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Prophylaxis in patents at risk of ischaemic stroke includes oral antcoagulants such as warfarin and antplatelet drugs such as acetylsalicylic acid forzest 20 mg visa. Treatment of acute ischaemic stroke includes use of acetylsalicylic acid cheap forzest 20mg fast delivery, antcoagulants such as heparin and of thrombolytcs trusted 20mg forzest, such as streptokinase. Long-term therapy with acetyl- salicylic acid reduces the risk of having another stroke. Antplatelet and thrombolytc drugs are not used in the management of haemorrhagic stroke, as they may exacerbate bleeding. Acetylsalicylic acid is normally given for at least one year afer coronary artery bypass surgery. It is also given to patents with prosthetc heart valves who have had cerebral embolism despite warfarin treatment. Contraindicatons Surgery within 10 days, including organ biopsy, puncture of noncompressible vessels, serious trauma, cardiopulmonary resuscitaton, actve bleeding, serious gastrointestnal bleeding within 3 months, previous cerebrovascular accident or actve intracranial process, thrombocytopenia, severe uncontrolled hypertension, aortc dissecton, acute pericardits. Precautons Monitor platelet count for thrombocytopenia; interactions (Appendix 6c); pregnancy (Appendix 7c). Dose Oral Adult-Prophylaxis of cerebrovascular disease or myocardial infarcton: 75 to 100 mg daily. Adverse Efects Bronchospasm;gastrointestnalhaemorrhage (rarely, major); also other haemorrhage (for example subconjunctval); urtcaria; hepatomegaly. Alteplase Pregnancy Category-C Schedule H Indicatons Acute myocardial infarcton, acute massive pulmonary embolism, acute ischaemic stroke. Dose Intravenous Acute myocardial infarcton Adult: The recommended total dose is 100 mg. Heparin therapy to be insttuted or reinsttuted near the end of or immediately following the alteplase infusion when the partal thromboplastn tme returns to twice normal or less. Acute ischemic stroke Adult: Use recommended within frst 3 h of onset of the symptoms. Caution in recent surgery or invasive procedures, diabetic hemorrhagic retinopathy, severe hepatic and renal impairment, pregnancy (Appendix 7c), lactation, children, elderly, interactions (Appendix 6c). Adverse Efects Hemorrhage including intracranial, gastrointestnal or genitourinary bleeding, transient hypotension, reperfusion dysrythmias, cerebral edema, seizures, allergic-type reactons, nausea, vomitng. Storage Store protected from heat, light and moisture at room temperature (<30°C) or under refrigeraton. Clopidogrel* Pregnancy Category-B Schedule H Indicatons Prophylaxis in thromboembolic disorders including myocardial infarcton, peripheral arterial disease and stroke, acute coronary syndrome. Contraindicatons Hypersensitvity, actve pathological bleed- ing such as peptc ulcer or intracranial hem- orrhage, coagulaton disorders, lactaton. Precautons Patient with increased risk of bleeding from trauma, surgery or other pathological conditions, ulcers, renal impairment, hepatic impairment, history of bleeding or haemostatic disorder, pregnancy (Appendix 7c); interactions (Appendix 6c). Adult- Thrombosis: 2,50,000 units over 30 min, followed by 1,00,000 units every h for 12 to 72 h according to conditon with monitoring of clotng parameters. Contraindicatons Recent haemorrhage; surgery (including dental); parturiton; trauma; heavy vaginal bleeding; haemorrhagic stroke; history of cerebrovascular disease (especially recent or if residual disability); coma; severe hypertension; coagulaton defects; bleeding diatheses; aortc dissecton; risk of gastrointestnal bleeding such as recent history of peptc ulcer; oesophageal varices; ulceratve colits; acute pancreatts; severe liver disease; acute pulmonary disease with cavitaton; previous allergic reactons; pregnancy (Appendix 7c). Precautons Risk of bleeding from any invasive procedure; including injecton; external chest compres- sion; abdominal aneurysm or where throm- bolysis may give rise to embolic complica- tons such as enlarged lef atrium with atrial fbrillaton (risk of dissoluton of clot and sub- sequent embolizaton); diabetc retnopathy (small risk of retnal haemorrhage); recent or concurrent antcoagulant treatment; platelet count; fbrinogen level; thrombin and pro- thrombin tme. Storage Store in a sealed container protected from light in refrigerator (2 to 8⁰C). Urokinase* Pregnancy Category-C Schedule H Indicatons Acute myocardial infarcton; pulmonary embolism; deep vein thrombosis; peripheral vascular thrombosis; peripheral arterial thromboembolism; arterial thrombosis. Dose Intravenous infusion Deep vein thrombosis: 