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By N. Ramirez. Pikeville College.

Studien im Anschluß an Georges Canghuilhem cheap estrace 1 mg line, edited by Cornelius Borck order estrace 2mg visa, 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. To analyse the emergence and functioning of the resulting serum regulation in France, I will make use of Herbert Simon’s concept of ‘satisfcing’, examining how the constraints and possibilities were ftted to one another over the course of parliamentary debates as well as the application of the offcial legislation. Thus, I will argue that while not ideal, this legislation was nonetheless satisfactory with respect to the immediate goals as conceived by the government and its partners, primarily the Pasteur Institute in Paris. In order to understand these developments, we need, therefore to examine all the constraints that entered into the discussion, such as the perception of the serum itself, its proposed use, the perception of diphtheria as a disease, the place of the local doctor in treatment, the status of bacteriology, etc. The heroic narrative of serotherapy I want to start my paper with a piece of French melodrama drawn from the experience of Paul Persy, a local doctor practicing in the Le Mans region of France at the end of the nineteenth century: On Saturday the nineteenth of January 1895, at around fve o’clock in the evening, a farmer from the Le Mans region introduced himself into my surgery, saying: ‘I have come, sir, in order to beg you to examine a child with a sore throat as soon as possible’ and, he added, now in tears ‘you see we are very worried; we lost one to croup four days ago, we only have this one left and “he is going the same way as the frst”: and we do believe it is the same illness’ ‘The child that you lost, was he treated by the new method, was he vaccinated? This modern miracle of medical science inspired the most sublime emotions in our hero’s breast, which he also valiantly struggled to put into words. Did I not think of my loved ones, all those who are dear to me and who might, one day, be affected by this cruel disease? Did I not think of the glory of France, my beautiful country, which I love and which I always want to see among the greatest of nations, for it is the blessed land of all devotions? This circular, dating from 14 January 1895, informed the Prefects of how to obtain the serum from the Pasteur Institute in Paris. Hence, at a moment when the Pasteur Institute was just beginning to produce suffcient serum to supply the whole of France, an emergency system was in place with the Prefect of each department distributing the still scarce medicine. This system by-passed the local pharmacies, which had hitherto constituted the standard channel for supplying medicaments to the French population. Indeed, the fact of leaving the pharmacist out of the circuit of distribution meant that the legal status of the serum under the legislation in force at the beginning of 1895 was unclear. If it was a medicament, then, according to legislation dating from 180 , only a qualifed pharmacist could supply it for medical use, which, as we have seen, was not the case. Nevertheless, as the serum represented a new therapeutic hope, widely acclaimed for its effectiveness in a deadly disease (particularly for young children), it is unsurprising that the Pasteur Institute was not pursued in court under the pharmaceutical legislation. Something else that is clear from the circular and the episode of the provincial doctor’s experience with 2 Paul Persy, Ma première application du sérum antidiphtérique. Morange (ed), L’Institut Pasteur: contributions à son histoire, Paris: La Découverte, 1991, pp. Another intriguing feature of Persy’s story is his repeated reference to the serum as a ‘vaccine’. As Louis Pasteur’s best-known innovation in human medicine was the rabies vaccine, it is perhaps not surprising that people, even doctors, should consider this new treatment for diphtheria to be another vaccine, even though this was not the case. It is interesting to note that Pasteur’s vaccine against rabies (which was used as a post-exposure treatment) occupied a similar precarious legal position to the serum, a situation famously compounded by the fact that Pasteur himself was not a qualifed physician. One reason for thinking that the rabies vaccine rather than the smallpox vaccine is the origin of the confusion between vaccine and serum is the close association made between this new treatment for diphtheria and the spiritual patron-heir relationship that existed between Louis Pasteur and Émile Roux. It was Roux who was responsible for developing the treatment in France, largely by following and reproducing the research being done in Berlin, where the serum was available much earlier than in Paris. Furthermore, vaccine plus Pasteur plus Roux all add up in Persy’s mind to the inevitable conclusion that the serum is a French invention, another sign (like the imposing basilique de Fourvière in Lyon) that, despite certain evidence to the contrary, God favoured the French over the Germans. Thus, Persy’s heroic story contains a number of elements that would, I want to argue, prove crucial in shaping the legislation around this serum in the months that followed. A) I have already cited the close association of the Pasteur Institute, Roux, and Pasteur with this novel treatment, and the patriotic, if not nationalistic implications of this association for French medicine. B) The