, echoing the doctors’ quest for a more scientifc medicine. More precisely, Wertbestimmung as practiced in the testing laboratory did not aim only at the measurement of biological and – putative – clinical effects. Quantifying the concentration of active substance in a given batch was central to the surveillance and control of production. Testing was implemented at the end of the production process, and at the beginning as well, as routine control of the raw materials. As from the late 1920s, preparation of the female hormone started with the treatment 49 Wimmer, op. Schering collected large quantities of urine, frst from pregnant women and later from pregnant mares. The content of the incoming cans was regularly tested in Junkmann’s laboratory to verify that it was worth processing. When production shifted to the use of horses, this was also a way of controlling the work done by the farmers benefting from a supply contract. Another industrial function of the biological assay was to compare the effects of changes in the preparation process (modifying the nature of solvents, changing concentrations, or varying temperature and pressure), which were indispensable to transform new procedures envisioned by in-house scientists and engineers into full-fedged manufacturing practices. Biological assays of batches produced under different conditions thus became part of the industrial search for increased productivity. The third level of regulatory activities stems from Schering’s discussions with a limited number of trusted physicians who on a regular basis contributed clinical reports on the observations they had made with the frm’s sex hormones. This was the case, for instance, 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.

Craik order avalide 162.5 mg without a prescription, Institute for Molecular Bioscience generic avalide 162.5mg on-line, The University of Queens- land order 162.5 mg avalide otc, Brisbane, Queensland, Australia Ayman El-Faham, Department of Chemistry, Alexandria University, Alexandria, Egypt; Department of Chemistry, King Saud University, Riyadh, Kingdom of Saudi Arabia Gregg B. During that period a number of great peptide drugs such as Sandostatin, Lupron, Copaxone, and Zoladex were developed with great therapeutic beneft. It was not until the last decade that we have seen a signifcant surge in the number of peptide therapeutics on the market (Figure 1. While 10 peptides were approved between 2001 and 2010, the current decade has thus far witnessed the approval of six new peptide therapeutics – a remarkable yearly increase [1, 2]. The number of peptides in development is also steadily growing roughly doubling every decade (Figures 1. This is due to the advances made in our understanding of peptide stability, peptide syn- thesis, and formulation over the last three decades. Although the market share of peptide drugs is still relatively small (about 2% of the global market for all drugs), the approval rate for peptide drugs is twice as fast as the rate for small molecules, and the market is growing similarly at a rate that is twice the global drug market [3, 4]. With the exception of a few peptides, the approved drugs so far tar- get the extracellular compartment, and thus have to compete with biologics. We have seen a great advance in extending the circulating half-life of the peptides through the use of unnatural amino acids and formulation technologies, but have not yet reached the half-life achieved by antibodies. To dramatically heighten their impact, peptides need to access the intracellular space to target protein–protein interactions. These interactions represent a vast source of potential targets with signifcant biological impact (there are estimated 300,000 such interactions in the cell), and will not in the majority of cases be modulated by small molecules. Peptides and biologics, given their relative size and ability to bind to extended surface areas, are the perfect candidates to inhibit protein–protein interac- tions. The duration of action of peptides needs to be extended, and while peptides are inherently selective against their targets, they need to more selectively distribute to the desired tissue. Finally, the route of administration needs to be expanded to include oral delivery. Many of the techno- logical advances are already proving that it is possible to make peptides permeable to cells, target tissues, have longer half-lives, and be orally bioavailable. The discovery that certain peptides can penetrate cells and can, therefore, be an effective therapeutic on their own or alternatively bring other drugs into cells allowed for the frst time to imagine targeting the intracellular