4,400 units/kg body weight in 15 ml Sodium Chloride (0. Contraindicatons In recent haemorrhage; trauma; or surgery (including dental extracton); coagulaton defects; bleeding diatheses; aortc dissecton; coma; history of cerebrovascular disease especially recent events or with any residual disability; recent symptoms of possible peptc ulceraton; heavy vaginal bleeding; severe hypertension; actve pulmonary disease with cavitaton; acute pancreatts; pericardits; bacterial endocardits; severe liver disease and oesophageal varices. They should also be used with cauton in external chest compression; pregnancy (Appendix 7c); elderly; hypertension; abdominal aneurysm or other conditons in which thrombolysis might give rise to embolic complicatons such as enlarged lef atrium with atrial fbrillaton (risk of dissoluton of clot and subsequent embolisaton); diabetc retnopathy (very small risk of retnal bleeding) and recent or concurrent use of drugs that increase the risk of bleeding; hematocrit platelet count; thrombin and prothrombin tme. Bleeding is usually limited to the site of injecton; but intracerebral haemorrhage or bleeding from other sites can occur. Serious bleeding calls for discontnuaton of the thrombolytc and may require administraton of coagulaton factors and antfbrinolytc drugs (aprotnin or tranexamic acid). Rarely, further embolism may occur (either due to clots that break away from the original thrombus or to cholesterol crystal emboli). It causes allergic reactons (including rash; fushing and uveits) and anaphylaxis has also been reported. Storage Store in a sealed container protected from light in refrigerator (2 to 8⁰C). The container should be sterile, tamper evident and sealed so as to exclude micro-organisms. They are rarely, needed when shock is due to Sodium and water depleton as, in these circumstances, the shock responds to water and electrolyte repleton. Plasma substtutes should not be used to maintain plasma volume in conditons such as burns or peritonits where there is loss of plasma protein, water and electrolytes over periods of several days. In these situatons, plasma or plasma protein frac- tons containing large amounts of albumin should be given. Plasma substtutes may be used as an immediate short-term measure to treat massive haemorrhage untl blood is avail- able, but large volumes of some plasma substtutes can increase the risk of bleeding by depletng coagulaton factors. Dextran may interfere with blood group cross-matching or biochemical measurements and these should be carried out before the infusion is started. Albumin* Pregnancy Category-C Indicatons Burns, hypoproteinaemia, shock, hypovolemia, acute liver failure, dialysis. Contraindicatons Congestve heart failure, severe anaemia, history of allergic reactons to human albumin; pregnancy (Appendix 7c). Administraton of albumin should be supplemented or replaced by packed red blood cells, history of cardiac or circulatory disease, increased capillary permeability. Adverse efects Allergic (or) pyrogenic reactons, tachycardia, rash, anaphylactc shock, increased salivaton. Human albumin stored at 2-8⁰C may be expected to contnue to meet the requirements of the monograph for fve years from the date on which it was heated at at 60⁰C for 10 hours. Human albumin stored at a temperature not exceeding 25⁰C may be expected to meet the requirements of the monograph for three years from the date on which it was heated at 60⁰C for 10 hours. Dextran 40* Pregnancy Category-C Schedule H Indicatons Plasma volume expansion during hypovolemic shock when blood not available, Prophylaxis of thromboembolic disorders to improve local circulaton in peripheral vascular occlusion. Dose Intravenous To improve local circulaton in peripheral vascular occlusion: Adult- 500-1000 ml (10- 20 ml/kg) in frst 24 hours; thereafer 500 ml every 1-2 days for up to 2 weeks. Thromboembolism prophylaxis: Adult- 500- 1000 ml (10-20 ml/kg) on day of surgery, then 500 ml daily for 2-3 days, then 500 ml every second or third day, for up to 2 weeks. Shock: Adult- initally 500-1000 ml (10-20 ml/ kg) infused as rapidly as needed; may follow with 500 ml (10 ml/kg) during the same 24 hour period; thereafer 500 ml (10 ml/kg) may be repeated daily for up to 5 days. Contraindicatons Hypersensitvity, cardiac decompensaton, oliguria or anuria, hemostatc defects, thrombocytopenia, blood coagulaton disorder, pulmonary oedema, neonates. Hydroxy Ethyl Starch* Pregnancy Category-C Indicatons Therapy for hypovolaemia, shock in surgery, trauma and infecton to improve haemody- namics, macrocirculaton, microcirculaton and oxygen supply; improve organ functon in blood loss.

