By U. Torn. Metropolitan College.

It is also notable that almost all rare disease classes are populated cheap 4mg reminyl with amex 7r medications, although within each class of disease the proportion of all diseases that are targeted by an orphan drug remains small purchase reminyl 8 mg otc symptoms for hiv. This is probably driven, at least in part, by the recent advances in genetic screening and analysis technologies, and a signicant increase in under- standing of the genetic basis for some diseases. This is an encouraging sign that basic science advances of the last decade are fuelling the clinical advances of the next. Companies such as Genzyme, Genentech, Shire Human Genetic Therapies, Amgen and Actelion were most closely associated with rare disease drug discovery. In recent years, the companies involved in rare disease R&D have become much more diverse, as was highlighted in Table 1. Alexion Pharmaceuticals is a small biotechnology company that View Online Denitions, History and Regulatory Framework for Rare Diseases and Orphan Drugs 23 Figure 1. Biogen Idec is another company that has built an impressive portfolio of rare disease treatments for diseases that include multiple sclerosis and non-Hodgkin’s lymphoma, and has embarked on a series of collaborations and acquisitions (Stromedix in 2012 for their idiopathic pulmonary brosis asset and Knopp Neurosciences for access to the Phase 2 asset dexpramipexole for amyo- trophic lateral sclerosis). Start-up biotechnology companies with a focus on rare diseases have attracted signicant investor funding in recent years. These companies are oen, but not always, established around a specic platform technology. The pricing debate will undoubtedly be reignited when the pricing of uniQure’s gene therapy product Glybera is announced. The pricing of a one- time series of intramuscular injections of Glybera is likely to exceed that of all existing orphan drugs that are dosed chronically, and could exceed the $1 m per patient level. More companies, including big pharma, are now involved in drug R&D than ever, and their attention is focused on more rare disease classes than ever. This increased level of investment is of course not a guarantee of successful drug products, but it certainly increases the chances of realising more new and innovative rare disease treatments. Much of this increased level of investment, and indeed the orphan drug model itself, has been predicated on the promise of premium pricing of drugs that are eventually brought to market, thereby guaranteeing a level of prot for the drug sponsor, and it is this aspect of orphan drug development that does seem set to evolve in the near to medium term. While the overall budget spend by healthcare systems around the world on orphan drugs is small compared to more mainstream products such as cardiovascular or anti-inammatory treatments, and the rare diseases that those drugs treat are oen serious and View Online Denitions, History and Regulatory Framework for Rare Diseases and Orphan Drugs 25 life-threatening, there does appear to be increasing scrutiny of orphan drug pricing. The key evidence for successful orphan drugs in the future will more than ever be safety and above all efficacy. This will be especially true in disease classes where multiple products exist, and one could envisage a system of ‘risk sharing’ in which a sponsor will be required to lower the cost of a drug treatment if it is shown to have less than expected efficacy. More accurate data of rare disease prevalence and genetic causal links will become available. Translational data sets to rene the targeting of small patient populations and measurement of meaningful clinical biomarkers to assess outcome measures as reliable indicators of drug efficacy will evolve. These resources bridge existing data gaps to complete the necessary studies to provide pre-clinical and clinical data required for regulatory purposes. Of particular interest are the translational research programmes offered by the National Center for Advancing Translational Sciences, the National Cancer Institute, The National Institute of Allergy and Infectious Diseases, The National Heart, Lung, and Blood Institute, and the National Institute of Neurological Disorders and Stroke. Although similar in many respects, there are differences in each of the translational research programmes, including the application and review processes. Some institutes make the traditional grants and contracts available for clinical trial planning and implementation. To avoid confusion with the different processes, it is advisable to identify those institutes with a research portfolio that includes aspecic disease interest. These activities within the translational research programmes are expected to complement or supplement the existing biopharmaceutical industry efforts and not to replace the exten- sive activities related to rare disease research and orphan product devel- opment activities. It will also be interesting to see if big pharma, and indeed smaller biotech companies, can be incentivised to work on rare diseases for which there is very little known and take the lead role in driving the basic science behind such diseases. Rare diseases can be staggering if you consider the need for sufficient resources to discover and develop products to diagnose, treat or prevent rare diseases experienced by approximately 6–8% of the population who have one of the more than 6000 rare diseases. Partnering and collaborating with the academic research community is an essential component of R&D efforts for the bio- pharmaceutical and medical device industries to develop a portfolio of potential interventions and diagnostics. The pharmaceutical industry, with its unique product R&D infrastructure and expertise, provides the academic research community with the capability of moving a discovery to the marketplace. Rare diseases do not respect geographical or national borders and offer numerous research and regulatory challenges requiring global efforts as we observe expansion of activities that include the academic research communities from around the world. Numerous academic and government technology transfer programmes are now available to industry. Many of these programmes are formal partnerships between the industry and the academic partners.