compartment (Figures 1. It is hard to compete with the screening of the mil- lions of small molecule compounds in various pharmaceutical companies and more recently in many academic centers. Indeed, over the last decade, there has been an explosion of very elegant tech- nologies that now allow the generation of large to extremely large libraries of linear and macrocyclic peptides with unnatural amino acids and unnatural linkers. For the frst time, it is possible to engineer stability, cell permeability, and possibly oral bioavailability at once and screen for the desired properties very rapidly. These major advancements have resulted in the generation of a number of companies that are pushing the limits of these technologies to rapidly screen and identify novel peptide therapeutics against protein–protein interaction targets (Figure 1. Through medicinal chemistry optimization, they have now identifed picomolar inhibitors with good properties [15]. These peptides contain a com- bination of natural, unnatural, and N-methyl amino acids and exhibit good physico- chemical properties and membrane permeability [17]. They recently presented on their discovery of potent antagonists of mcl-1 and Ras with good cell permeability [18]. David Craik and colleagues at Cyclotide are systematically exchanging the various loops present on cyclotides with sequences that have important biological function [19]. Moreover, novel technologies developed for the rapid generation and screening of extremely large libraries of knottins and cyclotides will undoubtedly have a major impact on this class of peptide therapeutics. Of note is the Intein-based technology from Julio Camarero capable of introducing unnatural amino acids to facilitate screening [21]. Sutro and MitiBio also have very sophisticated and effcient biosynthetic methods to generate very large libraries. Finally, Verdine and Wollensky and colleagues [22, 23] as well as the investiga- tors at Aileron Therapeutics have developed a novel stapling technology that imparts stability and membrane permeability to alpha helical structure. This is due to the fact that once the peptide enters the cell, the major elimination pathway is through enzymatic catabolism. Not only can stability be tuned for circulating half-life, it can also be tuned to withstand cellular catabolism to lengthen the desired effcacy. This could offer a signifcant advantage over (small) molecules that passively diffuse through the cell membrane. Main reasons for diminished safety are selectivity against the target and tissue/cell specifcity. If one could direct a therapeutic to only the site of pathology, then the therapeutic window of the agent increases and correspondingly decreases the side effects. Peptides, due to their specifcity against receptors, are perfect candidates to be able to home into one type of cell/tissue versus another. There has been a tremen- dous amount of progress in identifying homing peptides (cell-penetrating as well as nonpenetrating) that can then be conjugated to a cargo to deliver it to a specifc organ [26]. In vivo phage display by Pasqualini and colleagues marked the discovery of the frst homing peptide that was able to selectively target the blood vessel of brain and kidney [27]. Since then a number of peptides have been identifed that target many other tissues [28].

Patients with: cutaneous leishmaniasis (A) buy avalide 162.5 mg low price, mucocutaneous leishmaniasis (B) generic avalide 162.5mg online, visceral leishmaniasis (C) and post-kala-azar dermal leishmaniasis (D) (Adapted from Chappuis et al 162.5 mg avalide with mastercard. Leishmania metacyclic promastigotes are delivered to a vertebrate host by the bite of an infected sandfly (1). Within the phagolysosome, promastigotes differentiate into amastigotes (3) that replicate (4) and are released from the infected host cells (5) spreading the infection into the vertebrate host. When a sandfly ingests a blood meal from an infected host, the amastigotes differentiate back into promastigotes (6) and become metacyclic (7) (Adapted from Ponte-Sucre, 2003). Wright staining of Leishmania infantum intracellular amastigotes in mouse peritoneal macrophages (B) (Adapted from J. Leishmania infections typically occur through the bite of sandflies belonging to either Phlebotomus spp. Chemical structures of sodium stibogluconate (Pentostam®) and meglumine antimoniate (Glucantime®).................................................................................................................. Schematic representation of the seven human Sirtuins, which present core domain conservation and different subcellular localizations. N and/or C terminal