These tablets are light brown in color, sweetish-bitter taste, flat, 13 mm in diameter, beveled, with an average weight of 0.555 g. Aspirin, phenacetin, cocoa, caffeine, citric acid and starch enter the pantry of the tablet shop. In most cases, they are in the standard packaging of the supplying plants. Preparatory stages. These stages are as follows: 1. Potato starch is dried and sieved through a vibrating sieve No. 3. 2. Then 8.16 kg of cocoa and 8.16 kg of caffeine are sieved through a sieve (shaker) with a working surface hole diameter of 1-2 mm. Sifting is performed in order to remove foreign matter and lumps. 3. Citric acid in the amount of 5.43 kg is dissolved with 4.57 liters of water. The solution is allowed to cool and brought to 20 kg with cold water. 4. Received cooled solution in the amount of 20 kg moisten the loaded mixture in the mixer. Preparation of granules . In a mixer with a capacity of 300 liters load 65.235 kg of aspirin, 48.9 kg of phenacetin and a sieved mixture of cocoa with caffeine in the amount of 16.32 kg. The mixer is closed and the electric motor is turned on to drive the stirrer blades. The loaded powders are mixed for 30 minutes, i.e. until a uniform mixture is obtained.
There is a hole in the lid of the mixer through the grate of which humidification takes place . After adding 20 kg of citric acid solution to the mixture, stirring is continued for another 15 minutes, that is, until the moisture is completely evenly distributed. The electric motor is turned off, the lid is thrown back, the mixer is tilted and unloaded, the wet mass, which is then passed through a granulating machine with 2.5-3 mm holes. A duralumin tank serves as a receiver for wet granulate . The wet granulate yield is 150.255 kg. Losses at the stage of mixing reach 0.1%, and at wet granulation 0.025%. Wet granulate is sprinkled in an even layer on enamel trays (2.25 kg) and dried in an oven at a temperature of 50-55 ° C for 16 hours. Dry citramone granulate in the amount of 135.93 kg is removed from the trays into plywood boxes upholstered with tinplate, or into tanks and passed on a granulating machine for dry granulation through a perforated cylinder with a hole diameter of 1.5-2 mm. Losses at the drying stage are 0.2%, at the dry granulation stage 0.033%. Dry granulate in the amount of 135.885 kg is poured into a plywood box lined with tin, and 14.94 kg of potato starch with 10% moisture are added / The powdered mixture in the amount of 150.825 kg is transferred to the tablet compartment for compression. Dusting citramone is performed in three steps; the output from each is 50.275 kg. The powdered granulate is pre-sieved in a fume hood through a metal sieve with a hole diameter of 3 mm. The mixture is compressed on a rotary tabletting machine having 13 mm diameter punches. During the pressing of tablets, it is necessary to monitor their quality, that is, the correctness of the average weight, their appearance and disintegration . Substandard tablets are discarded. Conditioned tablets are screened out of dust and packaged in standard boxes lined with paper or in cans. The output of finished products at the tsa stage, pressing is 150 kg. The loss at the stage of pressing is 0.547%. The OTK controller takes an average sample of tablets from each batch and sends it to the central factory laboratory for analysis. Packaging. Tablets that meet all the requirements are packed in 10 kg tinplate boxes. The box is pre-lined with white wrapping paper so that it covers the inner walls and covers the top of the tablets. A label with the work number of the packer and typist is placed in the box on top of the tablets. Upon receipt of a positive OTK test, a label of an approved sample is attached to the box indicating the manufacturer, the name of the tablets, average, their weight, batch number and the total weight of the tablets in this box. The box is closed with a lid and tied with thick threads or twine, the ends of which are fixed with a label. The inspector puts the OTK stamp on the label. In addition to the indicated container, citramone tablets are packaged in significant quantities in aluminum cans of 2.5-8 kg each. The can is closed with a lid and tied. With the OTK stamp on the label, the products are handed over to the warehouse of semi-finished products for further packaging in the finished medicines workshop.
Alternative regimens for heparin therapy . Side effects of heparin.