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Like bombinins purchase 20 mg forzest free shipping, these peptides typically adopt a random coil structure in an aqueous environment and an amphipathic α-helix in apolar environments [98 buy forzest discount, 99] 20 mg forzest overnight delivery. The presence of d-amino acids results from a post-translational modifcation involving a l–d isomerization [100], with these peptides displaying better antimicrobial activity against some bac- terial strains than the pure l-isomer [98]. These peptides have potent activity against Leishmania by rapid perturbation of the plasma membrane, and are of interest for the development of new drugs against this global infectious disease [102]. Temporins were frst identifed in the frog Rana temporaria [94] and are the shortest α-helical peptides isolated from amphibians (10–14 residues). They tend to form an amphipathic α-helical structure in hydrophobic environments, and have a net charge of 0 to +3 [103]. They are active against a wide range of pathogens (bacteria, viruses, fungi, yeasts, and protozoa) [94, 104–106] and are not toxic to mammalian cells at concentrations that kill microbes [94]. An exception is temporin L, which is highly active on bacteria, erythrocytes, and cancer cells [107]. Peptides belonging to temporin family have attractive properties, such as high activity in physiological conditions, high stability in serum [106], and low cost synthesis due to their short amino acid sequence [108], making them exciting peptides for drug design applications. Defensins are cysteine-rich peptides that participate in the host defense of mam- mals [109], insects [110], and plants [111]. They are characterized by intramolecular disulfde bonds that stabilize the structures, and frequently contain small β-sheet structures [87]. Although defensins have been isolated from many species, the α- and β-defensins of human origin are the best studied. In the α-defensins, the cysteines are paired with a 1–6, 2–4, and 3–5 confguration, whereas in the β-defensins the pairing is 1–5, 2–4, and 3–6 [72]. Many potential therapeutic applications have been suggested for defensins due to their activity against Gram-positive and Gram-negative bacteria, fungi, viruses, and cancer cells [109]. Fundamental differences exist between microbial and mammalian cells, including membrane com- position and architecture, transmembrane potential and polarization, and structural features, including the presence of a cell wall [83]. Bacterial membranes contain sub- stantial amounts of negatively charged phospholipids, such as phosphatidylgercerol and cardiolipin, on the external leafet. In contrast, the outer membrane layer of eukaryotic cells is composed mainly of phosphatidylcholine, sph- ingomyelin and cholesterol, all of which are neutral at physiological pH [83]. These peptides make contact with the anionic outer layer of bacterial cytoplasmic mem- branes, while the hydrophobic domain favors insertion in the membrane [121]. Several disruption models have been proposed, including pore for- mation by a barrel-stave pore [123], a toroidal pore [124], or a carpet model [125]. Each of these mechanisms depends on the electrostatic and hydrophobic properties of both the peptide and membrane [80, 126]. When the activity is associated with a cytoplasmic target, the peptide might translocate without membrane permeabilization [127, 128]. They are considered in some cases to have the possibility of synergistic effects with conventional antibiotics [131]. The altered membrane composition of cancer cells appears to be a major factor in this selectivity [133]. Typically, cancer cells have a greater negative charge due to higher expression of anionic phospholipids such as phosphatidylgercerol [134], and have a more negative transmembrane poten- tial [135] and greater membrane fuidity [136]. Several structural features have been identifed as important for the antimicrobial activity of peptides. These include size, amino acid sequence, net charge, hydropho- bicity, and amphipathicity [137, 138]. Although electrostatic attraction increases peptide concentrations at the membrane surface, disruption of the membrane depends on hydrophobic interactions between peptide and membrane [137–139]. Therefore, subtle properties of peptides are crucial in determining the extent of insertion and disruption of membrane integrity [126, 138, 140]. Neither the role of membrane composition nor the structural features of peptides required for specifcity are, as yet, fully understood [107] and predicting antimicrobial or cytotoxic activity from a given amino acid sequence is not an easy task. Interestingly, many plants and animals synthesize a large number of peptides with relatively minor differences in sequence and structure between them. Combinations of structurally related peptides can increase the spectrum of antimicrobial activity by inducing changes in the biophysical properties of the peptides [141]. They provide good tem- plates for rational drug improvement, putting into practice the information on protein structure and protein–lipid interactions gathered over natural evolution and labora- tory research [83]. Bacteriocins thus typically target closely related bac- teria found in the same nutritional niche as the producer organism [144]. Bacteri- ocins of Gram-negative bacteria are either smaller than 10 kDa (microcins) or larger than 20 kDa (colicins). They are generally cationic, amphiphilic, and membrane-permeabilizing peptides [146]. Due to the large number and diver- sity in structure and function of Gram-positive bacteriocins, they have been further subdivided and although different classifcation systems have been proposed [5, 16, 147–151], a consensus has not yet been reached. Two bacteriocins, microcin J25 and subtilosin A, from Gram-negative