Резюме
Григор’єва Л.В. Пошук нових анальгетичних засобів серед похідних 2-N-R’-метіліден-5-сульфамоїлантранілової кислоти для купірування абдомінального синдрому в практиці сімейного лікаря.
Проведено дослідження впливу похідних 2-N-R’-метіліден-5-сульфамоїл-антранілової кислоти на рефлекторну збудливість вісцеральних ноцицепторів у щурів. Встановлено, що сполука № 4 - 2-N-(2’,4’-діхлорбензіл)метіліден-5-сульфамоїлантранілової кислоти знижує чутливість вісцеральних ноцицепторів на 41,2 % і за анальгетичної активності порівнянна з диклофенаком натрію.
Ключові слова: 2-N-(2’,4’-діхлорбензіл)метіліден-5-сульфамоїлантранілової кислоти, ноцицептори, анальгетична активність.
Резюме
Григорьева Л.В. Поиск новых анальгетических средств среди производных 2-N-R’-метилиден-5-сульфамоилантраниловой кислоты для купирования абдоминального синдрома в практике семейного врача.
Проведено исследование влияния производных 2-N-R’-метилиден-5-сульфамоилантраниловой кислоты на рефлекторную возбудимость висцеральных ноцицепторов у крыс. Установлено, что соединение № 4 - 2-N-(2’,4’-дихлор-бензил)метилиден-5-сульфамоилантраниловой кислоты снижает чувствительность висцеральных ноцицепторов на 41,2 % и по анальгетической активности сопоставимо с диклофенаком натрия.
Ключевые слова: 2-N-(2’,4’-дихлорбензил)метилиден-5-сульфамоилантра-ниловой кислоты, ноцицепторы, анальгетическая активность.
Summary
Grigorieva L.V. Searching new analgetic drugs among 2-N-R’- methilidene-5-sulfamoylanthranilic acid derivatives. Using these drugs for abdominal syndrome pain managment in family doctor’s practice.
 It was made research of influence of 2-N-R’-methylidene-5-sulfamoylanthranilic acid derivatives on rat’s reflex excitability of visceral nociceptors . It was determined that compound №4 - 2-N-(2’,4’-dichlorobenzyl)methylidene-5-sulfamoyl-anthranilic acid decreases excitability of visceral nociceptors on 41.2 % and it is comparable with diclofenac sodium by analgetic activity.
Key words: 2-N-(2’,4’-dichlorobenzyl)methylidene-5-sulfamoylanthranilic acid, nociceptors, analgetic activity.

Рецензент: д.фарм.н., проф. Б.А. Самура

УДК 615.212.3.015:616.3-071.4]:614.253.2

Харьковский национальный университет им. В.Н. Каразина

площадь Свободы 4, 61022, Харьков

V. N. Karazin Kharkiv National University

Svobody Sq. 4, 61022, Kharkiv, Ukraine

doctor-exclusive@mail.ua

Introduction. In contemporary clinical medicine the problem of anesthesia takes one of the important places in family doctor’s practice [3]. Pain syndrome accompanys many diseases [8, 10], so that using nonsteroidal antiinflammatory drugs (NSIAD) is important in symptomatic therapy. Analgesic end point of NSIAD is directed to peripheral mechanism of pain  elaboration. Also analgesic end point of NSIAD is involved with downstream of prostaglandins, leukotrienes, biogenic amines, kinins [13].

All pain relievers are divisible into narcotic and nonnarcotic analgetics [1, 5, 6]. This division depends on mechanism of action and speciality of clinical management. Generally nonnarcotic analgetics can suppress nociceptive system without obtundation of a whole body, impairment of consciousness, switching off sensation   [14].

Nonnarcotic analgetics  play a critical therapeutic part in treatment abdominal space  inflammatory diseases, which go along with pain syndrome and many other malconditions [11, 12, 15].

All  NSIADs are divisible into nonselective and selective inhibitors by degree of impact on potency of cyclooxygenase  (COX). Selective inhibitors have sparing action preferentially for COX-2. Nonselective inhibitors can block COX-1 and COX-2.  These medicinal agents have analgetic and anti-inflammatory action by blocking COX-2. Blocking action of COX-1 leads to depression of prostaglandin  shielding effect and spurs side effects  [5, 16].

The most wide-spread adverse effect of NSIAD is gastropathy, which ulcerates GI tract, often accompanies perforation and bleeding [13].

Reason fundamental of this effect is stipulated by blockade of COX, which initiates synthesis of gastroprotective prostaglandins, which grant protection of mucous coat of stomach.  These prostaglandins suppress releasing hydrochloric acid by initiation bicarbonates and mucus secretion. As gastroprotection is provided mainly by COX-1 activity, nonselective inhibitors more often than selective inhibitors cause GIT damage. NSIAD solutions have immediate irritant action at mucous coat of stomach. This action also conduces gastropathy germination [6].