It comprises of a posi- tively charged ring (also referred to as cylindrical collector electrode) order reminyl 8 mg treatment integrity checklist, whereas the flame jet serves as the negative electrode cheap 4 mg reminyl mastercard medicine 0829085. The flame jet has two inlets ; from the bottom of the column effluent is introduced and from the side H2 to form the fuel, whereas air is let in uniformly around the base of the jet. Exhaust Collector electrode Detector Electrode housing Polarization leads Flame jet Hydrogen Air Column effluent Figure 29. However, this valuable detector needs to be handled with a lot of skill and expertise so as to achieve wonderful and dependable results. These heavy-negative-ions will have less mobility as compared to the electrons ; therefore, they will have no other coice than to unite with positive ions. Thus, the net result would be fewer ions and electrons available to migrate to the electrodes, thereby causing a marked and pronounced reduction in the standing current of the detector. Ultimately, this observed current decrease represent as the ‘signal’ of the electron capture detector. The metal block of the detector housing itself serves as a cathode, whereas an electrode polarizing lead suitably positioned in the centre of the detector housing caters for a collector electrode (anode). The radioactive source from a beta-emitter is introduced from either sides of the detector housing below the electrode polarizing lead. The column-effluent is passed into the detector from the bottom whereas its exhaust goes out from the top. Exhaust Detector Collector housing electrode (cathode) (Anode) Electrode polarization leads Radio Radio active active source source Column effluent Figure 29. It may also be invariably termed as a nitrogen detector, a sulphur detector, a phophorus detector, and a halogen detector by virtue of the fact that its specificity in detecting organic compounds essentially containing these elements. If P- or S-containing hydrocarbons are ignited in a hydrogen-rich flame, it gives rise to chemiluminescent species spontaneously which may subsequently be detected by a suitably photomultiplier device. Two-charged electrodes serve as an electric field in the detector, the cathode becoming the collector electrode for the ions. The ion-current thus generated, that will be directly proportional to the ion concentration, then becomes the signal of the detector. Most frequently, a recorder of 1-10 mV full-scale deflection (~_ 10 inches) and having a response time 1 second or less is quite adequate. Essentially in a potentiometric recorder, the input signal is balanced continuously by a feedback signal making use of a servomechanism ; whereby a pen strategically connected to this system moves proportionally along the width of the chart paper, thus recording the signal, whereas simultaneously the chart paper keeps moving at a constant speed along its length. It carries a pen that writes along a span of about one inch, reserved for integrator on the recorder chart paper at the end. The zero line of the integrator moves almost parallel to the base line of the chromatogram and as soon as a peak appears on the recorder, the integrator-pen starts moving from right to left the vice-versa within its one-inch strip. Each one- inch traverse (counted along projection parallel to signal axis) is usually assigned a value of 100 counts ; the total number of counts corresponding to a peak are directly proportional to the area of the peak. The type of mechanical integrator* affords fairly good accuracy and precision ; and above all it is quite cheap. The main advantages of an electronic integrator are, namely : (i) Provides a much wider linear range, (ii) Changing the ‘attenuation’ is not required, and (iii) Offers highest precision in peak-area measurement. A commercially available*** fairly sophisticated computer system of such type are available abundantly that may be capable of undertaking load upto 100 gas- chromatographs with ample data-storage facilities. Generally, different components possess different response factors, application of which not only com- pensates for different detector response for different components but also take into consideration the other factors inherent with the procedure. However, these factors may be calculated by preparing a synthetic mixture absolutely identical to what is expected in the sample, and subsequently carrying out the gas-chromatography of this mixture exactly under idential experimental parameters as described in the method of analysis. In certain instances, like petroleum fractions, where it may be possible to assume that most of the components possess almost equal response factors, the area normalization formula in Eq. Graphical Approach : Many a times a ‘graphical approach’ as illustrated in Figure 29. In fact, the very purpose of this synthetic-blends is only to simulate a typical sample. Now, exactly equal (or known) amounts of both, the ‘synthetic blend’ and the ‘sample’are separately injected and chromatograms obtained. Thus, by actually comparing the areas of the desired component in both the chromatograms, the ‘unknown concentration’ may be determined by the following expression : A %X = (% X in synthetic blend) A′X where, A′X = Peak area of component X in the chromatogram of ‘synthetic blend’. However, this method is less accurate in comparison to the first two methods described earlier for quantitative analysis. It should be used judiciously if only a few components present in small concentration (i.

