One of the most effective platelet antiaggregants is clopidogrel, inhibiting platelet activation by selectively binding adenosine diphosphate (ADP) with specific receptors. However, in a number of clinical situations it is necessary to have a pronounced antithrombotic effect in the shortest possible time which gives rise to interest in the transmucose use of the drug, in particular, rectal route. The theoretical preconditions for the development of a rectal administration of clopidogrel are based on the data that the anti-aggregation effect of a substance is carried out by its main metabolite formed after “first hepatic passage”, while clopidogrel itself in this aspect is inactive. On the base of complex physico-chemical, pharmaceutical, biopharmaceutical, rheological and microbiological investigations, the rational composition of clopidogrel rectal dosage form – suppository on a hydrophilic base to prevent atherothrombotic events in patients with myocardial infarction, acute coronary syndrome, ischemic stroke, peripheral arterial occlusion, is proposed by the employees of the Department of Technology of Medications of the Zaporizhzhia State Medical University. The aim of the work is to investigate the specific activity of rectal suppositories with clopidogrel. Materials and methods. Experimental suppositories with clopidogrel 0,075 g for rectal administration were used as the objects in pre-line studies. The ability of clopidogrel to reduce the inhibitory effect of ADP on adenylate cyclase activity and decrease the number of binding sites for 2-methylthio-ADP (analogue of ADP) without altering the receptor topography is used as a base of the method of comparative study of its specific activity in the rectal dosage form (suppository) and in comparison with the reference medication Plavix (SANOFI WINTHROP INDUSTRIE, France) in the tablet form. Studies were performed on white non-linear rats of different sexes with different mass 150–210 g, aged 3.5–5.0 months. Results. Statistically significant differences in the inhibition of induced platelet aggregation were registered after 6 hours of rectal administration of clopidogrel and gastric administration of the reference medication, indicating the effectiveness of the rectal applicative transmucosal route for this active pharmaceutical ingredient (API). On the 5th day of administration, inhibition of induced platelet aggregation significantly increased, and that is supported by literature on the cumulative effect of clopidogrel in daily life. When comparing the digital material of the table, it is obvious that the rectal administration of clopidogrel is more effective in comparison with oral route which is probably due to the rapid delivery of API to the liver and the formation of an active metabolite of clopidogrel inhibiting the induction and spontaneous aggregation of platelets in human’s and animal’s blood. Obtained data provide with sound arguments for development of rectal suppositories with clopidogrel because in clinical care faster achievement of an anti-aggregation effect in patients with acute coronary syndrome is the primary task of clinical pharmacology and pharmacy. Conclusions. Using the biochemical model of pathology, it was established that the applicative semisolid medication of clopidogrel in the form of rectal suppository exhibited inductive anti-aggregation activity and its administration didn’t reveal any side effects and undesirable events. Rectal suppositories with clopidogrel have been shown to exhibit faster reliable anti-aggregation effect in comparison with intragastric administration.
Uncomplicated hypertensive crises without acute or progressive damage to the target organs pose a potential threat to the patient’s life and require rapid reduction of arterial pressure within hours or days in an outpatient setting. The existing protocol for the treatment of this pathology is not entirely perfect, as it does not offer the primary physician a clear and unambiguous description of the use of effective and complementary drugs. The use in these cases of nasal transport of antihypertensive active pharmaceutical ingredients in appropriate dosage forms makes it possible to ensure their rapid delivery to the bloodstream and perivascular structures of the brain. Based on previous experience, and taking into account biopharmaceutical research on pharmacodynamics and pharmacokinetics of captopril innovative captopril dosage form has been developed and put into practice for trasmucosal administration as 2.5 % intranasal gel with controlled releasing of captopril substance in Zaporizhzhia State Medical University. The aim of the research was to study the pharmacodynamics of captopril gel in patients with arterial hypertension with uncomplicated hypertensive crises. Materials and methods. 58 outpatients with stage 2 arterial hypertension with uncomplicated cardiac crises were surveyed, an experienced group had 30 patients aged from 38 to 69 years (average age 52.60 ± 5.03 years) with average duration of disease 11.50 ± 2.72 years, obtained the intranasal application into two nasal routes 0.5 ml 2.5 % captopril gel with a dose syringe. Comparison group had 28 patients with stage 2 arterial hypertension with uncomplicated cardiac crises aged from 37 to 65 years with duration of arterial hypertension 10.8 ± 2.63 years, obtained peroral captopril in equivalent dose. Captopril tablets 0.025 g were used as a reference drug. In the course of treatment, the indicators of office blood pressure and heart rate in the crisis state were determined after 60, 120 and 240 minutes after the use of captopril. Because of asymmetric distribution, the non-parametric method – the Wilcoxon signed-rank test – was used. Results. There has been a significant reduction in systolic and diastolic arterial pressure one hour after the gel’s intranasal application by 19.9 % and 23.8 % respectively, whereas, after the use of captopril in tablets, there is only a tendency to decrease systolic and diastolic pressures by 8.8 % and 11.6 % respectively. Two hours after the use of the gel, systolic and diastolic blood pressure decreased by 23.5 % and 23.5 % respectively, reaching the level recommended by the leading cardiologists of Ukraine. After oral administration of the captopril tablets, systolic arterial pressure decreased by 13 %, diastolic arterial pressure, and heart rate showed only a downward trend. Four hours after the use of the captopril gel, there was a gradual increase in systolic arterial pressure, and the level of diastolic arterial pressure remained almost the same. After application of captopril gel, the heart rate in the treatment dynamics remained unchanged, with a trend of acceleration in the first time of treatment, and decreased by 4 hours by 12.4 %. Conclusions. A randomized, controlled study of nasal captopril pharmacodynamics in the form of 2.5 % hydrophilic gel compared to its tableted dosage form in patients with arterial hypertension with uncomplicated hypertensive crises was carried out. It has been established that the nasal dosage form of captopril provides for the reduction of the arterial pressure to the level recommended in the case of uncomplicated hypertensive crises for 4 hours more efficiently than the oral agent. Captopril nasal gel has been shown to have good tolerance and there are practically no side effects from its use.
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