In venous thromboembolism, the thrombus is formed by erythrocytes held together by fibrin threads (“red”), so aspirin is not so effective in these cases and cannot slow down or prevent venous thrombosis. Thus, aspirin plays a modest role in its prevention and is not an alternative to heparin and warfarin . Sometimes aspirin is prescribed in a low dose (80 mg / day ) after the end of the warfarin course . With intravenous heparin therapy for 7 days, PA obstruction is usually only slightly reduced, although MCC improves. A significant part of perfusion defects (according to VPSL data) decreases only after 30 days of UFH treatment. So, with treatment with UFH alone, about 40% of defects on PPSL disappear after 5 days, by the end of the 2nd week – half of the defects, and only by the end of the 3rd week – 75% of defects. This delayed effect is due to the fact that heparin itself does not dissolve the formed blood clots in the vascular bed of the lungs, this is gradually done by the body’s own fibrinolytic system. Heparin reduces the spasm of pulmonary arterioles and bronchioles (weakening the effects of platelet serotonin and histamine), accelerates the action of antithrombin III (which blocks the transition of fibrinogen to fibrin and deposits of the latter), prevents further thrombus formation (thrombus growth distal and proximal to the embolus ), and limits the recurrence of PE in the next 3 weeks. Heparin therapy followed by warfarin reduces the risk of recurrent venous thrombosis and mortality by 80%. The risk of recurrent pulmonary embolism while taking indirect anticoagulants is about 5-10%. Without such treatment, mortality within the first 3 months after the development of PE is 20% (much higher than with MI).
An alternative way of administering heparin is periodic intravenous or subcutaneous (15,000 units , 2 times a day) injections under the control of aPTT. If intravenous administration of UFH is not possible, then it is prescribed subcutaneously (in the abdomen) at 10,000 units every 6-8 hours. Periodic injections of UFH (5,000 units every 4 hours in a daily dose of 30,000 units ) have disadvantages: a high risk of bleeding (in contrast from continuous administration) and low bioavailability (less than 30%) when administered subcutaneously. In addition, with periodic administration of UFH, the frequency of recurrent PE is 20%, and with constant administration, only 5%. In general, subcutaneous administration of UFH is not effective enough for PE. Therefore, at present, they prefer to inject subcutaneously for 5-7 days LMWH – fragmin ( dalteparin ), clexane ( enoxaparin ) or fraxiparin ( nodroparin ) at a dose of 100 IU / kg. These drugs are better dosed (do not require monitoring, therefore they can be used on an outpatient basis), and their effectiveness is similar to that of UFH. Low molecular weight heparin can be administered 2 times a day due to a long half-life (this does not require frequent control of hemostasis), their bioavailability is more than 90%. When administered subcutaneously, LMWH is as effective in treating VTE as intravenous UFH. The minimum conditions for discharging and treating the patient on an outpatient basis: stable clinical condition of the patient; normal parameters of basic vital functions; low risk of bleeding and creatinine level less than 150 MCM / L or creatinine clearance over 60 ml / min (calculated for men – 1.77 • (140 – age) • body weight (kg) / blood creatinine level ( MCM ) and for women – 1.5 • (140 – age) • body weight (kg) / blood creatinine level ( μM / L); the possibility of prescribing LMWH or warfarin and regular monitoring of the patient in terms of the appearance of complications (bleeding), evaluation of the effectiveness of treatment and . prevention of recurrence of PE Side effects following heparin • bleeding (in 5-10% of cases) are usually mild -. the most common and dangerous complication during the initial period of intravenous heparin therapy the risk of bleeding is increased in elderly patients with concomitant diseases, recently. operated ( or those who have had trauma), or in individuals with hemostatic defects or predisposing factors for bleeding (for example, an unrecognized duodenal ulcer, bleeding colon tumor, or dissecting th aortic aneurysm). The risk of bleeding increases as the daily dose of heparin increases. In case of bleeding, it is necessary to stop the administration of heparin, after which the APTT returns to normal within 6 hours (since the half-life of heparin elimination is 60-90 minutes). • Mild (100,000 / mm3), immunologically mediated thrombocytopenia (without serious clinical consequences) rarely occurs in patients receiving continuous intravenous heparin. Thrombocytopenia (or a decrease in platelets by 50% or more from the initial level) usually appears after 7-10 days from the start of treatment (the development of antibodies to platelets begins from the 5th day), therefore, during treatment, it is necessary to control the platelet level. Sometimes this thrombocytopenia can be dangerous due to the development of thrombocytopenic bleeding or arterial, venous thrombosis. • Hypersensitivity to heparin (rash, rarely anaphylaxis) is also rare. • Possible osteopenia , osteoporosis (with subsequent bone fractures) if heparin therapy is carried out in large doses and for a long time.