extensions of different length may flank the core domain (Adapted from Frye et al. The small domain is coloured blue and is composed of a zinc binding domain (light blue) and of a flexible loop (royal blue). Nicotinamide (A), Sirtinol (B), Splitomicin (C), an Indole derivative, 6-chloro-2,3,4,9-tetrahydro-1-H-carbazole-1-carboxamide (D) and Suramin (E). Since then, more than 20 Leishmania species and subspecies with the ability to cause the disease in humans have been described (Ashford et al. They belong to the Trypanosomatidae family in the Kinetoplastidae order, which is mainly characterized by the presence of a kinetoplast in their members. Indeed, the protozoan parasites of the genus Leishmania are the causative agents of leishmaniasis, whose broad spectrum of clinical manifestations reflects the heterogeneity between the Leishmania species (Table I). The ulcers usually self-heal in immunocompetent individuals, but leave disfiguring scars (Figure 1A). High fever, substantial weight loss, anaemia, and swelling of the liver and spleen are the main symptoms of this disease (Figure 1C). Nevertheless, all forms of this protozoan infection share three pathogenic features: resident tissue macrophages are targeted and support intracellular parasite multiplication; the host’s immunoinflamatory response regulates the outcome of the disease, and persistent tissue infection is characteristic (Murray et al. Patients with: cutaneous leishmaniasis (A), mucocutaneous leishmaniasis (B), visceral leishmaniasis (C) and post-kala-azar dermal leishmaniasis (D) (Adapted from Chappuis et al. Principal Leishmania species and their geographical distribution Species a Pathology Reservoir Distribution L. Indeed, two main morphological forms of the parasite can be 4 Chapter I Leishmania spp. However, other cell types like fibroblasts and dendritic cells may also harbor the parasite (Moll et al. Leishmania metacyclic promastigotes are delivered to a vertebrate host by the bite of an infected sandfly (1). Within the phagolysosome, promastigotes differentiate into amastigotes (3) that replicate (4) and are released from the infected host cells (5) spreading the infection into the vertebrate host. When a sandfly ingests a blood meal from an infected host, the amastigotes differentiate back into promastigotes (6) and become metacyclic (7) (Adapted from Ponte-Sucre, 2003). A vertebrate host becomes infected with Leishmania after the bite of an infected Phlebotomine female sandfly when it takes a blood meal, by the injection of metacyclic promastigotes. These non-dividing and infective forms are present on the salivary glands of the sandfly vector and display increased resistance to host complement-mediated cell lysis (Sacks et al. Indeed, once injected into the vertebrate host, the metacyclic promastigotes are engulfed by the resident dermal or recruited phagocytic cells. Then, the parasite-containing phagosome fuses with a lysosome forming a phagolysosome within which the promastigotes differentiate into the parasite vertebrate stage, the amastigote form. Contrarily to other pathogens that are destroyed by the hostile environment of the phagolysosome, the Leishmania parasites are not only resistant to the acidic pH, hydrolytic enzymes 5 Chapter I Leishmania spp. When a sandfly vector takes a blood meal from an infected vertebrate host, it ingests either free Leishmania amastigotes or amastigote-infected mononuclear cells. Within the insect midgut, the amastigotes transform into the flagellated procyclic promastigotes that multiply by binary fission. Wright staining of Leishmania infantum intracellular amastigotes in mouse peritoneal macrophages (B) (Adapted from J. Indeed, the promastigotes’ metacyclogenesis can be mimicked in vitro, since procyclic forms correspond to promastigotes in the exponential phase of their growth, and metacyclic forms are found in stationary phase cultures (Sacks and Perkins, 1985). The morphological, biochemical, biological and immunogical properties of the axenic amastigotes resemble the amastigotes isolated from host infected cells, thus representing an in vitro model to Leishmania differentiation, immunogical and drug research studies (Hodgkinson and Soong, 1997). Moreover, the compartmentalisation of energy metabolism with the glycolytic pathway and other enzymes sequestered in glycosomes, a redox metabolism based on a unique thiol called trypanothione, and a polycistronic transcription with post- translational regulation of gene expression are among the unusual characteristics of trypanosomatids. Indeed, the Old World Leishmania species have 36 chromosomes, compared with 35 from New World species and 34 from the L.