position of the Pasteur Institute as the unoffcial offcial producer of the serum. This situation was endorsed on a national scale by the French government’s mobilization of its regional administrators to ensure the distribution of the serum, meaning that the state was clearly implicated (at least in terms of medical and popular perception) in the generalized practice of serotherapy. C) The fact that the serum escaped the traditional means for the distribution of medicaments; the pharmacist and his pharmacy. This was the case from the beginning, and in this respect followed the pattern of Pasteur’s treatment for rabies. Nevertheless, this was no longer a question of a few dozen patients per year who could be treated at the rue d’Ulm and later the Pasteur Institute, as the serum implied the injection of thousands of patients at hospitals and in homes across the country. There are other elements that feature in Persy’s narrative that are also relevant to the trajectory of the diphtheria serum throughout Europe and the rest of the world.

Is cold room or Thermal deep freezers mapping required for records storage of goods? Sampling If yes cheap estrace 2mg mastercard, what is the is done in control on entry of material and men classified into the sampling area(A/D) area estrace 2mg otc. If not what Suitable provision has been pressure made for sampling so as to prevent difference contamination, is cross contamination and maintaine mix-ups at a time d. Specify the arrangements Sampling Separate area is --- -- provided to sample the primary booth earmarked packaging provided materials foils, bottles, etc which are used as such. Cleaning Cleaning Which type of Dedicated procedure is procedure is sampling tools are used and how they washing validated not validated are cleaned, dried facility in and maintained. Sampling Portable area has dehumidifier centralize available d system for controllin g humidity 2. If yes pls explain how and attach copy of plan of premises of each category of drug. Which each provide sequential Productio / logical manner so as to prevent n suite contamination and cross contamination? How many sets of protective garments provided for each personnel entering production area. How quarantined, Segregate under test and d area for tested animals quarantin housed and controlled. In case of contractual testing what are the responsibilities of contract giver and contract acceptor. Whether entry to the sterility area is -- Yes, 15 P No -- through three air lock systems. Class- A/C What is the air class of these testing areas and whether pressure difference is maintained in these areas? Pls specify nature and type of dress used by the personnel in 169 various areas of operation. Please specify whether cross over bench is in place in the change room and if so whether it rule out the possibility of entering dust particle to the clean side. Whether arrangements provided for cleaning of outside dust and dirt from foot Please specify whether hands are disinfected before entering the production area Whether for sterile garments in house clean laundry has been provided. Batch no, Batch Size, and stage of manufacture along with signature of technical staff. Whether equipments use for production are labeled with their -- Yes No -- current status. Whether records of line clearance -- Yes No - is maintained according to appropriate checklist. Names of the authoriz ed personn el are displaye d -- Yes No -- Whether separate gowning provision is follows before entering into the procedure. Whether first in / first out or first expiry principal has been -- Yes No -- adopted. Pre Purchas No system -- What is the procedure for approving the source for audit is ing incoming materials. Up to 5 No system -- 0 stacked stacke d or more if load bearing study is in place 11 Equipment: - 11. Dedica Stored No separate -- ted separat area area ely in provid processi ed with ng area manuf acturin g area 11. Edible Edible Non edible -- Specify the quality and control grade grade grade reference No. If by electronic data processing authoriz system then how access is ed controlled to enter, modify etc. Whether re-conciliation of used Destro packaging materials is -- Returned -- yed maintained. Stored System No as per Please provide list of reference requir as per deficient refere standard and reference impurities require nce ement procured from the authentic sources. Please specify the sampling procedures from various stages -- As per No sop found -- of production. Arrheni ous equatio n Whether records of stability -- Yes No -- studies are maintained. Specify the validation procedure is responsible for validation of -- Yes No -- procedures. Whether specification of finished product include (a) the designated name of the product and the code reference; (b) the formula or a reference to the formula and the pharmacopoeial reference; (c) directions for sampling and testing or a reference to procedures; (d) a description of the dosage form and package details; (e) the qualitative and quantitative requirements, with the acceptance limits for release; (f) the storage conditions and precautions, where applicable, and (g) the shelf-life. Whether head of production, quality control and quality -- Yes No -- assurance unit endorse this documents. Mention shall be made of any substance that may „disappear‟ in the course of processing. Whether the Batch Processing Records for each product on the basis of currently approved master formula is being maintained.