As with Hmb protection buy discount reminyl 4 mg line medications education plans, they also have a long-range effect order 4mg reminyl otc medicine 50 years ago, the proline motif provides a deliberate change of native structure usually in the region of 6–10 residues after its incorporation. When comparing this strategy with Hmb protection, the introduction of ψPros has been proven to be superior [141]. After careful examination of the secondary structure of the peptide, four of these residues were replaced by ψPros: Ser64 (to initially alter chain conformation into the C-terminal part); Thr30 and Thr43 (which are crucial during folding due to hydrogen bonding formation, and located in distinct β-sheets); and Thr7 (positioned in the N-terminal region). Using ψPros, other otherwise inaccessible peptides have also been assembled [140, 142–144]. The main limitation of this approach is that a Ser, Thr, or Cys residue needs to be present in the sequence. Based on previous work on the synthesis of the more soluble o-acyl prodrug analogs [149, 150], this technique involves the assembly of the O-acyl isopeptide and its later conversion to its peptide counterpart under physiological conditions (Scheme 2. Due to the better solubility of the O-acyl isoform, this is obtained in better yields and purities. Presence of the ester is believed to change the secondary structure of the peptide. These studies have provided a tool to disrupt amyloid-derived peptide assemblies [153] and to identify antiamyloid agents [154]. Analysis of side-products indicated incomplete Fmoc deprotection and incomplete acetylation arising from aggregation. Based on these previous results, a completely convergent approach to suppress racemization was also developed [158]. Thus, for a given peptide, an N-terminal fragment, bearing a C-terminal O-acyl isopeptide, was coupled to a C-terminal fragment. Owing to the presence of the urethane-protected Ser/Thr residue, oxazolone formation, and, therefore, racemization, is avoided. To overcome this side reaction, the Bsmoc group, which can only be removed using 2% piperidine, was used [160, 161]. This methodology has been recently used to synthesize a peptide–polymer conjugate [162], which self-assembles with the formation of microstructures on the recovery of the native peptide backbone by O–N acyl migration. For these small peptides, the market price of which is moderate, the solution method dramatically reduces production costs, thanks to the starting materials needed and reagents-related expenses, and most importantly due to the low cost of the isolation and purifcation techniques this method requires. This is of great importance due to the fact that during the process every step can be relatively easily controlled and due to the less laborious fnal purifcation process. Thus, the purifcation and isolation of the fnal product is the major beneft of solution peptide synthesis. This disadvantage is somehow reduced if several segments of the pep- tide are synthesized in parallel and a convergent strategy is applied, instead of linear step-by-step synthesis in solution. Furthermore, the use of the relatively expensive solid supports and linkers is avoided. Finally, in solution it is possible and always desirable to keep the use of side protecting groups to a minimum. Unprotected amino acids can be successfully used in solution without side-reactions during the process [163]. In solution synthesis (step-by-step or convergent), except for the reversible masking of the N-amino group of the frst amino acid or fragment, orthogonal pro- tection of the carboxyl group of the second amino acid or fragment that participates in the reaction is required (Scheme 2. Instead, the C-terminal derivative has to be protected to the carboxy terminal (Z-group). The most known nonurethane type N -protecting group is the o-nitrophenylsulfenyl (Nps, 66) group [175]. The advantage of the Nps-group, except for the cleavage with acids [176], is that it can be selectively removed by nucleophilic reagents [177, 178]. These reagents avoid the problems encountered with protecting groups requiring acids for their cleavage. Thiolytic cleavage of the Nps group with a number of reagents has been described, and has been shown to enable rapid deprotection (Figure 2. Alternatively, the C-terminal protecting group can be hydrazides or protected hydrazides. Regarding peptides with amide function at the C-terminal, protection is commonly not essential.

