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D. Vandorn, M.B.A., M.D.
Associate Professor, Tufts University School of Medicine
Polysorbate 20 and 80 and sodium dodecyl sulfate are effective and acceptable surfactant stabilizers in marketed protein formulations (Table 6-6) allergy forecast ft lauderdale cheap prednisolone 20 mg online. The chemical structure of polysorbates allergy patch test generic 5 mg prednisolone overnight delivery, factors affecting micelle formation and degradation pathways of polysorbates 20 and 80 are the subject of a review article by Kerwin (41) allergy to zpack symptoms buy prednisolone 40mg on line. Other surfactants that have been used in protein formulations for clinical studies and/or found in the patent literature include Pluronic F68 allergy forecast new york 5 mg prednisolone with visa, and other polyoxyethylene ethers. The choice of surfactant and the final concentration optimal for stabilization is quite dependent on a variety of factors including other formulation ingredients, for example, sugars, protein concentration, headspace in the container, the type of container, and test methodology. Aggregation from mechanical stress can be substantially reduced in the presence of surfactants (43). The reasons for these differences in stabilizing concentrations are not clear, but simply reflect differences in interactions between different surfactants and proteins. Surface-active agents, particularly polysorbate 80, protect proteins against surfaceinduced denaturation during freezing (44). A strong correlation exists between freeze denaturation (quick freezing of the protein) and surface denaturation (shaking the protein in solution). Proteins that tend to denature under these conditions are protected by the addition of polysorbate 80 (0. The authors pointed out that surfactants may be needed to protect proteins from denaturation during the freezing step only, and that other stabilizers, for example, sucrose, may be needed to further protect the protein during freeze drying. Tween 80 was more effective in reducing the amount of measurable particles due to aggregation of recombinant human hemoglobin. Peroxide levels from different sources of polysorbate 80 ranged from less than 1 mEq/kg to more than 27 mEq/kg. Peroxide levels increased upon storage at ambient temperatures probably due to headspace oxygen and/or the container/closure interface allowing ingress of air. Improvements have been made in the manufacturing of polysorbate, for example, certified peroxide-free polysorbates are now readily available. Cyclodextrins come in a wide variety of structural derivatives, the most common being -, -, and -cyclodextrins, which consist of six, seven, and eight glucopyranose units, respectively. They have been used widely for increasing the solubility stability, and bioavailability of small drug molecules (see chap. Hydroxypropyl- -cyclodextrin at a 1% concentration was shown to enhance the reconstituted solution stability of keratinocyte growth factor (49) and several other proteins in solution (50). Albumin preferentially competes with other proteins for binding sites on surfaces, but why this is so is not clear. Indeed, the use of animal-source excipients (and this includes not only albumin, but also glycerol and polysorbate 80) is no longer practiced. Fibroblast growth factors, acidic and basic, are prone to acid and thermal inactivation and can be stabilized by a number of heparin and heparin-like molecules (25). Human keratinocyte growth factor, also prone to aggregation at high temperature, is stabilized by heparin, sulfated polysaccharides, anionic polymers, and citrate ion (55). This great difference in compendial requirements for preservative efficacy has caused many problems in the formulation of protein dosage forms for various markets. One unpublished example involved a new protein product where the scientist developing the formulation was unaware of the different compendial requirements. The formulation failed miserably and the product had to be reformulated with start of the clinical study delayed by almost a year. Figure 8-8 Effect of benzyl alcohol on recombinant human interferon gamma aggregation. For example, phenolic preservatives have a profound effect on the conformation of insulin in solution (57) and the assembly of the specific type of LysPro insulin hexamer (58). Furthermore, phenol and/or m-cresol in insulin solutions will have a tendency to be adsorbed by and permeate rubber closures (59). Therefore, rubber formulations must be designed to minimize these potential problems.
