EXPERIMENTAL RESEARCH OF DIURETIC PROPERTIES OF NEW 7-METHYL-N-BENZYL-8- SUBSTITUTED THEOPHYLLINE

Abstract

EXPERIMENTAL RESEARCH DIURETIC PROPERTIES OF NEW 7-METHYL-N-BENZYL-8-SUBSTITUTED THEOPHYLLINE.

Matviychuk O.P., Gladchenko O.M., Matviychuk A.V., Ivanchenko D.G.

National University of Pharmacy

Zaporozhye State Medical University

Introduction.  Diuretics are widely used in the treatment of a number of diseases caused by a variety of diseases, in which the need to use these drugs. In many cases there is a clinical need to increase urine output for excretion of fluid, reducing its content in tissues and serous cavities. Especially great role of diuretic drugs in the treatment of patients with chronic congestive heart failure. Thanks to properties diuretics cause increased excretion of sodium and water from the body is given a real opportunity to actively influence the fluid and electrolyte disturbances in these patients.

The use of diuretic agents (hydrochlorothiazide, furosemide, etacrynic acid, etc.) are often accompanied by side effects, which primarily relate to fluid and electrolyte homeostasis, acid-base balance, carbohydrate metabolism, phosphate, creatinine and uric acid.

The search for new medicines that improve the functional activity of the kidneys, is one of the urgent problems of modern experimental pharmacology. Synthesis of modified analogs of biologically active substances of natural origin is a priority for research to address this issue.

Given this, it was interesting to conduct forecasting of possible types of pharmacological activity of derivatives 7,8-disubstituted theophylline using the «PASS» (Predectum of Activity Spectra for Substances: Complex & Training), whose work is based on an analysis of dependencies "structure - activity".

The results of the computer forecast derivative 7-p-metylbenzyl-8-substituted theophylline showed a high likelihood of these types of compounds of pharmacological activity, diuretical, spasmolytical, psycho-stimulant, analgesic, anti-inflammatory.

Investigation methods. To solve the tasks as object of study was first taken 20 compounds synthesized derivatives of 7-n-metylbenzyl-8-substituted theophylline. The influence of new derivatives of p-20 metylbenzyl-8-substituted theophylline on renal function was performed on white male rats weighing 140-190 g Ye.B.Berhina method [1; 5].  Animals in the experiment were in individual metabolic cages adapted to collect urine. Number of animals in the group amounted to 5. Investigated derivatives intragastric administered at a dose of 1/100 of LD50. After 30 minutes, the rats were injected with tap water at the rate of 3 ml per100 g body weight. Urine recorded 2 hours to 4 hours. As a comparison drug used hydrochlorothiazide (hypothiazid) production «Sanofi Aventis»,France.

Results and discussion.  Study diuretic activity 7-p-metylbenzyl-8-substituted theophylline showed that these compounds affect renal function. Most of the studied derivatives showed diuretic activity, which used to range from 23.2% to 153.7%. Marked diuretic effect compound found 14 - 7 p-metylbenzyl-8-p-bromobenzylidenhidrazynoteofilin which stimulates excretory renal function in rats and increases urine 4 hours of observation at 153.7% (p <0.01).

Thus, our experimental studies demonstrate the effectiveness of computer prediction. The results forecast for the derivatives of 7-n-metylbenzyl-8-substituted theophylline, envisaged a high probability vasodilatation (peripheral) and diuretic activities that were specifically synthesized to produce the intended biological activity that was confirmed by our experiments.

Conclusions. Investigated derivatives of 7-n-metylbenzyl-8-substituted theophylline affect renal excretory function that confirms your computer forecast. The most severe action has diuretic compound 14 - 7- p-metylbenzyl-8-p-bromobenzylidenhydrasinotheophylline which revealed a strong diuretic activity that exceeds the effect hypothiazid 2 times. Among the studied compound found 14 derivatives with diuretic activity high, which makes it promising for further in-depth study of specific diuretic activity as a potential diuretic drug.

References

1. Berhyn, E. B. Methods Study novyh action of chemical compounds on kidney function // Chemical. Pharm. Zh. - 1977. - T. 11, № 5.- P. 3 - 11.

2. Brukhanov, V. M., Zverev, J. F.  Side effects of modern diuretics. - Novosibirsk, 2000. -242 p.

3. Glaser, G. A. Diuretics. Guidelines for doctors. - M .: Interbuk Business, 1993. - 352 p.

4. James A. Sheiman. Pathophysiology of the kidney. Trans. with Eng. 2nd ed., Rev. - M. - SPb .: "Publisher Binom" - "Nevsky Dialect", 1999. - 206 p.

5. Preclinical studies of medicines. / Ed. O.V. Stefanova. - K .: Publishing house "Avicenna", 2001. - 528 p.

6. Lapach, S. N.  Statistic Methods in Medical and Biology with Research Using EXCEL / S. N. Lapach, A.V. Chubenko, P.N. Babich - K .: Morion, 2000. - 320 p.

7. Mashkovskiy,  M. D.  Medicines / M. D.  Mashkovskiy. - [15th ed., Rev., Corr. and add.]. - M .: RIA "Novaya Volna", 2008. - 1206 p.

8. Natochin, V. Clinical and molecular physiology of osmoregulation renal function (the 200th anniversary of the birth F.G.YA. Henle) / Y. Natochin // Clinical Nephrology. - 2009. - № 4. - S. 25-31.

