By J. Sanuyem. United States Air Force Academy.

Serum Evaluation On several different occasions in the beginning of his research on diphtheria serum cheap 800mg renagel free shipping, Behring had insisted that the antitoxin theory was mainly of „heuristic value” for him 400 mg renagel mastercard, both in extracting the therapeutic serum and in measuring its effcacy. Behring carefully elaborated his evaluation techniques parallel to the diphtheria serum research, as can easily be surmised from his publications: in 1891, he adopted one of Ehrlich’s methods,93 which he completely changed in 189 in collaboration with Wernicke94 and again in 1893, this time working together with Oscar Boer,95 before a partnership with Ehrlich gave rise to a refned and standardized method at the end of 1893. The serum was injected 24 hours before the guinea pigs were infected with a dose of diphtheria culture strong enough to kill an untreated animal. The quality of the serum was now no longer measured by its capacity to prevent symptoms, but by its capacity to prevent 89 On this issue, see the letters between Behring and Metschnikoff from May 1894 (Behring to Metschnikoff, 5. Medicinisch- chirurgisches Handwörterbuch für praktische Aerzte, edited by Albert Eulenburg, vol. Furthermore, the strength of a serum being tested now had to be specifed in relation to a so called „normal serum“ defned by Behring as a therapeutically effective dose for humans. Its actual strength was assessed against a toxin of confrmed high potency that Behring had extracted from two-years-old diphtheria cultures. The standard toxin was now made and defned by Behring and Ehrlich, and they asserted that no one had the right to reference their „titer“ without express permission. Secondly, a network of strategic cooperation between bacteriological research, clinicians, pharmaceutical enterprises, and state authorities developed around the serum: the concept of the serum’s „value” bridged the differences between these diverse interest groups because it was broad and fexible enough to be translated from a laboratory to a therapeutic measure and because it assumed an economic and a public health value. Indeed, Behring was enough of a businessman to recognize the advantages of having a metric for the „value” of the serum and of course the Farbwerke Hoechst were eager to have such a useful accounting tool. Thus, it was probably no accident that Behring redefned the evaluation method at the same time that Wernicke and Aronson were presenting their dog-sera. Aronson in particular threatened Behring’s ambitious plans because he too was aiming to enter the private sector. Considering Wernicke’s publication on dog-sera, it’s noteworthy that he felt obliged to reassess the value of his sera based on the newly developed method, because it was viewed as being more rational and exact. See the report of Laubenheimer to the board of Hoechst („Bericht an Aufsichtsrat“, 0. On the basis of his evaluation method, Behring tried to denigrate the serum and to call Aronson’s scientifc credentials into question, alleging that he had provided unreliable specifcations for the „therapeutic value” of Schering’s serum and was motivated only by its potential „monetary value”. In addition, their method became institutionalized once a central state institute was established in the German Reich in 1895. Unlike his German colleagues, Roux was under no pressure to maneuver through such a point of passage, primarily because in France value comparison was of less eminent importance: there it did not serve to control competing providers because the Pasteur Institute in Paris held a monopoly over serum-production. However, for the sake of comparability with the German sera, Roux made the effort to measure the serum using one of the accepted evaluation methods. He decided on the method published by Behring and Wernicke in 189 ,108 which he and Vaillard had already used in a modifed form for measuring tetanus serum. This meant that for Roux and his collaborators the living body and its ability to respond was an obligatory point of passage between the injection of the serum and the infection. On the other side of the Franco-Prussian border, Behring and his antitoxin hypothesis could basically rationalize away the vital variability of the guinea pigs. His ideal test animal was not regarded as an organism which reacted individually, but merely as a standardized indexing device. Roux and his collaborators varied the method by injecting pure toxin instead of diphtheria culture (Roux and Martin 1894, p. Analogously, Gradmann has pointed to the instrumentalization of animals as „cultural media“ in the experimental system of Robert Koch (Christoph Gradmann, „Das Maß der Krankheit - das pathologische Tierexperiment in der medizinischen Bakteriologie Robert 92 French and German Diphtheria Serum Research and the Reconfguration of Cultural Boundaries Conclusion The history of diphtheria serum research in Berlin and Paris tells us much about the differences between the two research cultures. In this article I have described the methods of chemical weakening versus biological attenuation of the diphtheria bacteria (or toxin) that comprised an important technical basis for immunization. I have also discussed the humoral versus cellular or phagocytic theories of immunity, and fnally the in vitro- versus „vital response” method of evaluating the serum. These differences were effected by the respective research traditions in Berlin and Paris, but they were also reconfgured in the interplay of the protagonists on both sides of the Franco-Prussian border in efforts to demarcate and profle their concepts and theories. These dynamic interrelations were at the same time also bridging the research activities of Roux/ Metschnikoff and Behring: Thus, I have shown how the researchers developed a considerable scientifc interest in each other and how both Roux and Behring drew on each other’s basic experimental techniques. Conceptualizing the relationship as dynamic interplay between the „two cultures of bacteriology“ in Paris and Berlin takes us away from the well-worn dichotomies of „national“ or „personal rivalry“ versus „cooperation“. Of course, the present article treats only a very short timeframe and cannot serve as a basis for generalizations about the history of Koch’s and Pasteur’s research schools as a whole. But this micro-study at least suggests that a shift in focus could lead to a subtler picture of the story than one based on the notion of essentially separate cultural worlds of science that only occasionally cooperate. Instead it shows the value of closely analyzing the multi-layered forms of interactions that not only demarcate research schools from one another, but also bind them together. Studien im Anschluß an Georges Canghuilhem, edited by Cornelius Borck, Volker Hess and Henning Schmidgen, 71-90. Jonathan Simon Abstract1 While it would be reassuring to believe that state regulation of drugs refects the best available response to any given public health problem, it is clearly wishful thinking. Indeed, much recent research points to the complex interactions and often intense negotiations that lie behind legislation in this feld, both in the past and today. In the present paper, I argue in the same sense, although in an arena where explicit debate was (apparently) limited. Retracing the history of serum regulation in France in 1895, I will present the context of suspicion and trust that framed a series of (largely silent) negotiations around the manner to ensure the safety of the French people while giving them access to what was seen as a valuable ‘scientifc’ treatment for a deadly disease.