This approach was predicated on empirical observations made in the United States that many of those involved in confrontations in which Taser was used were under the influence of drugs allergy medicine making symptoms worse buy prednisolone 40mg low cost. The hypothesis tested was that the drugs per se could predispose an individual to an adverse cardiac event allergy medicine ear infection prednisolone 40 mg, irrespective of Taser use allergy forecast venice italy buy prednisolone 40 mg on line. The pulses represent the current predicted to flow in the heart during discharge of the M26 Taser allergy report oklahoma discount prednisolone 40mg otc. The assessment is designed to investigate the effect of the pulses on heart rhythm, the threshold for any effects observed and the effects of selected drugs of abuse upon this threshold. These studies necessitated the development of novel, complex computer models of the interaction of M26 Taser pulses with the human body, in order to predict the shape and magnitude of current flowing in the heart. Seven recreational drugs, or their active metabolites, were examined in the sheep isolated cardiac Purkinje fibre preparation. Although cocaine, cocaethylene (a psychoactive metabolite formed when cocaine and alcohol are concurrently abused) and (+)-methamphetamine did not induce action potential prolongation, a critical review of the scientific and clinical literature revealed that these drugs still have the potential to compromise cardiovascular function in a way that could precipitate a life-threatening cardiac event. The clinical literature suggested that morphine (the principal metabolite of heroin) and 9-tetrahydrocannabinol (the principal psychoactive component of cannabis) are likely to be relatively benign in terms of cardiovascular toxicity at doses likely to be employed by abusers. The results from the study, together with evidence gleaned from the literature, suggest that some frequently abused drugs have the potential to contribute to any cardiac-related morbidity or mortality that may arise in the context of Taser use. Furthermore, it seems reasonable to assume that this conclusion could be generalised to other emotionally charged and possibly violent confrontations with law enforcement personnel. The adverse cardiac effects produced by any individual drug are likely to be dependent on several risk factors, including dose consumed, co-use with other drugs (including pharmaceutical drugs and ethanol) and pre-existing heart disease. Officers should be aware that the risk of any adverse response in the aftermath of Taser deployment may be higher in drug-impaired individuals and, accordingly, they should be vigilant of any unusual behaviour displayed by the apprehended person that may signal the need for early medical intervention. The current work provides experimental evidence to support the original statement. The complex mathematical modelling underpinning the second experimental approach has never been undertaken before and has challenged the limits of current knowledge. Early setbacks with the modelling have been overcome and the quantitative modelling of the M26 9. Prolongation of the action potential duration is thought to be a possible marker for a potentially lethal type of ventricular arrhythmia known as torsades de pointes. The implanted devices examined in the review included cardiac pacemakers, cardioverter defibrillators, cochlear implants and other implantable neurostimulatory devices, such as phrenic and vagal nerve stimulators. Published material on the construction of the devices was consulted to assess the likely consequences of Taser barb impact on the device. An assessment of available published information on the observed interaction of external electromagnetic fields with active implantable devices was also undertaken. It was concluded that the probability of direct impact and physical damage to implanted electronic devices was very low. The effects of M26 Taser electrical fields on the function of cardiac pacemakers are unlikely to be permanent. The limited number of studies that have been reported on devices similar to Tasers indicate that effects are likely to be limited to reversion to asynchronous pacing mode, and that these effects are temporary. The nature of the cardiac rhythm sampling process indicates that application of a Taser for a period of 5 seconds is unlikely to result in inappropriate therapy delivery. The effect of Taser outputs on other active implantable devices, such as cochlear implants and nerve stimulators, has not been reported. The interaction with nerve stimulators could produce deleterious effects but the risk of such interaction occurring is low, and it is unlikely that the effects will be long-term or life-threatening. The age profile of cardiac pacemaker recipients is significantly different from the overall population and that of persons arrested in situations where a Taser may be deployed. The probability of an individual wearing a pacemaker being present in such a situation is therefore likely to be considerably lower than the overall incidence of pacemakers in the population. It is concluded that there is no requirement to undertake experimental studies on the vulnerability of active implantable medical devices to the output of the M26 Taser.
Further direction the viva could take You are unlikely to be asked about the clinical features of hypovolaemia: unless your performance has been very shaky the examiners will take as read your ability to recognise a patient who is losing blood allergy testing how many needles buy prednisolone 5 mg cheap. Symptoms and signs of blood loss allergy symptoms swollen glands buy generic prednisolone 5 mg, however allergy omega 3 symptoms purchase prednisolone 40mg free shipping, may briefly be discussed in the context of responses to resuscitation allergy symptoms cough phlegm generic prednisolone 20mg amex, as you are asked about your fluid management. Summary: Redistribution of blood flow is responsible for the typical pallor, cold peripheries, peripheral cyanosis and oliguria. Sympathetic stimulation explains the tachycardia, and the increase in respiratory rate. Systolic blood pressure is a relatively crude index which may show little change until substantial volumes have been lost. This occurs because diastolic blood pressure is under the influence of catecholamines, which rise in response to haemorrhage. A delay of more than 2 s is abnormal, and trends can be used