Specific inhibition of acetylcholinesterase as an approach to decrease muscarinic side effects during myasthenia gravis treatment

© 2017 The Author(s). Non-selective inhibitors of cholinesterases (ChEs) are clinically used for treatment of myasthenia gravis (MG). While being generally safe, they cause numerous adverse effects including induction of hyperactivity of urinary bladder and intestines affecting quality of patients life. In this study we have compared two ChEs inhibitors, a newly synthesized compound C547 and clinically used pyridostigmine bromide, by their efficiency to reduce muscle weakness symptoms and ability to activate contractions of urinary bladder in a rat model of autoimmune MG. We found that at dose effectively reducing MG symptoms, C547 did not affect activity of rat urinary bladder. In contrast, at equipotent dose, pyridostigmine caused a significant increase in tonus and force of spontaneous contractions of bladder wall. We also found that this profile of ChEs inhibitors translates into the preparation of human urinary bladder. The difference in action observed for C547 and pyridostigmine we attribute to a high level of pharmacological selectivity of C547 in inhibiting acetylcholinesterase as compared to butyrylcholinesterase. These results raise reasonable hope that selective acetylcholinesterase inhibitors should show efficacy in treating MG in human patients with a significant reduction in adverse effects related to hyperactivation of smooth muscles

Application of clinical and economic analysis methods in assessment of the effectiveness of benign prostatic hyperplasia surgical treatment

Aim To determine the effectiveness of transurethral resection (TUR) and transvesical adenomectomy (TA) in the treatment of benign prostatic hyperplasia (BPH) by methods of clinical and economic analysis (CEA). Materials and methods We investigated the results of surgical treatment of BPH with the method of TA with a deaf seam of the bladder (n = 252) and a monopolar TUR (n=40). The duration of urethral drainage was 3.1 ± 0.8 and 2.9 ± 0.6 days, respectively. The cost of one treatment case for TA was 37,309.07 rubles, and for TUR - 50,391.46 rubles. Clinical efficacy (Eff) was determined from three indicators: uroflowmetry, I-PSS, and QoL with performance criteria set for them. In the TA group after 1 month after the operation Eff was 100%. In the TUR group after the same period, Eff by three indicators was 43.3%. Drug therapy (DT) with tolterodine and tamsulosin for 2 months allowed to achieve 100% Eff in the TUR group, but led to an increase in the cost of treatment. CEA was determined by using the cost-effectiveness and cost minimization methods. Conclusion TA with a deaf seam of the bladder has better clinical efficacy and lower costs than TUR. To increase the efficiency of TUR additional DT may be required.Цель: Определить эффективность трансуретральной резекции (ТУР) и аденомэктомии (АЭ) в лечении аденомы предстательной железы (АПЖ) методами клинико-экономического анализа (КЭА). Материалы и методы: Изучены результаты хирургического лечения АПЖ методом чреспузырной АЭ с глухим швом мочевого пузыря (n=252) и монополярной ТУР (n=40) . Длительность госпитализации в группе АЭ была 14,3±1,3, а в группе ТУР - 13,9±1,8 койко-дней. Сроки уретрального дренирования составили 3,1±0,8 и 2,9±0,6 суток соответственно. Стоимость одного случая лечения АПЖ для АЭ составила 37 309,07 руб., а для ТУР - 50 391,46 руб. Клиническая эффективность (Eff) определялась по данным трех показателей сравнения: урофлоуметрии, шкалы I-PSS и индекса QoL с заданными для них критериями эффективности. В группе АЭ через 1 мес. после операции Eff составила 100%. В группе ТУР на том же сроке Eff по трем показателям составила 43,3%. Медикаментозная терапия (МТ) толтеродином и тамсулозином в течение 2-х мес. позволила достичь 100% Eff в группе ТУР, однако привела к удорожанию лечения 1 случая на 1756,1 руб. Экономическую эффективность (Keff) определяли по методу «стоимость-эффективность». Keff для АЭ на сроке 1 мес. был равен 373,09. Для ТУР Keff на сроке 1 мес. составил 1163,78, а после 2-х мес. МТ – 521,5. Методом «минимизация затрат» установлено, что стоимость лечения 1 случая АПЖ в группе ТУР на 15148,39 руб. дороже, чем в группе АЭ. Выводы: Оперативное лечение методом АЭ с глухим швом мочевого пузыря имеет лучшую клиническую эффективность и меньшие затраты, чем ТУР. Для повышения эффективности ТУР может потребоваться дополнительная МТ

Diagnostic algorithm of recurrence after organ-preserving surgical treatment of bladder cancer