bacteria and Gram-positive bacteria, respectively, were chosen here to illustrate applications (Table 6. Their production is stimulated in nutritionally limited media and they are actively secreted into the extracellular medium [145]. They are thermostable, resis- tant to extreme pH and some proteases, and are relatively hydrophobic [145]. Their structures are diverse and range from linear, unmodifed peptides, to structures having extensive post-translational modifcations [153]. Like their chemical structures, their biological applications vary widely [154] and this diversity has encouraged their use in the design of new-generation drugs for cancer [155, 156] and for infectious diseases [156, 157]. Microcin J25 (MccJ25) is plasmid-encoded, ribosomally synthesized and was frst isolated from E. MccJ25 is active at extremes of pH (from pH 2 to 12) and also after exposure to temperatures as high as 120 ∘C [158]. Initially MccJ25 was thought to be a macrocyclic peptide with a head-to-tail cyclization [159]. However, further inspection showed that it instead incorporates a sidechain-to-backbone cycle that sequesters the N terminus, but also protects the C-terminus via a threading mech- anism. It contains an eight-residues cyclic segment, resulting from the formation of an internal lactam bond between the α-amino group of Gly1 and the γ-carboxyl group of Glu8, followed by a 13-residues linear segment that loops back and threads through the cyclic segment [160–162]. The tail is sterically entrapped within the ring due to the bulky side chains of Phe19 and Tyr20 (see Table 6. Despite this unusual structure, only a small number of residues are essential for MccJ25 function and many residues can be substituted [164]. MccJ25 production and release increases when cells reach stationary phase and nutrients become limiting [158, 165] and occurs both under aerobic and anaerobic conditions [158], independently of pH [165], giving MccJ25-producing cells an advantage over non-producers. This hypothesis was sup- ported by molecular modeling [172] and kinetic analysis of the transcription process in the presence of MccJ25 [173]. A signifcant inhibition of oxygen consumption and increase in reactive oxygen species when MccJ25 is present seems to be the reason, while in anaerobic condi- tions MccJ25 lost the antibiotic effect [168].

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The routine operating environment purchase forzest 20 mg visa, however purchase forzest overnight delivery, chemistry at Sanofi in Frankfurt purchase genuine forzest line, Germany. The method requirements and variables that are causing the performance issues and the exercise conditions are defined according to the measurement is repeated. As in the case of the initial method validation activity, requirements given in the analytical target profile and the transfer exercise is typically performed as a one-off process. There is a risk that the exercise will focus more on producing • Stage two: method qualification. During this stage, the the method-transfer report than on ensuring the ability of the method is confirmed as being capable of meeting its design receiving laboratory to run the method accurately and reliably intent and the critical controls are established. Ongoing as- The recognition that an analytical method can be considered surance is gained which ensures the method remains in a process that has an output of acceptable quality data led Bor- a state of control during routine use. It follows, therefore, that the concepts of life- verification following any changes. When con- Once the important method characteristics are identi- sidering a lifecycle approach to method validation a similar fied, the next step is to define the target criteria for these definition could be adopted, “the collection and evaluation of (i. After data and knowledge from the method design stage through- ensuring safety and efficacy, a key factor in selection of the out its lifecycle of use, which establishes scientific evidence appropriate criteria is the overall manufacturing process that a method is capable of consistently delivering quality capability. A method, as defined in this article, is a synonym for and the expected process mean and variation is helpful in analytical procedure and includes all steps of the procedure setting meaningful criteria. These include: Stage one: method design • The importance of having predefined objectives The method design stage involves selecting appropriate • The need to understand the method (i. Appropriate studies are then performed of the method input variables) to understand the critical method variables that need to be • The need to ensure that controls on method inputs are controlled to ensure the method is robust and rugged. This includes both continuous method-performance moni- method complexity and potential for robustness or ruggedness toring of the routine application of the method as well as perfor- issues), an exercise focused on understanding the method (i. From this, a set include an ongoing program to collect and analyze data of operational method controls is identified. Knowledge accumulated during method devel- data from regular analysis of a reference lot. Ideally, by using a lifecycle that maximum understanding is gained from a minimum num- approach to method validation, laboratories should encoun- ber of experiments. When developing an understanding of the method’s rug- Method performance verification. Method performance verifi- gedness, it is important that variables that the method is likely cation is undertaken to verify that a change in the method to encounter in routine use are considered (e. Precision or ruggedness studies may instead be performed as part of Stage two, particularly if a developer has sufficient prior knowledge to choose appropriate method conditions and