to gauge the effectiveness of fluid resuscitation. Changes in mental state, such as confusion, indicate cerebral hypoxaemia and hypoperfusion. Although congenital heart disease is common, occurring in approximately 1 in 250 live births, most lesions are identified early and the problems are referred on to specialist paediatric cardiac teams. Patients do occasionally present later in life, but it is the applied pathophysiology itself which seems to be of particular interest to examiners, who will want to discover whether or not you understand the principles of rational management. There are connections between the systemic and pulmonary circulations via the ductus arteriosus (which links the pulmonary artery to the aorta) and the foramen ovale (which is a communication between the left and right atria). Enhanced pulmonary venous return into the left atrium raises the left atrial pressure above the right, and the foramen ovale closes by a flap valve effect. It is a functional closure which can be reversed if there is a sudden increase in right atrial pressure. The increase in left-sided, and fall in right-sided pressures decrease, or even reverse, shunting through the ductus arteriosus. The ductus closes in response to oxygen, prostaglandins, bradykinin and acetylcholine. It can be accelerated should the duct remain patent, by giving a prostaglandin antagonist such as indomethacin. In duct-dependent congenital cardiac disease it is important that the duct should be prevented from closing. Direction the viva may take the practical application of this information may lie in the rational management of children, and later adults, with uncorrected lesions. There is a risk of paradoxical emboli and bacterial endocarditis (as with any cardiac structural abnormality). There is a risk of paradoxical emboli, and so it is vital to avoid injection of any air. The condition associated with Fallot may be dramatic, but it is not a composition, and whoever named it, you can state airily, was disappointingly imprecise in their use of language. It combines physiology and pharmacology and you will be expected to demonstrate that you understand the underlying physiological principles and that you can recognise patients who are at risk. You may also be asked about treatment, although this in itself is a large subject. If the examiner wants to cover all three areas then time constraints mean that the questioning will be relatively superficial. Do not be surprised, however, if instead you are examined in more depth on one or other aspects of this substantial topic. The afferent and efferent pathways by which they are mediated are linked to a central integrator: the vomiting centre, which is an anatomically ill-defined area located in the medulla oblongata. Obvious causes include intestinal obstruction or perforation, gastric stasis and gastric irritation. These include opiates (which also sensitise the vestibular apparatus to motion), cytotoxic drugs, cardiac glycosides, volatile anaesthetic agents and many others, including drugs which have sympathomimetic actions.
The report will also be re-issued by end-Oct 2002 to include the new information allergy histamine buy prednisolone 40mg cheap, and to incorporate the editorial changes to Iss 1 allergy shots side effects generic prednisolone 20 mg with amex. The medical implications of the use of electrical incapacitation devices (Tasers) allergy forecast victoria bc buy prednisolone 5mg online. Additionally allergy on eyelid generic prednisolone 40mg otc, use of Tasers has provided officers with a less-lethal alternative to the use of handguns and other lethal weapons, thereby reducing the use of lethal weapons against violent or threatening suspects. Bozeman (a physician and educator in Emergency Medicine at the University of Florida) provided Dstl with a draft copy of his review on the medical risks associated with the M26 [1]. The review is brief and objective, but (not surprisingly) provides no new information. Metabolic changes arising from Taser use that may exacerbate the risk of fatal outcome: acidosis and potassium release; Initiation of a national database to track all uses of Taser and medical complications. It is a thorough review, and includes Taser outputs measured to support a study (funded by the National Institute of Justice) being undertaken on pigs to determine Taser effectiveness. Dstl recommended caution in extrapolating this experience with the lowpower Tasers to the modern "high-power" Tasers such as the M26 (used in North America for about 2 years). It is not declared when he died, but it is implied that this was some time after the Taser application. He was subjected to the Taser, handcuffed and placed in a vehicle for a journey to hospital. Although initially conscious and "ranting", he became unconscious and died on the way to hospital. Spencer) died of a drug overdose, and the Taser did not contribute to his death [3]. There have been additional Taser-associated deaths reported in the press since the April 2002 report. Baralla) died as police tried to arrest him in May 2002; he had suffered a heart attack [4]. The reported official cause of death was "sudden death occurring with agitation during necessitated restraint". He was shot with a Taser in the morning and in the afternoon of his death, and went into respiratory arrest during a struggle with jail staff. Canady) died at the scene after being subdued with a Taser (type not specified) [6]. The newspaper report states that the Medical Examiner declared that the cause of death was cocaine use and coronary disease. There have been no submissions of phencyclidine to forensic agencies over the last two years. Methylamphetamine/Amphetamine - a greater focus on Amphetamine since availability of Methylamphetamine is judged to be limited in Europe. A pregnant women was subjected to a Taser and had a stillbirth four days later [8]. An autopsy failed to link the death of the 6 month old foetus to the electric shock. The reports - numbered 1 to 1704 - were reviewed by a military surgeon attached to Dstl. There was a total of 1645 separate reports of deployments and the field use reports; analysis provided by Taser International stated a success rate of 94. Suspect Injury Level None Minor Moderate Severe Total Number of Incidents 1443 176 19 7 1645 Table 10; M26 associated injury frequency reported by Taser International 16. In 800 incidents in which the duration of the Taser application was reported, 55% were for 5 s.