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Bradyarrhythmias may also result from disease of the sinus node (ineffective automaticity) 2mg estrace sale, such that no appropriate pacemaker 1 buy estrace 2mg cheap. However, the mechanism that underlies each can often be categorized as automatic or reentrant. An automatic tachycardia results from a cell or cluster of cells acquiring abnormal automaticity, such that this region of the heart spontaneously depolarizes more rapidly than the sinus node, establishing the heart rate at greater than physiological rates. Examples of automatic tachycardias include ectopic atrial tachycardia, multifocal atrial tachycardia, and junctional ectopic tachycardia. Automatic tachycardias tend to exhibit “warm-up” and/or “cool-down” phases at onset and termination, and, despite the overall rapid rate, there is subtle variability in heart rate over time. In contrast, reentrant tachycardias result from nonphysiological electrical pathways that allow con- duction of an impulse back to a region of the heart that has repolarized after the earlier conduction of the same impulse. Such “short circuits” essentially allow the same impulse to recycle itself and lead to successive depolarizations. Reentrant tachyarrhythmias characteristically have an abrupt onset and ter- mination and a nonvarying rate during the tachycardia. Cardiovascular Physiology Care of the patient with hemodynamic derangements remains rooted in basic physiological concepts—preload, contractility, and afterload—first described in the late 19th century. These factors directly impact stroke volume, which, along with heart rate, are the key determinants of cardiac output (Figure 1-4). Preload, contractility, and afterload each impact cardiac output via their effects on stroke volume. Munoz Preload Preload refers to the ventricle’s intrinsic ability, within a physiological range, to alter the force of contraction based on the degree of ventricular filling just before contraction (end-diastolic volume/fiber length). The greater the end-diastolic volume, and, thus, ventricular myofiber stretch, the greater the force of contraction. Conceptually, preload is most often equated with the intravascular volume status of a patient. Contractility As already noted, within physiological range, the greater the myofiber stretch (preload), the greater the force of contraction. However, contractility (or inotropic state) specifically refers to the magnitude of response to a given preload and can be thought of as the “multiplication factor” for any given preload (Figure 1-5). Contractility is an intrinsic property of the muscle fiber that is relatively inde- pendent of changes in preload or afterload. In other words, for any given preload, the force of contraction will be greater under conditions of increased inotropy (e. Each of these therapies has multiple effects, aside from enhanced inotropy, which may limit their therapeutic efficacy (e. Afterload Afterload is defined as the ventricular wall stress during contraction and is often conceptualized as the load against which the ventricle contracts. Cardiac Physiology Review 7 increased B contractility A normal decreased contractility Left ventricular end-diastolic volume (preload) Figure 1-5. Frank-Starling curve illustrating the relationship between various preloads inotropic states and cardiac output. However, for a given preload A or B, cardiac output is, in part, determined by the inotropic state (contractility). In other words, afterload determines the size of the ventricular cavity at the end of contraction, independent of the ventricular volume before contraction (preload). Munoz Pressure-Volume Loops Visual representations of these physiological concepts can be helpful to best appreciate their individual characteristics and their impact on one another in vivo. One particularly useful way to appreciate the contributions of and interactions between