High frequency of recurrence is the main problem of organ-preserving tactics in the treatment of bladder cancer. The article presents the results of sensitivity and specificity analysis of urine cytology, BTA-stat test, ultrasound (transabdominal, transrectal, transurethral) and instrumental methods (cystoscopy, photodynamic diagnostics, microcystoscopy) in the diagnosis of recurrence after organ-saving surgical treatment in patients who underwent organ-saving surgery about bladder cancer at the urological clinic of Kazan State Medical University. An algorithm based on the obtained data has been developed for the diagnosis of recurrent bladder cancerОсновной проблемой органосохраняющей тактики в лечении рака мочевого пузыря является высокая частота рецидивов. В статье представлены результаты анализа чувствительности и специфичности цитологии мочи, ВТА-stat теста, ультразвуковых (трансабдоминальное, трансректальное, трансуретральное) и инструментальных методов (цистоскопия, фотодинамическая диагностика, микроцистоскопия) в диагностике рецидивов после органосохраняющего хирургического лечения у пациентов, которым была выполнена органосохраняющая операция по поводу рака мочевого пузыря урологической клинике Казанского государственного медицинского университета. На основании полученных данных, разработан алгоритм диагностики рецидивов рака мочевого пузыря

MORPHOLOGICAL TRANSFORMATION OF INTESTINAL GRAFT AFTER CYSTECTOMY WITH ORTHOTOPIC PLASTIC OF THE URINARY BLADDER

Introduction. The histomorphological state and mechanisms of transformation of the intestinal epithelium of the orthotopic urinary bladder are unexplored.Purpose of research. The study the morphological adaptive and compensatory changes in the intestinal graft wall (IGW) and their relationship with homeostasis at various stages after surgical treatment. Materials and methods. The morphological state of the intestinal graft wall (IGW) was studied in 42 patient’s cystectomy undergoing with the formation of an orthotopic intestinal bladder (15-ileum, 27-sigmoid) at terms from 1 to 6.5 months and 1 year or more after the treatment.Results. Morphological changes occurring in the IGW wall begin with the moment of urine entering the lumen, which occurs in combination with changes in the stereotyped dynamics of the organ. Expressed changes are observed in all parts of the wall of the small and large intestine. There is regeneration and restructuring of the epithelium, expressed in atrophy and a decrease in the number of suction cylindrical cells and an increase in the number of mucus-forming goblet elements, terminating by 12 months and more after the operation. This combined with a decrease in the number and size of villi and crypts, reduction of the lymphatic channel and sclerosis of the blood vessels and stroma blocks suction. An increase in the number of mucus-forming goblet cells provides a barrier that protects the IGW mucosa from the effects of urine.Conclusion. Morphological changes occurring in the IGW wall under the influence of urine contribute to the preservation of homeostasis and are identical in the thick and thin-intestinal variant of plastic of the bladder.Disclosure: The study did not have sponsorship. The authors have declared no conflicts of interes

P2-receptors of the urinary bladder as potential targets for novel drugs

Purinergic P2 receptors, the basic endogenous agonist of which is adenosine triphosphoric acid (ATP), are widely spread in the organs and tissues of human and animals including urogenitary system. Physiologically, in the peripheral nervous system the role of P2 receptors in most cases is not leading, they only complement or modulate the action of main neuromediators (acetylcholine, norepinephrine). But in pathology the role of P2 receptors significantly increases and often takes the lead in the pathogenesis of one or another disease. In particular, it was determined that purinergic component of contractile bladder response increases from 2-5% in normal state to 40% in some pathological processes (such as interstitial cystitis, neurogenic bladder, urinary obstruction). In the bladder of experimental animals different subtypes of P2 receptors were revealed, their functional role was established in normal conditions and models of pathological processes. Certain subtypes of P2 receptors were also detected in the human bladder, including in some urinary tract diseases. The level of ATP in patients’ urine was established to significantly increase in lower urinary tract obstruction that holds certain promise for the diagnosis of these diseases. Variety and large representation of P2 receptors in lower urinary tract make them attractive as potential targets for novel drugs. On this evidence, evaluation of effect of P2 receptor agonists and antagonists as well as medications affecting the metabolism of endogenous nucleotides and nucleosides, is one of promising direction for the search for new urological drugs

Specific inhibition of acetylcholinesterase as an approach to decrease muscarinic side effects during myasthenia gravis treatment

© 2017 The Author(s). Non-selective inhibitors of cholinesterases (ChEs) are clinically used for treatment of myasthenia gravis (MG). While being generally safe, they cause numerous adverse effects including induction of hyperactivity of urinary bladder and intestines affecting quality of patients life. In this study we have compared two ChEs inhibitors, a newly synthesized compound C547 and clinically used pyridostigmine bromide, by their efficiency to reduce muscle weakness symptoms and ability to activate contractions of urinary bladder in a rat model of autoimmune MG. We found that at dose effectively reducing MG symptoms, C547 did not affect activity of rat urinary bladder. In contrast, at equipotent dose, pyridostigmine caused a significant increase in tonus and force of spontaneous contractions of bladder wall. We also found that this profile of ChEs inhibitors translates into the preparation of human urinary bladder. The difference in action observed for C547 and pyridostigmine we attribute to a high level of pharmacological selectivity of C547 in inhibiting acetylcholinesterase as compared to butyrylcholinesterase. These results raise reasonable hope that selective acetylcholinesterase inhibitors should show efficacy in treating MG in human patients with a significant reduction in adverse effects related to hyperactivation of smooth muscles