If a spice that also (2) The antioxidant preservatives imparts color is used reminyl 8 mg line medications knee, it shall be des- listed in subpart D of part 182 of this ignated as "spice and coloring" generic reminyl 8 mg overnight delivery daughter medicine, unless chapter that may be used to retard de- the spice is designated by its specific velopment of rancidity of the fat con- name. If ascorbic acid is used to retard tent of the food, in amounts within the development of dark spots on the limits prescribed by that section. If any other (c) (1) to (6), inclusive, of this section, antioxidant preservative, as provided and following the numbered sequence in paragraph (d) of this section, is used, of such subparagraph, as follows: such preservative shall be designated (1) "Breaded fantail shrimp. Standard Series)," under (c)(6) of this section, is as follows: the heading "Definitions of Terms and (1) Equipment needed. Standard sieve, 1⁄2-inch sieve (ix) Copper sulfate crystals opening, 12-inch diameter. Fill the container three- vidually in a water bath that is main- fourths full of water at 70°–80 °F. Sus- tained at 63 °F–86 °F, and allow to re- pend the paddle in the container, leav- main until the breading becomes soft ing a clearance of at least 5 inches and can easily be removed from the below the paddle vanes, and adjust still frozen shrimp material (between speed to 120 r. Inspect each shrimp saturated solution of copper sulfate (1 pound and use the rubber-tipped rod and the of copper sulfate in 2 liters of tap water) is spray to remove the breading material necessary. The correct dip time is the min- that may remain on any of them, being imum time of immersion in the copper sul- careful to avoid undue pressure or rub- fate solution required before the breading can easily be scraped off: Provided, That the bing, and return each shrimp to the "debreaded" units are still solidly frozen and sieve. Remove the top sieve and drain only a slight trace of blue color is visible on on a slope for 2 minutes, then remove the surface of the "debreaded" shrimp mate- the shrimp to weighing pan. I (4–1–10 Edition) (v) Calculate the percentage of Thunnus alalunga (Bonnaterre, 1788)—Alba- shrimp material in the sample, using core the following formula: Thunnus atlanticus (Lesson, 1830)—Blackfin tuna Percent shrimp material=(Weight of de- Thunnus obesus (Lowe, 1839)—Bigeye tuna breaded shrimp sample)/Weight of sam- Thunnus albacares (Bonnaterre, 1788)—Yel- ple×100 lowfin tuna Thunnus tonggol (Bleeker, 1851)—Longtail (i) Label declaration. Each of the in- tuna gredients used in the food shall be de- Katsuwonus pelamis (Linnaeus, 1758)—Skip- clared on the label as required by the jack tuna applicable sections of parts 101 and 130 Euthynnus alletteratus (Rafinesque, 1810)— of this chapter. In containers (a)(5) of this section, and may contain of 1 pound or less of net contents, such one or more of the seasonings and segments are cut in lengths suitable flavorings specified in paragraph (a)(6) for packing in one layer. For the purpose of in- of more than 1 pound net contents, hibiting the development of struvite such segments may be cut in lengths crystals, sodium acid pyrophosphate suitable for packing in one or more may be added in a quantity not in ex- layers of equal thickness. It is packed in hermetically their transverse cut ends parallel to sealed containers and so processed by the ends of the can. It is la- ment may be added if necessary to fill beled in accordance with the provisions a container. Canned following vegetables: Beans, cabbage, smoked tuna shall be labeled in accord- carrots, celery, garlic, onions, parsley, ance with the provisions of paragraph peas, potatoes, green bell peppers, red (a)(8)(v) of this section. When lemon units of value, determined in accord- flavoring is added, a safe and suitable ance with paragraph (a)(7) of this sec- solubilizing and dispersing ingredient tion. A