preload, contractility, and afterload is by examination of pressure-volume loops. As shown in Figure 1-6a, ventricular diastolic perform- ance (compliance) and changes in preload are illustrated by the curve at the bottom of the graph (end-diastolic pressure volume relationship), ventricular volume throughout the cardiac cycle is illustrated by the rectangle, and con- tractility is illustrated by the diagonal line (end-systolic pressure volume rela- tionship). With the onset of systole (Point A), there is an increase in pressure (isovolumic contraction) until ventricular pressure exceeds aortic pressure, at which point, the aortic valve opens and blood is ejected from the ventricle (Point B). As the ventricle continues to empty, there is the onset of relaxation of the ventricle, with an eventual drop in pressure below that of the aorta (Point C). At this point, ventricular pressure falls but the volume remains unchanged (isovolumic relaxation) until the pressure drops below that of the left atrium and the mitral valve opens (Point D). The ventricular volume then increases during diastole, until the cycle repeats itself with the next contraction. The area within the rectangle represents stroke work, and the distance along the x axis between the vertical lines is the stroke volume. As illustrated in Figure 1-6b, increased preload results in a greater stroke volume as compared with baseline, but the end-systolic volume in both instances is limited by the afterload (and contractility).

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Precautons Renal impairment (Appendix 7d); hepatc disease (see below); pregnancy (Appendix 7c) and lactaton (Appendix 7b) (see notes above); interactons (Appendix 6c) cheap estrace 1mg with visa. Potentally life-threatening lactc acidosis and severe hepatomegaly with steatosis reported therefore cauton (partcularly in obese women) in liver disease buy estrace 1 mg otc, liver enzyme abnormalites, or risk factors for liver disease; suspend or discontnue if deterioraton in liver functon tests, hepatc steatosis, progressive hepatomegaly or unexplained lactc acidosis. Recurrent hepatts in patents with chronic hepatts B may occur on discontnuaton of lamivudine. Adverse Efects Nausea, vomitng, diarrhoea, abdominal pain; cough; headache, fatgue, insomnia; malaise, fever, rash, alopecia, muscle disorders; nasal symptoms; peripheral neuropathy reported; rarely, pancreatts (discontnue); neutropenia, anaemia, thrombocytopenia and red-cell aplasia; lactc acidosis; raised liver enzymes and serum amylase. Dose Oral Adult- Under 60 kg: 30 mg every 12 h preferably at least 1 h before food. Precautons History of peripheral neuropathy (see below); history of pancreatts or concomitant use with other drugs associated with pancreatts; hepatc disease (see below); renal impairment; pregnancy (Appendix 7c) and lactaton (Appendix 7b) (see notes above); fat redistributon, immune reconsttuton syndrome. Suspend if peripheral neuropathy develops- characterized by persistent numbness, tngling or pain in feet or hands; if symptoms resolve satsfactorily on withdrawal and if stavudine needs to be contnued, resume treatment at half previous dose. Potentally life-threatening lactc acidosis and severe hepatomegaly with steatosis reported therefore cauton in liver disease, liver enzyme abnormalites, or risk factors for liver disease (partcularly in obese women); suspend or discontnue if deterioraton in liver functon tests, hepatc steatosis, progressive hepatomegaly or unexplained lactc acidosis. Adverse Efects Peripheral neuropathy (dose-related, see above); pancreatts; nausea, vomitng, diarrhoea, constpaton, anorexia, abdominal discomfort; chest pain; dyspnoea; headache, dizziness, insomnia, mood changes; asthenia, musculoskeletal pain; infuenza- like symptoms, rash and other allergic reactons; lymphadenopathy; neoplasms; elevated liver enzymes (see hepatc disease, above) and serum