Aspirin in the treatment of stable exertional angina
A meta-analysis of 300 studies involving 140,000 patients confirmed the preventive effect of aspirin in men and women with angina pectoris, MI, MI, or after bypass surgery. In a Swedish study of men and women with chronic stable angina pectoris, administration of 75 mg of aspirin in combination with β-AB sotalol reduced the incidence of AMI and VS by 34%. In a smaller study of men with chronic stable angina pectoris without a history of MI, taking aspirin 325 mg every other day reduced the risk of MI by 87% over 5 years of follow-up. Based on this, daily intake of aspirin is recommended for all patients with chronic stable angina pectoris who have no contraindications to this drug. Prescribing aspirin in doses from 75 to 162 mg / day for the purpose of secondary prophylaxis resulted in an effect comparable to taking 160-325 mg / day , but was associated with a lower risk of bleeding. In this regard, when conducting secondary prophylaxis in patients who have not undergone intracoronary stenting in the recent past , daily intake of aspirin at a dose of 75-162 mg is considered more preferable. Despite the fact that warfarin has a certain positive effect in patients with myocardial infarction , the need for constant prescription of anticoagulants for stable angina pectoris has not been proven.
Duration of taking aspirin and clopidogrel for acute coronary syndrome (ACS)
After acute coronary syndrome without segment elevation ST (ACS bpST ) dual antiplatelet therapy (ASA + clopidogrel ) is recommended to continue for at least 1 year, regardless of whether he or CHKB patient received only conservative therapy was carried out (Study CURE). For ST-segment elevation myocardial infarction ( STEMI ), there is strong evidence of the advisability of continuing dual antiplatelet therapy for 1 month. (the COMMIT and the CLARITY), however, taking into account the effect of treatment in ACS bpST , it is appropriate to continue such combination therapy in all patients with acute coronary syndrome (ACS), including patients who have had a myocardial infarction-segment elevation ST (MI pST ). In addition, the majority of patients will undergo PCI and thus the duration of treatment will depend on the type of stent inserted , as well as the risk of recurrent MI (depending on a number of other factors, in particular the presence of diabetes mellitus and impaired LV function), which follows compare with the risk of bleeding. Patients who have received a drug- eluting stent should receive dual antiplatelet therapy for at least 1 year, since its premature termination is strongly correlated with the risk of stent thrombosis , which is accompanied by high mortality. This was demonstrated in the PREMIER study, in which patients with drug- eluting stents who stopped taking clopidogrel had a nine-fold increase in the risk of death (7.5% versus 0.7%, p <0.0001). Premature discontinuation of the drug during drug treatment may also increase the risk of death and re-myocardial infarction (MI). Thus, in all patients who require non-cardiac surgery or who develop bleeding, the question of discontinuing antiplatelet therapy should first be discussed with the cardiologist.
Antiplatelet agents for the prevention of stroke. Use of aspirin Which of the patients who have had a stroke needs antiplatelet drugs for secondary prevention? What are the benefits and risks of such treatment? All stroke patients who do not meet the criteria for anticoagulant prescribing should receive anticoagulant therapy with aspirin, clopidogrel, or a combination of aspirin with extended-release dipyridamole . In terms of preventing the development of recurrent stroke, these three drugs have approximately the same effectiveness, reducing the risk of stroke by 14-18%. Ensuring that the antiplatelet agent is taken regularly is more important than the specific drug given to the patient. Therefore, the choice of the drug should be made taking into account the concomitant pathology, portability and price. Clopidogrel may be preferred in patients who have had severe gastrointestinal bleeding and in patients with peripheral atherosclerosis or who have undergone implantation of a drug- eluting coronary stent . Sustained -release dipyridamole does not interfere with cardiac function and can be used safely in patients with cardiac pathology. Moreover, as a result of meta-analysis , it was shown that this dosage form of dipyridamole , possibly, has the ability to prevent the development of non-stroke vascular events. Combination therapy with aspirin and dipyridamole in the initial period may cause headaches and therefore may be poorly tolerated by stroke patients with chronic headache.
In addition, dipyridamole capsules do not pass through most of the gastrointestinal tubes and cannot be crushed, so this treatment is not a good choice in patients on tube feeding. The PROFESS trial was recently initiated to compare the efficacy of combination therapy with aspirin and dipyridamole to that of clopidogrel . At the time of this writing, the results of the study have not yet been published, however, based on the preliminary report, the benefits of clopidogrel have not been identified; against the background of its administration, the incidence of hemorrhagic complications slightly increased. Aspirin alone in the absence of contraindications may be a good choice, especially in cases where the cost of alternatives may negatively affect the regularity of their use. For secondary prevention of stroke, aspirin should not be given in combination with clopidogrel , since, compared with clopidogrel alone, such combination therapy has no advantages in preventing recurrent stroke, but is accompanied by an unacceptably high risk of bleeding. Some patients (eg, those who have received drug- eluting coronary stents ) require aspirin and clopidogrel ; in such cases, this treatment can be continued after the stroke. At the time of this writing, a study is underway to compare the efficacy of aspirin therapy with aspirin and clopidogrel in patients with small focal stroke.