substance used in accord- (albacore), and is not darker than ance with this paragraph is deemed to Munsell value 6. This color designation in- no greater than necessary to achieve cludes any tuna not darker than the intended flavor effect, and is Munsell value 5. This color designation in- ditive as defined in section 201(s) of the cludes all tuna darker than Munsell Federal Food, Drug, and Cosmetic Act value 5. This color designation defined, it is used in conformity with may be applied only to tuna flakes regulations established pursuant to specified in paragraph (a)(3)(iii) of this section 409 of the act. I (4–1–10 Edition) separations of pressed cake resulting between 550 mμ and 560 mμ. The filter from the method prescribed in para- does not pass appreciable visible radi- graph (c)(2) of this section. Pass the ation of wavelengths below 540 mμ or combined portions through a sieve above 570 mμ. The passed wavelength fitted with woven-wire cloth of 1⁄4-inch band is of a monochromaticity suffi- mesh complying with the specifica- cient to cause a sample and a neutral tions for such cloth set forth in "Offi- standard of equal reflectance to appear cial Methods of Analysis of the Asso- of the same hue. The comparator is rig- ciation of Official Analytical Chem- idly mounted on a vertical stand at- ists," 13th Ed. Standard Series)," under the positioning two cans of size 307 × 113 in heading "Definitions of Terms and Ex- the two fields of view. Mounted on the planatory Notes," which is incor- base are two shaded lamps, which di- porated by reference. Mix the sieved ma- lamps are strong enough to furnish terial and place a sufficient quantity adequate and convenient illumination into a 307 × 113 size container (bearing through eyepiece and filter.

Other strategies include replacement of specifc the amino acids with the N-methyl derivatives buy cheap reminyl 4 mg online medications zyprexa, with topographically constrained derivatives discount reminyl 4mg without a prescription medicine that makes you poop, or with the halogenated derivatives of aromatic amino acids. Finally, the use of the “multiple-antigenic-peptide” approach where many molecules are attached to a carrier with multiple attachment points can produce molecules that, due to their size, are not recognized by proteases. This chapter emphasizes the role of creative synthetic chemistry is the modifcation of peptides to achieve stability and bioavailability. The book concludes with Chapter 8, provided by Jeffrey-Tri Nguyen Yoshiaki Kiso, that discusses the important area of peptide delivery. While progress in the past 50 years has permitted peptide chemists to make almost any sequence of amino acids that is desired in high yield and purity, getting those molecules into humans and into the specifc area in the body where they can exert a therapeutic effect is a problem that has not progressed as rapidly. Thus, this chapter is very important for future advances in drug discovery based on peptides. Many of the readers may already be familiar with the Lipinski’s Rule of Five that includes recommendations for the size of a molecule, the number of hydrogen bonding atoms, and the lipophilicity. These rules are discussed in this chapter, but much more information is provided regarding solubility, membrane transport, and metabolic stability. In conclusion, this book provides a primer for anyone in the feld of drug discovery and specifcally in the area of the use of peptides as molecules for both the discovery phase and, in favorable cases, the fnal phase of the creation of new molecular entities that can be moved into further studies to evaluate their potential as therapeutic drugs. I want to thank the authors of the chapters for their friendship, for many discussions, and for their excellent writing for this book. Craik, Institute for Molecular Bioscience, The University of Queens- land, 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.