amylase; neutropenia, thrombocytopenia. Precautons Should be used with cauton in patents with chronic hepatts B or C (greater risk of hepatc side-efects), in hepatc impairment, in renal impairment and in pregnancy (Appendix 7c). Test renal functon and serum phosphate before treatment, then every 4 weeks (more frequently if at increased risk of renal impairment) for 1 year and then every 3 months, interrupt treatment if renal functon deteriorates or serum phosphate decreases; concomitant or recent use of nephrotoxic drugs; on discontnuaton, monitor patents with hepatts B (risk of exacerbaton of hepatts). Adverse Efects Gastro-intestnal disturbances (such as nausea, vomitng, abdominal pain, fatu- lence and diarrhoea); anorexia; pancreatts; liver damage; dyspnoea; cough; headache, insomnia, dizziness, fatgue; blood disorders (including anaemia, neutropenia and throm- bocytopenia); myalgia, arthralgia, rash, urt- caria and fever. See notes above for metabol- ic efects and lipodystrophy; hypophospha- taemia; reduced bone density; nephrogenic diabetes insipidus and renal failure; lactc acidosis, decrease in bone mineral density, acute exacerbaton of hepatts. Child- neonates- 2 mg/kg every 6 hour for frst 6 weeks of life, startng with12 hour afer birth. Contraindicatons Abnormally low neutrophil counts or haemoglobin; neonates either with hyperbi- lirubinaemia requiring treatment other than phototherapy or with raised transaminase; life threatening allergic reactons. Adverse Efects Anaemia (may require transfusion), neutropenia and leukopenia (all more frequent with high dose and advanced disease); also nausea and vomitng, abdominal pain, dyspepsia, diarrhoea, fatulence, taste disturbance, pancreatts, liver disorders including faty change and raised bilirubin and liver enzymes (see hepatc disease, above); chest pain, dyspnoea, cough; infuenza-like symptoms; headache; fever; paraesthesia, neuropathy; convulsions; dizziness; somnolence, insomnia; anxiety; depression; malaise; anorexia; asthenia; myopathy; myalgia; pancytopenia, thrombocytopenia; gynaecomasta; urinary frequency; rash, pruritus, pigmentaton of nail, skin and oral mucosa. Contraindicatons Pregnancy (see notes above and (Appendix 7c); substtute nevirapine for efavirenz in pregnant women or women for whom efectve contracepton cannot be assured); hypersensitvity. Precautons Hepatc impairment (avoid if severe; Appendix 7a); severe renal impairment; lactaton (Appendix 7b) (see notes above); elderly; history of mental illness or substance abuse; interactons (Appendix 6b, 6c); psychiatric symptoms. Rash, usually in the frst 2 weeks, is the most common adverse efect; discontnue if severe rash with blistering, desquamaton, mucosal involvement or fever; if rash mild or moderate, may contnue without interrupton-rash usually resolves within 1 month. Child- 2 months to 8 years: 4 mg/kg body weight once a day for 14 days, if tolerated and no rash is observed increase to 4 mg/kg body weight two tmes a day. Contraindicatons Acute porphyria; severe hepatc impairment; post-exposure prophylaxis; breast feeding. Precautons Hepatc impairment (see below and Appen- dix 7a); history of chronic hepatts (greater risk of hepatc adverse efects), pregnancy (Appendix 7c) and lactaton (Appendix 7b); interactons (Appendix 6b, 6c). Potentally life-threatening hepatotoxicity including fatal fulminant hepatts reported usually occurring in frst 8 weeks; monitor liver functon before long-term treatment then every 2 weeks for 2 months then afer 1 month and then every 3-6 months; discontn- ue permanently if abnormalites in liver func- ton tests accompanied by hypersensitvity reacton (rash, fever, arthralgia, myalgia, lym- phadenopathy, hepatts, renal impairment, eosinophilia, granulocytopenia); suspend if severe abnormalites in liver functon tests but no hypersensitvity reacton-discontnue permanently if signifcant liver functon ab- normalites recur; monitor patent closely if mild to moderate