controls. These conditions should be optimized based on an under- standing of their impact on method performance. If the respective experimental results have already been obtained during Stage one, they only need to be summarized for the final evaluation. These activities may range from a review to en- equipment is qualified and appropriate knowledge transfer sure that the post-change operation of the method continues and training of analysts has been performed. The method to meet the system suitability requirements to performing conditions and detailed operating controls along with all the equivalency studies aimed at demonstrating that the change knowledge and understanding generated during the design has not adversely affected the method’s accuracy or preci- phase are conveyed to the location in which the method will sion. The extent of the method- Change control installation activities should be based on an assessment of During the lifecycle of a product, both the manufacturing risk and should consider, for example, the level of preexist- process and the method are likely to experience a number ing knowledge of the analysts in the new location with the of changes through continuous improvement activities or product, method, or technique. As part of the initial quali- the need to operate the method or process in a different en- fication of a method, a second laboratory may be involved in vironment. It is essential that all changes to the method’s producing data to determine the method’s reproducibility. In operating conditions are considered in light of the knowledge such a case, the second laboratory can be considered as being and understanding that exists on the method performance. Nevertheless, the described activities with respect Appendix 2 in the expanded, online version of this article to method installation would be performed before starting at PharmTech. Other sce- knowledge transfer, need to be performed in addition to a narios exist in which a laboratory may need to use a method method-performance verification exercise. Method instal- for which it has no access to the original method design lation focuses on ensuring that the location at which the or qualification information, such as in a contract-testing method is intended to be operated is adequately prepared laboratory. In these situations, it is important that the per- 78 Pharmaceutical Technology OctOber 2012 PharmTech. Because this approach could be adopted for all users of analytical methods, it also offers the potential to standardize industry terminology and create a harmonized method validation approach. This ap- proach aligns terminology to that used for process validation and equipment qualification, supports a lifecycle approach, removes existing ambiguities in validation terms (e. Table I summarizes this comparison of the traditional and lifecycle approaches to method validation. Conclusion The switch to a QbD approach to method development is al- ready beginning to bring improvements to the performance of analytical methods. Opportunities also exist to modernize and standardize industry’s approach to method validation and transfer. By aligning method validation concepts and terminol- ogy with those used for process validation as well as equipment qualification, there is an opportunity to ensure that efforts in- vested in method validation are truly value adding, rather than simply being a check-box exercise, and to reduce confusion and complexity for analytical scientists. A quality risk-management risks are assessed and mitigated throughout the product life- program systematically identifies and analyzes cycle. Risk assessment is especially critical when changes are the risks associated with a product or process, made to validated processes or systems to ensure the integ- mitigates those risks deemed unacceptable, and rity of the product is preserved as the risk profile evolves. Thus, an effective risk as- decision-making within a company regarding a sessment will ensure that maximal resources are directed product’s quality and provide greater assurance to a towards products, equipment, and processes deemed high company’s stakeholders of the ability to deliver the risk and minimal resources towards those deemed low risk. In this paper, the authors describe risk-assessment tools used in Less-formal tools for managing change control Risk management tools provide the necessary means by change control. It is, therefore, important to select the appropriate tool based on the objective and scope the assess- ment. The greater the risk and complexity of the system (or process) under review, the greater the level of formality and detail is required of the risk tool (see Figure 1). There are two primary goals in the assessment of risk when managing change: to assure that a company is not taking on 80 Pharmaceutical Technology OctOber 2012 PharmTech. These critical param- Current state Proposed state overall risk parameter rationale profile eters will serve as the input into the risk assessment process. Identify critical parameters for the system under re- into consideration the nature (i. Determine what the differences between the current The overall risk profile may be increased if the proposed and proposed states mean from a risk-based perspec- change increases variability, reduces reproducibility or ro- tive (i. Evaluate whether changes to overall risk profile are ac- versely, the exposure to overall risk may be reduced if the ceptable. Overall risk may remain following attributes as critical parameters: bioburden speci- the same if the change does not affect that particular critical fications, environmental exposure, vessel type, and vessel parameter or if it is proven or expected to be equivalent to 82 Pharmaceutical Technology OctOber 2012 PharmTech.

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