When rapid discount reminyl 8 mg free shipping medicine evolution, efficient absorption of drugs is desired order reminyl 8 mg otc symptoms 8 days after conception, aqueous solutions represent the oral dosage form of choice. Drugs in suspension are also readily absorbed because, as described above, the large available surface area of the dispersed solid facilitates rapid dissolution and absorption. Suspensions are also suitable for young children and patients who have difficulty in swallowing tablets and capsules. Emulsions are potentially useful for improving the bioavailability of lipid-soluble drugs. Soft gelatin capsules have been shown to be efficient and reliable dosage forms, and their use has grown in recent years. Effervescent tablets are less common, but provide a convenient method for supplying sufficient amounts of a drug for relatively rapid dissolution. They are based on an acidic material in combination with a dry carbonate salt, which react in water to liberate carbon dioxide. Buccal and sublingual tablets are also available for both local and systemic drug delivery and are described in Chapter 7. The various formulation factors which affect oral absorption from conventional oral dosage forms, such as: • particle size, and • the presence of additives (wetting agents, diluents, binders, etc. These conventional dosage forms are not considered as advanced drug delivery systems and are therefore not discussed here in further detail. These “enteric” coatings have traditionally been reserved for drug substances that: • cause gastric irritation; • produce nausea if released in the stomach; • are destroyed by acid or gastric enzymes. Common polymers used for enteric coating include methacrylic acid and ethyl acrylate copolymers (Eudragit L 30D), cellulose acetate phthalate (Aquateric), and polyvinyl acetate phthalate (Coateric). Such polymers possess free carboxylic acid groups on the polymer backbone and therefore demonstrate a highly pH-dependent solubility, being insoluble in gastric acid but soluble at intestinal pH. Depending on the number of carboxylic acid groups present, different polymers exhibit different solubilities at different pHs; for example, a sharp increase in the solubility of cellulose acetate phthalate occurs at pH 5. Enteric-coated dosage forms have been shown to provide a more desirable therapeutic effect. For example, a new enteric-coated formulation of sodium ursodeoxycholate, in which the barrier film disintegrates and releases the drug only at pH≥5. Enteric-coated sulodexide tablets administered once daily demonstrated greater efficacy and similar tolerability to a standard capsule formulation administered twice daily. However, it should be remembered that enteric-coated formulations are not suitable in some situations. Enteric-coated tablets contain indigestible solids and are often of considerable size. Thus, seriously ill patients, who may have gastric hypomotility or pyloric channel narrowing, are probably not good candidates for therapy with large enteric-coated dosage forms. A further disadvantage of this approach is the uncertainty of the location in which the enteric coating starts to dissolve. In general, synthetic water-soluble polymers tend to be widely used for reservoir and Table 6. In a matrix system, drug release is facilitated by the gradual dissolution of the matrix and is controlled by solubility and porosity of the matrix. In a reservoir system, drug release is facilitated by the gradual dissolution of the coat and is controlled by thickness and solubility of the coating. The Indas (insoluble drug absorption system) is a matrix tablet designed to improve the solubility and absorption characteristics of poorly water-soluble drugs. The gel-forming erodible tablet system facilitates controlled release of the active moiety. A further system from Elan is the Modas (multiporous oral drug absorption system), which is specifically designed to control absorption of highly water-soluble drugs. Modas tablet formulations are reservoir systems which employ a permeable membrane which controls drug dissolution and allows diffusion from the tablet into the gastrointestinal tract. For example, in a reservoir multi-dose system, individual drug particles/pellets are coated with a poorly soluble polymer.

Behring had worked intensively on this subject in the eighteen eighties 8mg reminyl mastercard z pak medications, turning himself into an expert on the question of disinfectants generic 8mg reminyl fast delivery internal medicine, a subject of much importance in military medicine. As Jonathan Simon has argued, this practical achievement in working with antiseptics served as the basis for Behring’s initial approach to the therapy of infectious diseases. That approach involved a kind of „inner disinfection“ using antagonistic substances to render microbes innocuous within a living body. Nevertheless, a direct trial of iodine trichloride on infected children failed because of the chemical’s unacceptably caustic effects. In contrast to Behring’s progress, Roux and Yersin attempted to manipulate the pathogenic power of diphtheria cultures or the fltered toxin using heat, antiseptic chemicals, and other methods in such a way that immunization would result. In an article from 1889, Roux and Yersin were still convinced it was promising to search for a „chemical attenuation“ that would allow the animals to recover from the infection and thus gain immunity (Roux and Yersin 1889, 282). As Mendelsohn has argued, this period of their work was marked by a return to Pasteurian research