abnormalites in liver func- ton tests with no hypersensitvity reacton. Rash, usually in frst 8 weeks, is most common adverse efect; incidence reduced if introduced at low dose and dose increased gradually; discontnue permanently if severe rash or if rash accompanied by blistering, oral lesions, conjunctvits, swelling, general malaise or hypersensitvity reactons; if rash mild or moderate may contnue without interrupton but dose should not be increased untl rash resolves. Patents should be told how to recognize hypersensitvity reactons and advised to seek immediate medical atenton if symptoms develop. Adverse Efects Rash including Stevens-Johnson syndrome and rarely, toxic epidermal necrolysis (see also Precautons above); hepatts or jaundice reported (see also Precautons above); nausea, vomitng, abdominal pain, diarrhoea, headache, drowsiness, fatgue, fever; hypersensitvity reactons (may involve hepatc reactons and rash, see Precautons above); anaphylaxis, angioedema, urtcaria also reported; granulocytopenia. Storage Store protected from light and moisture at a temperature not exceeding 30⁰C. Precautons Hepatc impairment (Appendix 7a); ensure adequate hydraton to reduce risk of nephro- lithiasis; diabetes mellitus; haemophilia; preg- nancy (see notes above and Appendix 7c); lactaton (Appendix 7b) (see notes above); metabolism of many drugs inhibited if admin- istered concomitantly; interactons (Appendix 6c, 6d); hyperbilirubinemia, tubulo-intersttal nephrits. Adverse Efects Nausea, vomitng, diarrhoea, abdominal discomfort, dyspepsia, fatulence, pancrea- tts, dry mouth, taste disturbances; head- ache, dizziness, insomnia; myalgia, myosits, rhabdomyolysis, asthenia, hypoaesthesia, paraesthesia; hyperglycaemia; anaphylactoid reactons, rash (including Stevens-Johnson syndrome), pruritus, dry skin, hyperpig- mentaton, alopecia, paronychia; intersttal nephrits, nephrolithiasis (may require inter- rupton or discontnuaton; more frequent in children), dysuria, haematuria, crystallu- ria, proteinuria, pyuria (in children); hepa- tts, transient hyperbilirubinaemia; blood disorders including neutropenia, haemo- lytc anaemia; lipodystrophy and metabolic efects, see notes above; hydronephrosis. Storage Store protected from light and moisture at a temperature not exceeding 30⁰C. Note:Ritonavir increases efect of lopinavir; low dose in combinaton does not have intrinsic antviral actvity. Precautons Hepatc impairment-avoid if severe; renal impairment; haemophilia; pregnancy (see notes above and (Appendix 7c); lactaton (see notes above and Appendix 7b); diabetes mellitus. Signs and symptoms suggestve of pancreatts (including raised serum amylase and lipase) should be evaluated-discontnue if pancreatts diagnosed. Adverse Efects Diarrhoea, nausea, vomitng, colits, abdomi- nal discomfort, asthenia, headache, insom- nia; rash; less frequently, dry mouth, hepatc dysfuncton, pancreatts (see also Precau- tons), dyspepsia, dysphagia, oesophagits, infuenza-like syndrome, appette changes; hypertension, palpitatons, thrombophlebi- ts, vasculits, chest pain, dyspnoea, agita- ton, anxiety, ataxia, hypertonia, confusion, depression, dizziness, dyskinesia, paraes- thesia, peripheral neurits, somnolence; Cushing syndrome, hypothyroidism, sexual dysfuncton, anaemia, leukopenia, dehy- draton, oedema, lactc acidosis; arthralgia, myalgia, abnormal vision, otts media, taste disturbances, tnnitus; acne, alopecia, dry skin, pruritus, skin discolouraton, nail disor- ders, sweatng; lipodystrophy and metabolic efects (see notes above); raised bilirubin and lowered sodium, low platelet and low neutrophil counts also reported in children; myocardial infarcton, loss of taste. Contraindicatons Moderate to severe liver disease; concurrent use of alprazolam; midazolam; lactaton; hypersensitvity. Oseltamivir Pregnancy Category-C Schedule X Indicatons Infuenze A, B and its subtypes like swine fu.

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