9. Alexandrov, K. V. Synthesis of i-junction of two physical hіmіchnі vlastivostі vodorozchinnih pohіdnih 3 benzilksantinu / K. V. Aleksandrov, S. V.  Levіch, O. S.  Skoda, D. M. Yurchenko // Current issues of pharmaceutical and medical science and practice - (2015), №1 (17) c. 60-65.

10. Pruglo, Ye. S.  Diuretic activity of 3- (5-bromfuran-2-yl) -4-R- (4H) -1,2,4-triazoles-5-thiones, their derivatives and S-2- (5-bromfuran-2- yl) -5-Rґ-thiazolo [3,2-b] [1,2,4] triazoles-6 (5H) -ones / Ye. S. Pruglo, A. S. Gotsulya, O. I. Panasenko, Ye. G. Knysh.  // Topical issues of pharmaceutical and medical science and practice. - 2015. - № 3 (19). - S. 9-13.

11. Ivanchenko, D. G. Synthesis, physicochemical and biological properties of 1,8-disubstituted theobromine. IV. 8 thioderivatives-R-1-n-metylbenzylteobrominu / D. G. Ivanchenko // Topical issues of pharmaceutical and medical science and practice. - 2015. - № 3 (19). - P. 4-8.

12. Lysyuk, R. M.  Analysis of the range and modern herbal medicines for the treatment of urinary tract / R. M.  Lysyuk,  R. Darmohray, N. I. Gudz, T. Kalyniuk // Technology of medicines and organization of pharmaceutical business. - Coll. Science. works co. NMAPE named P. L. Shupyk - 24 (4) / 2015 c. 264-269.

13. Thomas, D.  Complement receptor 3 mediates renal protection in experimental C3 glomerulopathy  / Thomas D. Barbour , Guang Sheng Ling, Marieta M. Ruseva  at all //  Kidney International (2016) р. 1-9.

14. Wayne, Lam.  Is Routine Postoperative Diuresis Renography Indicated in All Adult Patients After Pyeloplasty for Ureteropelvic Junction Obstruction  /  Wayne Lam, Archana Fernando, Rami Issa  at all. //  Urology, Volume 85, Issue 1, January 2015, Pages 246-251.

15. Caffeine and diuresis during rest and exercise: A meta-analysis. / Yang Zhang , Aitor Coca , Douglas J. Casa at all. //  Journal of Science and Medicine in Sport - Volume 18, Issue 5, September 2015, Pages 569–574.

16. Sunal Makadia, MD. The Diuresis Clinic: A New Paradigm for the Treatment of Mild Decompensated Heart Failure / Sunal Makadia, MD,,Tanya Simmons, RN, BSN, CHFN, Sharon Augustine, CRNP at all. //  The American Journal of Medicine - Volume 128, Issue 5, May 2015, Pages 527–531.

17. Kushal, Kumar. Terminalia arjuna bark extract improves diuresis and attenuates acute hypobaric hypoxia induced cerebral vascular leakage / Kushal Kumar, Sarika Sharma, Vivek Vashishtha at all. // Journal of Ethnopharmacology - Volume 180, 2 March 2016, Pages 43–53.

18. Chen,  Y .  Basic research ASSA14-03-08 Gastrin and D1 Dopamine Receptor Interact to Induce Natriuresis and Diuresis / Y Chen, LD Asico, S Zheng, at all. // Heart 2015;101:A11 doi:10.1136/heartjnl-2014-307109.27.

19. Boscolo, P.  Renal toxicity and arterial hypertension in rats chronically exposed to vanadate /  Paolo Boscolo, Marco Carmignani, Anna Rita Volpe, at all. // Heart 2015;101:A11 doi:10.1136/heartjnl-2014-307109.27.

20. Incidence of acute kidney injury in critically burned patients resuscitated with crystalloid and colloid according to parameters of transpulmonary thermodilution, diuresis and lactic acid / P Extremera Navas, M Sanchez Sanchez, I Pozuelo Echegaray, at all. //  Crit Care. 2015; 19(Suppl 1): P358.

21. Alexander, JJ.  CD11b is protective in complement-mediated immune complex glomerulonephritis.  / Alexander JJ, Chaves LD, Chang A, et all. // Kidney Int. 2015;87:930–939.

22. Wang, T.D. 9c.04: Treatment with lcz696 compared to at1-receptor blockade is associated with non-sustained increases of natriuresis and diuresis in asian patients with salt-sensitive hypertension / Wang, T.D.; Tan, R.S.; Lee, H.; Ihm, S.H. at all. // Journal of Hypertension: June 2015, - Volume 33 - Issue, doi: 10.1097/01.hjh.0000467685.39554.d4.

23. Robert A. Fenton. Caffeine-induced diuresis and natriuresis is independent of renal tubular NHE3 / Robert A. Fenton, Søren B. Poulsen, Samantha de la Mora Chavez at all. //  American Journal of Physiology - Renal Physiology Published 15 June 2015 Vol. 308 no. 12, F1409-F1420 DOI: 10.1152/ajprenal.00129.2015.

 24. Sufei Yang. Enhanced Natriuresis and Diuresis in Wistar Rats Caused by the Costimulation of Renal Dopamine D3 and Angiotensin II Type 2 Receptors / Sufei Yang, Yu Han, Shuo Zheng at all. //  American Jnl of Hypertensionpublished online March 13, 2015.

25. Shailesh Bihari. Addition of indapamide to frusemide increases natriuresis and creatinine clearance, but not diuresis, in fluid overloaded ICU patients / Sufei Yang,  Andrew W. Holt , Shivesh Prakash  at all. // Journal of Critical Care Available online 27 January 2016.