axioms, with the researchers trying to vary the „virulence“ of the diphtheria cultures – conceived as a kind of biological property – in order to fnd a stable attenuated microorganism that could be used to develop a method for „microbic vaccination“24. One approach was to try to simulate in in vitro cultures the clinical conditions of patients who had recovered spontaneously from diphtheria. They also searched for „naturally attenuated” cultures and interpreted pseudo-diphtheria-bacilli as such rather than as a separate species of bacteria (as was commonly believed at the time). In their publications they showed themselves increasingly interested in a biological „hereditary attenuation” of microbes that they distinguished from a chemical or mechanical deactivation or weakening that would not affect subsequent generations. But there were no indications in his lecture (or in other sources) that, in the meantime, he or his collaborators had been conducting systematic immunization experiments against diphtheria since Yersin had left for Indochina at the end of the summer of 1890. Immunization and Immunity Given Roux’s conceptual and practical distance from diphtheria immunization, the question arises: How did he return to diphtheria serum research? As opposed to a „chemical vaccination“ using toxins (Roux 1891, 518; Émile Roux and Alexandre Yersin, “Contribution à l’étude de la diphthérie. The difference between „microbic“ and „chemical vaccination“ probably refects, in a distorted way, Pasteur’s shift from a „biological“ theory of immunity, based on the nutritional exhaustion of the pathogenic organism, to a „chemical“ theory, that viewed a chemical „vaccinal substance“, produced by the living bacteria, as the immunising agent (Gerald L. Mendelsohn has pointed out that the difference between the schools of Koch and Pasteur was not the French admission of virulence variability versus a German rigid species concept of frm properties. Instead, after a few initial doubts, Koch embraced Pasteur’s concept of variable virulence even though – on account of his own strict causal concept – he couldn’t agree with Pasteurian conclusions about the functional relativity of microorganisms to their milieu (Andrew Mendelsohn, “’Like All That Lives’: Biology, Medicine and Bacteria in the Age of Pasteur and Koch. In the words of Louis Martin (1864-1946), who collaborated with Roux on diphtheria after Yersin had left, the underlying diffculty was due to the complexity of achieving a diphtheria toxin of constant strength. The preservation method with carbolic acid, that would allow to keep the force of the toxin nine months and even longer,31 was probably of especially great interest for Roux because he and Yersin – at least in 1889 – had only been able to conserve their toxin for fve months. Around the summer of 1891, Roux teamed up with Louis Vaillard, a professor at the military medical school at Val-de- Grâce, who, in the frst half of 1891, had already replicated Behring’s method of diminishing the strength of tetanus toxin using (among other methods) iodine trichloride as a way of achieving immunization. Roux himself stressed in a publication from 1894 how important it was to have a stable toxin at one’s disposal in order to compare experimental results. At the same time, however, he admitted that this was no easy task (Roux and Martin 1894, 612). Shortly before the frst horse experiment, Roux had received via Metschnikoff a recent article by Behring and his colleague Wernicke. But they also outlined that, given their limited private funds, they were unable to produce serum in suffcient quantities for well-founded clinical tests on humans. Nevertheless, it seems probable that the German article encouraged the French researchers to undertake again systematic diphtheria immunization experiments, beginning immediately with large animals. Hence, there is no evidence to support an assumption that Roux did not pursue diphtheria serum experiments and that he subsequently adopted the immunization procedures on horses that were worked out by Behring with the help of Paul Ehrlich (1854-1915) in Berlin in the second half of 1893. And Friedrich Theodor Althoff (1839-1908), ministerial director in charge of the academic affairs in the Prussian Ministry of Culture, was aware of Behring’s and Wernicke’s intent to form a partnership with private enterprises (Behring to Wernicke, 0. The availability of horses for experiments thanks to the collaboration with the veterinary school provided Roux and his colleagues with a practical advantage over Behring and Wernicke at this stage of diphtheria serum research. Besides, in 189 at least, Behring was convinced that sheep, not horses, were the most „effcient“ producers of a therapeutic diphtheria serum. This, however, required that the research not be conducted at the state-funded Institute for Infectious Diseases. Behring – like all the other employees of the institute – had signed a declaration waiving all claims to fnancial benefts derived from his research at the institute. Ehrlich recounted in 1894 that Behring had „often“ said to him that horses would be the best producers of diphtheria-antitoxin, but this remark presumably refers to the second half of 189 (Paul Ehrlich, “Über Gewinnung, Werthbestimmung und Verwerthung des Diphtherieheilserums. March 189 , 84 French and German Diphtheria Serum Research and the Reconfguration of Cultural Boundaries This is the background to Behring’s and Wernicke’s article that indirectly sought large-scale funding for their promising diphtheria-serum research.