Practice shows even short-term using low doses of NSIAD can provoke adverse reactions. Registered adverse reactions of NSIAD medication is determined by occurrence of clinical use. According to world statistics, NSIADs is used by more than 300 mln patients all over the world  every year. And only 100 mln patients use it on doctor's orders, others use it like over the counter drugs (OTC) [12].

Thereat searching for new active harmless pharmacological substances, which have analgesic end point, is topical issues of experimental  pharmacology [4]. Computer forecast was realized by PASS  programme for searching eventual kinds of pharmacological action. Outcomes show high probability that 5-N,N-diethylsulfamoyl-N-phenylanthranilic acid  derivatives have analgesic endpoint. The outcomes grounded presented research.

Connection of this study with scientific agenda, plans, topics: the research was made as part of scientific agenda of National University of Pharmacy on subject «Development new medicines» (state registration  № 0198U007008).

The aim of this investigation is study influence 2-N-R'-methylidene-5-sulfamoylanthranilic acid derivatives at visceral nociceptor excitability.

Substances and research methods

Targets of research were selected 9 new-synthesized compoundings from the range of 5-N,N-diethylsulfamoyl-N-phenylanthranilic acid  derivatives. Analgesic potency of these substances have been searched in tests with white wistar rats (mass 160 – 185g). It have been used acetic acid writhing analysis with reflex action of acetic acid on visceral     nociceptor excitability. Writhing was promoted by intraperitoneal introduction of 0.75 % acetic acid aqueous solution (dosage 1ml – 100g of  body mass). Calculations of writhes were made during 30 minutes after 30 minutes intraperitoneal introduction. 30 Minutes before introduction of acetic acid, the test substances were administered intragastrically by metal probe at a dose 0.05 LD50. It was compared number of writhes in test and control groups. Outcome have shown         analgesic activity of analyte. Analgesic activity was expressed on a percentage base decrement of acetic writhes in test and control groups of animals [9].

During experimental studyings animals were cared in standard conditions accordingly to norms and principles of DIRECTIVE 2010/63/EU on the protection of animals used for scientific purposes [2].

Findings were estimated by standard analysis methods of  variance, with using t Student criterion,  software  “Windows-2003”, spreadsheet  Excel. [7, 9].

Findings and their discussion

Estimation of findings shows that (tab. 1), compound №1 – 2-N-benzilenmethylidene-5-sulfamoylanthranilic acid   moderates  antinociceptive effect at a dose 11.9 mg/kg. This compound gives rise to elevation of reflectory excitability limen of visceral nociceptors, also it  subdues count of acetic acid-induced writhing on 8%. Increas of pain alleviating effect on 15.4%  was reached by replacement 2-N- benzilenmethylidene  phenyl ring on the second place of 2-N-R'-methylidene-5-sulfamoylanthranilic acid derivatives (comp. №1) by  2-N- nitroben- zilenmethylidene (comp. №2).

Stimulation of  reflex excitability  and   increas of pain alleviating effect on 5.7%  were gotten due to changing  two hydrogen atoms (comp. №2) in sulfamoyl         group, which locates in 5th place of molecule of anthranilic acid, by two methyl residues.

Increasing reflex excitability of visceral nociceptors was observed after inseting 2',4'-dichlorobenzyl radical (comp. №4) instead of 2-nitrobenzyl (comp. №2) on the second place in 2-N-R'-methylidene-5-sulfamoylanthranilic acid derivatives.  It was  registered the  highest analgesic end point and rising        reflex activity on 41.2% (р <0.05)  as affected comp. №4 at a dose 6.9mg/kg.

Decrease reflex excitability of visceral nociceptors  and reduction pain alleviating effect on 24.9% have been results from substitution two hydrogen atoms (comp. №4) in sulfamoyl group, which locates in 5th place of molecule of anthranilic acid, by two methyl residues (comp. №5).

Loss of influence at reflex excitability of visceral nociceptors have been result from put in hexyl (comp. №8) and  hexil (comp. №9) substituents on the fifth place in 2-N-R'-methylidene-5-sulfamoylanthranilic acid derivatives.

Analgesic endpoint  have been lost after inclusion phenylethyl  (comp. №6) and difurylglyoxal (comp. №7) residuals on the fifth place in 2-N-R'-methylidene-5-sulfamoylanthranilic acid derivatives.

