Berberine (BB) is an isoquinoline alkaloid, which is obtained from Berberis (Barberry), more often Berberis vulgaris, of the Berberidaceae family. The interest of the scientific community in this molecule was caused by its vast number of pharmacological effects: antitumor, hypolipidemic, anti-inflammatory, antiarrhythmic, antidiabetic, etc. The antitumor effect of BB consists in the inhibition of the cell cycle in the G1 phase, the induction of apoptosis in tumor cells, the effect on mitogen-activated kinases, and the suppression of metastasis. The main reason for the infrequent use of this molecule is its poor solubility and low bioavailability. Thus, the best solution to overcome these problems is intratumoral implantation. During the analysis of scientific publications, it was found that in the process of developing intratumoral implants when creating matrices with various active substances, it is most often preferred to use poloxamers, since the temperature stimulus is the most characteristic and reliable in therapy. Thus, the aim of the study is to develop the composition and technology of an intratumoral thermosensitive implant of berberine bisulfate (BBB). The study used 101.6% BBB substance (Vifitech, Russia). Kolliphor® P188, Kolliphor® P338, Kollisolv® P124 and Soluplus®, polysorbate-80, PEG-1500 (BASF, Germany) were used as solubilizers. N-methylpyrrolidone was also considered as a candidate for dissolution media. Solubilization of BBB was carried out by adding surfactants and their combinations, by the method of solid dispersions, liquid-liquid extraction. BBB showed very low solubility in N-methylpyrrolidone. The final composition contained Kolliphor® P 407 (15.0%), Kolliphor® P 188 (2.0%), Kollisolv® P124 (2.0%), BBB (1.3%) with a phase transition rate of 2 minutes and phase transition temperature 37-38℃. For the obtained optimal composition, the “Dissolution” test was carried out using a dialysis bag, in a phosphate buffer solution pH 6.8, at a constant temperature of 37℃. Sampling was carried out after 1 hour, 2 hours, 3 hours, 5 hours, 24 hours and 96 hours. The concentration of the substance was determined using spectrophotometry. As a result of the studies carried out, the most suitable composition for an intratumoral implant was created, and the necessary tests were carried out. It can also be concluded that the use of poloxamers is effective in improving the dissolution of BBB. Further research is required.
Background Recent studies have shown proven efficacy of renal denervation in arterial hypertension, but there is a continuing need to assess the duration of antihypertensive effect. Purpose Evaluation of the long-term antihypertensive effect of renal denervation in patients with resistant hypertension. Methods 125 apparently resistant patients without comorbidities after a 3-week standardized treatment with Losartan 100 mg, Amlodipin 10 mg and Indapamid 1.5 mg and confirmation of their resistance were randomly assigned into three groups depending on treatment supplemented to previously administered: group I - selective I1-imidazoline agonist Moxonidine, group II - cardioselective beta-blocker Bisoprolol and group III – renal artery denervation. The compliance to treatment was confirmed using 8-item Morisky Medication Adherence Scale. Renal denervation was performed in the main renal arteries and their branches. Patients were assessed by ambulatory blood pressure monitoring at baseline, 3, 12, 24 and 36 months follow-up. Results The mean 24 hour systolic blood pressure (SBP) at baseline were 179.0±2.02 mmHg in group I versus 177.96±2.44 mmHg in group II and 176.92±1.97 mmHg in group III, p>0.05. A statistically significant reduction in SBP m/24 h was noted in all three groups starting at 3 months, the group of patients undergoing renal denervation showing superiority over both groups of pharmacological treatment: −6.48±0.81 mmHg in group I versus −6.2±0.88 mmHg in group II and −23.28±1.9 mmHg in group III, p<0.001. The progressive improvement continued until the end of the study, so at 3 years of evaluation in observational group supplemented with Moxonidine SBP m/24 h were 146.36±1.36 mmHg with a total reduction of −32.64±1.56 mmHg from baseline, in Bisoprolol group −152.88±1.56 mmHg with a reduction of −25.08±1.65 mmHg and 133.16±0.73 mmHg in renal denervation group with a total reduction of −282±1.30 mmHg in group III, p<0.001. The mean 24 hour diastolic blood pressure (DBP) increased at baseline in all three observational groups (105.52±1.28 mmHg in group I versus 108.6±1.6 mmHg in group II and 107.24±0.92 mmHg in group III, p>0.05) similar with SBP m/24 h noted an authentic reduction at 3 months follow-up. The maximum reduction in DBP m/24 h were registered at 3 years of evaluation, a comparative analyses of dynamics between groups showing a presence of statistical difference due to superiority of renal denervation in amelioration of this parameter: −18.36±1.88 mmHg in group I versus −16.84±1.76 mmHg in group II and −28.2±1.30 mmHg in group III, p<0.001. Conclusions All three regimens have been shown to be effective in reducing SBP and DBP m/24 h in patients with resistant hypertension, with a superior but comparable effect of Moxonidine to Bisoprolol and the absolute superiority of renal denervation treatment, the beneficial effect being maintained for a period of 3 years. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): National Agency for Research and Development
Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Agency for Research and Development Purpose The increased activity of the sympathetic nervous system is the pathophysiological key of several pathologies, such as hypertension, heart failure, diabetes, etc., the modulation of its activity can improve the management of these diseases and represents an increased scientific interest. Aim Comparatively evaluation of the effects of modulating SNS activity at different levels through various therapeutic approaches on the NYHA functional class of heart failure and physical capacity to exercise in patients with resistant hypertension. Material and method 75 patients with resistant hypertension and heart failure with the preserved ejection fraction were enrolled in the study. All patients for 21 days underwent standardized ambulatory treatment with Losartan 100 mg, Amlodipine 10 mg and Indapamide 1.5 mg, and were subsequently randomized into three equal groups of 25 patients according to treatment supplemented to the previous treatment: group I M - Moxonidine, group II B - Bisoprolol and group III D – renal denervation. Patients were evaluated clinically, echocardiographically and by the 6-minute walking test at baseline, 3 and 6 months. Results The clinical improvement of NYHA class was confirmed by the progressive increase of the distance traveled in the 6 minute walk test. Thus, the groups being comparable according to the distance traveled at the enrollment stage in the study, noted a statistically authentic dynamic starting with 3 months of continuous medication constituting 392.48 ± 14.88 m in the I M group (+ 20.45% from initial values ) versus 359.84 ± 15.15 m in group II B (+ 15.0% of initial values) and 386.08 ± 11.99 m in group III D (+ 24.33% of initial values), p> 0.05. The increase of the distance traveled continued until 6 months of evaluation in all three observation lots with the following values: 416.12 ± 13.50 m (+ 25.06% from the initial) versus 387.80 ± 12.85 m (+ 21.55% from the initial) and 424.28 ± 10.30 m (+ 31.06% from the initial) in lots I M, II B and III D, respectively. Comparative analysis of the dynamics between groups showed a comparable beneficial effect in improving the distance traveled in the 6 minute walk test in groups of patients treated with Moxonidine and Bisoprolol and the superiority of minimally invasive renal denervation treatment over drug treatment, an event notable starting with 3 months of evaluation and maintained until the end of the supervision period. Conclusions Blockade of the sympathetic nervous system at the central level with the selective imidazoline receptor agonist I1 Moxonidine, at the peripheral level by administration of the β1-cardioselective adrenoblocker Bisoprolol or by the minimally invasive method of renal artery denervation resulted in progresive amelioration of NYHA class and increasing physical capacity to exercise, the pharmacological treatment groups showing a comparable effect, but lower than the group of patients undergoing renal denervation.
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