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Imbalances between vasodilators/vasoconstrictors buy renagel 800mg on line, platelet activation/inhibition generic renagel 400mg without a prescription, and endothelial and smooth muscle cell proliferation/inhibition conspire to cause chronic pathological changes in pulmonary vessels and worsening clinical symptoms (Figure 10-1). Importantly, these contributing factors to the pathophysiol- ogy of pulmonary hypertension also serve as emerging targets for treatment. Strategies that reverse these underlying contributors to pulmonary hyperten- sion seem able to improve clinical function in patients. Histori- cally, the incidence of true postoperative pulmonary hypertensive crises in patients who were judged preoperatively to be at risk for these events was high, probably greater than 50%. Vasodilators by class Drug class Advantages Disadvantages Nitrates Easily titratable, rapid onset and 1. Little effect on pulmonary myocardial remodeling circulation Calcium channel blockers Orally active, best defined role 1. Intravenous forms produce systemic increase cardiac output, some hypotension pulmonary selectivity, titrat- 2. Aerosolized delivery systems not well established, with frequent administration required Endothelin receptor Effective for disease states with 1. Minimal experience in critically ill pulmonary specificity patients on mechanical ventilation 3. Intravenous forms more suitable for postoperative setting but not yet approved for use in humans βagonists Increases cardiac output, titratable 1. Hypotension at high doses for pressures, acts synergistically refractory pulmonary hypertension with catecholamines, not 3. Slightly long duration of action arrhythmogenic (1–3 h) Phosphodiesterase Orally active, act synergistically 1. Longer-acting oral forms under agent pulmonary vasodilator, development may have additive effects with 4. Complex delivery compared with shunt, no myocardial depres- oral medication sion, may have benefit from 4. Pharmacological Treatment 231 markedly reduce the incidence of postoperative pulmonary hypertension and mortality associated with this condition. In an early report of a series from one large center, half of the postoperative cardiac children who had pulmonary hypertensive crises died during their hospitalization. Clinicians and investigators are reluc- tant to join a placebo-controlled trial for this drug. Consequently, there is a paucity of randomized controlled trials to demonstrate efficacy of the drug and establish evidence-based practice for its use. Because these effects are still not clarified, establishment of lowest effective dosage therapy is indeed more important to minimize possible toxicities. In adults with ischemic cardiomyopathy, sudden pulmonary vasodilation may occasionally unload the right ventricle sufficiently to increase pulmonary blood flow and harmfully augment preload in a compromised left ventricle. Older style vasodilators, such as tolazoline, phenoxybenzamine, nitroprusside, or isoproterenol had little biological basis for selectivity or enhanced activity in the pulmonary vascular bed. Moreover, they seldom targeted the pathophysiology, which is now better understood. However, if myocardial function is depressed and the afterload reducing effect on the left ventricle is beneficial to myocardial func- tion and cardiac output, then there may be considerable value to these drugs. Phenoxybenzamine is still proclaimed to reduce sympathetic vasolability in postoperative patients and has its devotees among cardiac surgeons. Pharmacological Treatment 235 Prostacyclin Prostacyclin therapy has been widely studied in treatment of pulmonary hyper- tension. Because of its potent vasodilatory activity in the pulmonary vasculature, it is a useful drug for such patients, although the precise mechanism of action is not known. Prostacyclin therapy has been shown to improve hemodynamic func- tion, exercise tolerance, quality of life, and survival for patients with pulmonary hypertension (Barst et al. Prostacyclin (epoprostenol) is most commonly administered as a continuous intravenous infusion through a central venous catheter. The initial dose is 1 to 2 ng/kg/min, which is carefully titrated over time, based on patient tolerability and response. Epoprostenol can be effective regard- less of clinical response to acute pulmonary vasodilator testing. Because epopros- tenol requires continuous intravenous access, patients are subject to a variety of complications, including catheter sepsis and significant hemodynamic changes if treatment is interrupted inadvertently. The mechanisms of resistance or tolerance to prostacyclin therapy are not well characterized. Because of the usefulness of epoprostenol, a variety of prostacyclin formulations have been developed that allow oral (beraprost), inhaled (iloprost), or subcutaneous (treprostinil) administration. Prostacyclin seems to have somewhat more selectivity for the pulmo- nary circulation, but, at high doses, can precipitate a hypotensive crisis in unstable postoperative patients with refractory pulmonary hypertension. Admin- istration of aerosolized iloprost requires multiple doses during 24 hours in critically ill patients. The pharmacokinetics, when iloprost is administered by this route, are not well worked out for adults or children.

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