Safety of purifed decolorized (low anth- etary high-purity aloe vera inner leaf fllet prepara- raquinone) whole leaf Aloe vera (L) Burm cheap avalide 162.5 mg. Inhibition of cytochrome P450 enzymes Yokohira M buy 162.5mg avalide otc, Matsuda Y buy avalide 162.5mg without a prescription, Suzuki S, Hosokawa K, by rhein in rat liver microsomes. J Chromatogr B Analyt Ulbricht C, Armstrong J, Basch E, Basch S, Bent S, Technol Biomed Life Sci, 796(1):113–9. Exposure Data Common names: Hydrastis; Golden seal; Yellow Indian plant; Yellow seal Goldenseal (Hydrastis canadensis L. Goldenseal has one Medica of the United States, the American bota- long-trunked basal leaves, a single stem, and two nist Benjamin Smith Barton frst mentioned the smaller leaves attached to the fowering stem. Name: Golden seal root Berberine is usually found in the roots of golden- Botanical name: Hydrastis canadensis L. Pharmacopeia: a dry extract from roots and Powdered goldenseal root and leaf products rhizomes contains at least 2% hydrastine and are available as capsules and teas in combination 2. Additional analyses report on the use of gold- As a consequence of the high cost of genuine enseal and illicit drugs. Goldenseal may prevent goldenseal, some commercial products contain the detection of illicit drugs (such as tetrahydro- little or no goldenseal plant material (Govindan canabinol and barbiturates) in urine by inducing & Govindan, 2000). Coptis chinensis has been their rapid elimination (Mikkelsen & Ash, 1988; sold in place of “Chinese goldenseal” and has Hamon, 1990; Schwarzhof & Cody, 1993). Native Americans used goldenseal to treat common conditions such as wounds, ulcers, digestive disorders, cancer, and skin and eye ailments (Hamon, 1990; Hobbs, 1990). Over the years, goldenseal has been used to treat a variety of digestive and haemorrhagic disorders. No data on production processes or volumes A clinical trial using berberine suggested were available to the Working Group. Other Hydrastine, another major goldenseal alka- countries known to sell products containing loid, is claimed to be an abortifacient, antibiotic, goldenseal include Canada. According to data from the United States National Health (b) Medical research and Nutrition Examination Survey, there has In medical research, berberine is used as a been a decline in the prevalence of goldenseal fuorescent stain for cells, chromosomes, and use as follows: 1999–2002 (0. Survival of the females at cure, or prevent any disease” (Croom & Walker, 9000 ppm was lower than that of controls. Tere were no signifcant increases in and at recommended oral dosages for short-term the incidence of tumours in female mice. Cancer in Humans major alkaloids (berberine, hydrastine and cana- dine) characteristic of goldenseal at a concentra- No data were available to the Working Group. Survival of the females at 9000 ppm was glucuronidation, but not sulfation, while the greater than that of controls. At 105–106 weeks, phase I metabolites of berberine were primarily goldenseal root powder caused increased inci- sulfated (Gupta et al. Te area under the dences of hepatocellular adenoma in males and curve of hydrastine in plasma is signifcantly females at the highest dose. One male rat at the higher than that of berberine, suggesting that the highest dose also developed a rare hepatocel- oral bioavailability of hydrastine is also higher. Tere was a treatment-related Tere was enterohepatic recycling of berberine, statistically signifcant increase in the incidence which also had a high volume of distribution of liver eosinophilic foci in male and female rats. For literature showed that hepatocellular adenomas example, the plasma Cmax of berberine was only may progress to malignant tumours in F344/N 0. Mechanistic and Other discrepancy between pharmacokinetic parame- Relevant Data ters for purifed berberine compared with those for goldenseal. In 11 healthy subjects treated orally (aged 21–28 years) were given berberine chloride with a single dose of goldenseal (2. Urine samples were collected both berberine and hydrastine were absorbed and the metabolites isolated and purifed by from the gastrointestinal tract, and their phase polyporous resin column chromatography. Te amounts of these Te elimination half-life (t1/2β) of hydrastine purifed metabolites in the urine were 250, 17, was 4. Using Oxidative demethylenation was the major meta- nuclear magnetic resonance spectroscopy in bolic pathway and the metabolite obtained can addition to liquid chromatography–mass spec- subsequently undergo glucuronidation (Liu trometry, the study identifed the above three et al. In one study in vivo, male Wistar conjugated metabolites, plus previously unseen rats (age, 8–10 weeks) were given berberine at a conjugates: demethyleneberberine-2-O-sul- dose of 100 mg/kg bw, and urine samples were fate, jatrorrhizine-3-O-β-D-glucuronide, collected for 48 hours; the fve urinary metabo- thalifendine-10-O-β-D-glucuronide, berberru- lites of berberine isolated and identifed included bine-9-O-β-D-glucuronide, jatrorrhizine-3-O-sul- berberrubine-9-O-β-D-glucuronide, demeth- fate, 3-10-demethylpalmatine-10-O-sulfate, and yleneberberine-2,3-di-O-β-D-glucuronide, columbamin-2-O-β-D-glucuronide (40 mg, demethyleneberberine-2-O-sulfate, 3,10-demeth- 6 mg, 4 mg, 6. In this study, both sulfates and glucuronides of Berberine was found to undergo extensive frst-pass metabolism in the rat intestine. Tey found that by the small intestine, resulting in an extremely the cellular uptake of berberine was 30. In one experiment, poor; in rats given berberine at an oral dose of Etheridge et al. In one study, berberine exhibited diferent binding afnities to diferent No data were available to the Working Group.