It can be supposed that analgesic endpoint  of  explored 2-N-R'-CH-ylidene-5-sulfamoylanthranilic acid derivatives is based on inhibition of gene expression,  which has responsibility for leukotriene synthesis [13].  

As a result,  compound №4 has the most analgesic endpoint  among  of  explored 2-N-R'-methylidene-5-sulfamoylanthranilic acid derivatives.  This compound decreases excitability of visceral nociceptors on 41.2% and it is comparable with diclofenac sodium by analgetic activity.

Inference

1.Compound  №4  -  2-N-2',4'-dichlorobenzylmethylidene-5-sulfamoyl-anthranilic acid  decreases excitability of visceral nociceptors on 41.2% and it is comparable with diclofenac sodium by analgetic activity.

2. Established findings can afford to recommend 2-N-R'-methylidene-5-sulfamoylanthranilic acid derivatives for carrying out pharmacological screening and further synthesis with the aim of drug development for medication nociceptive and inflammatory process  of various ethiology.

Литература
1. Ананьева Л.П. Современные противоболевые средства / Л.П. Ананьева, Е.В. Подчуфарова. - М., 2005. - 157 с.
2. Доклінічні дослідження лікарських засобів / За ред. О.В. Стефанова. - Київ: Авіцена, 2001. - 528 с.
3. Загальна практика-сімейна медицина / За ред. О.В. Синяченка. - Донецьк: Норд-Прес, 2011. - 670 с.
4. Каратеев А.Е. Гастродуоденальная переносимость нимесулида (нимесил, Berlin Chemic) у больных с язвенным анамнезом: первое проспективное исследование безопасности селективных ЦОГ-2 ингибиторов у больных с высоким риском развития НПВП-индуцированных гастропатий / А.Е. Каратеев, Д.Е. Каратеев, Е.Л. Насонов // Научно-практическая ревматология. - 2003. - № 1. - С. 45-48.

5. Каратеев А.Е. Применение нестероидных противовоспалительных препаратов. Клинические рекомендации / А.Е. Каратеев, Н.Н. Яхно, Л.Б. Лазебник. - М.: ИМА-ПРЕСС, 2009. - 167 с.
6. Колобов С.В. Терапия НПВП в общемедицинской практике: методические рекомендации / С.В. Колобов [и соавт.]. - М., 2006. - 31 с.
7. Лапач С.Н. Статистические методы в медико-биологических исследованиях с использованием EXCEL / С.Н. Лапач, А.В. Чубенко, П.Н. Бабич. - Киев: Морион, 2000. - 320 с.
 8. Осипенко М.Ф. Хроническая абдоминальная боль и синдром раздраженного кишечника / М.Ф. Осипенко, С.И. Хомин, А.Н. Рыжичкина // Лечащий врач. - 2011. - № 2. - С. 8-14.
9. Сернов Л.Н. Элементы экспериментальной фармакологии / Л.Н. Сернов, В.В. Гацура. - М., 2000. - 352 с.
10. Щульпекова Ю.В. Симптом висцеральной боли при патологии органов пищеварения / Ю.В. Щульпекова, В.Т. Ивашкин // Врач. - 2008. - № 9. - С. 12-16.
11. Drossman D.A. Severe and refractory chronic abdominal pain / D.A. Drossman // Clin Gastroenterol Hepatol. - 2008. - Vol. 6, № 9. - P. 978-982.
12. Pilotto A.The risk of upper gastrointestinal bleeding in eldery users of aspirin and othe non-steroidel anti-inflammetory drugs: the role of gastroprotective drugs / A. Pilotto, M. Franceschi, G. leandro // Aging Clin Exp Res. - 2003. - Vol. 15, № 6. - P. 494-499.
13. Sachs C. Oral analgesics for acute nonspecific pain / C. Sachs // Am. Fam. Physician. - 2005. - Vol. 71. - P. 913-918.
14. Schmidt L.E. Alpha-fetoprotein is a predictor of outcome in acetaminophen-induced liver injury / L.E. Schmidt, K. Dalhoff // Hepatology. - 2005. - Vol. 41, № 1. - Р. 26-31.
15. Wang P. Determination of ibuprofen in dog plasma by liquid chromatography and application in pharmacokinetic studies of an ibuprofen prodrug in dogs / P. Wang, M. Qi, L. Liu, L. Fang // J. Pharm. Biomed. Anal. - 2005. - Vol. 38, № 4. - P. 714-719.
16. Wilcox C.M. Patterns of use and public perception of over-the-counter pain relievers: focus on nonsteroidal antiinflammatory drugs / C.M. Wilcox, B. Cryer, G. Triadafilopoulos // J. Rheumatol. - 2005. - Vol. 32, №11. - P. 2218-2224.