Home About us Current issue Back issues Submission Instructions Advertise Contact Login   

Search Article 
  
Advanced search 
 
Saudi Journal of Kidney Diseases and Transplantation
Users online: 1939 Home Bookmark this page Print this page Email this page Small font sizeDefault font size Increase font size 
 


 
Table of Contents   
ORIGINAL ARTICLE  
Year : 2014  |  Volume : 25  |  Issue : 2  |  Page : 333-337
The protective effect of theophyline in cisplatin nephrotoxicity


1 Chronic Renal Failure Research Center, Department of Internal Medicine, Faculty of Medicine, Jundishapur University of Medical Sciences, Ahvaz, Iran
2 Diabetes Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Khuzestan, Iran
3 Department of Pediatric, Faculty of Medicine, Jundishapur University of Medical Sciences, Ahvaz, Iran
4 Islamic Azad University, Omidiyeh, Khuzestan, Iran

Click here for correspondence address and email

Date of Web Publication11-Mar-2014
 

   Abstract 

Cisplatin is a potent and a major anti-neoplastic drug in the treatment of a broad spectrum of malignancies. However, its clinical use is limited by renal tubular dysfunction that occurs in a significant percent of patients. The aim of the present study was to evaluate the possible protective effect of theophyline in the prevention of cisplatin-induced nephrotoxicity. The trial design was prospective, randomized, double-blinded and placebo controlled. Chemotherapeutic patients who received cisplatin at a dosage of at least 50 mg/m 2 alone or in combination with other chemotherapy agent(s) were included in the study. There were a total of 76 patients who were randomly divided into two groups. In group 1 (n = 38), placebo was advised; in group 2 (n = 38), patients received 4 mg/kg aminophyline as an intravenous loading dose, followed by theophyline in a dose of 200 mg three times daily orally for four consecutive days. The placebo group had 22 males and 16 females and the theophyline group had 26 males and 12 females. The mean age was 51 ± 17.6 years and the mean dose of cisplatin was 86.71 ± 43.18 mg. The prevalence of cisplatin nephrotoxicity in groups 1 and 2 was 7.9 and 5.3%, respectively, and the difference was not significant (P = 1). In addition, there was no significant association of cisplatin nephrotoxicity with age (P = 0.1), gender (P = 0.64) and mean dose of cisplatin (P = 0.8). These results indicate that prophy-lactic application of aminophyline and theophyline does not have a protective effect against cisplatin nephrotoxicity.

How to cite this article:
Mousavi SS, Zadeh MH, Shahbazian H, Khanzadeh A, Hayati F, Ghorbani A, Golzari K, Valavi E, Motemednia F, Mousavi MB. The protective effect of theophyline in cisplatin nephrotoxicity. Saudi J Kidney Dis Transpl 2014;25:333-7

How to cite this URL:
Mousavi SS, Zadeh MH, Shahbazian H, Khanzadeh A, Hayati F, Ghorbani A, Golzari K, Valavi E, Motemednia F, Mousavi MB. The protective effect of theophyline in cisplatin nephrotoxicity. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2019 Aug 23];25:333-7. Available from: http://www.sjkdt.org/text.asp?2014/25/2/333/128528

   Introduction Top


Cisplatin is a major anti-neoplastic drug and a valuable chemotherapy agent that is used in the treatment of a broad spectrum of malignancies. [1],[2],[3] Cisplatin is eliminated predominantly by the kidneys and acute renal failure (ARF), occurring in more than 50% of the cases, is one of the most important side-effects of the drug and is also associated with major in-hospital morbidity and mortality. [4],[5],[6] In addition to ARF, other clinical manifestations of cisplatin-induced nephrotoxicity, including thrombotic microangiopathy, a Fanconi-like syndrome and Hypomagnesemia, have also been described in a significant percentage of these patients. [7],[8],[9],[10]

Different strategies and a number of pharmacologic agents such as N-acetylcysteine and Glycine have been evaluated to prevent and/or to diminish cisplatin nephrotoxicity in experimental models. However, unfortunately, none of them has an established beneficial role. [11],[12] The use of theophylline was suggested by a study in rats in which this drug prevented cisplatin-induced nephrotoxicity. [13] The aim of the present study was to evaluate the possible protective effect of theophyline in the prevention of cisplatin-induced nephrotoxicity.


   Materials and Methods Top


The present study is a cross-sectional, prospective, randomized, double-blinded and placebo-controlled study performed on patients receiving chemotherapy in Shafa Hospital, Ahvaz city, Iran during the period from June to October 2010. The study was approved by the ethics committee of the Chronic Renal Failure Research Center of Ahvaz Jundishapur University of Medical Sciences.

A standardized questionnaire was used to collect general information such as age, gender, vital signs, the record of previous diseases and drugs taken, kind of cancers, dose of prescribed cisplatin and the results of laboratary data including blood urea nitrogen (BUN) and serum creatinine levels (SCr). We explained the study program to the chemotherapy patients and all participants provided written informed consent.

Chemotherapy patients who received cisplatin at a dosage of at least 50 mg/m 2 alone or combined with other chemotherapy agent(s) were included in the study.

We randomly divided our patients in two groups. In group 1 (n = 38), placebo was advised; the placebo was prepared by using lactose material in the Chemistry Department of Ahvaz Jundishapur University of Medical Sciences. In group 2 (n = 38), patients received 4 mg/kg aminophyline as an intravenous loading dose within 30 min before and 0.4 mg/kg intravenously for 6 h after cisplatin administration. Subsequently, they received tablets of theophyline at a dose of 200 mg three times daily orally for four conse-cutive days.

In both groups, 2-3 h before the cisplatin administration, the patients received at least 1000 mL of isotonic saline plus 20 mEq of KC1 and 2 g of MgSC>4/L and then after the administration of chemotherapy, they also received a minimum of 500 mL of the mentioned solution over 2 h. The rate of solution administration in our study was to the extent that could provide a urinary flow rate of at least 100 mL/h for 2 h prior and after cisplatin administration.

A day before and then five consecutive days after chemotherapy, we checked the blood sample of patients for BUN and SCr by using commercial kits. Cisplatin nephrotoxicity was defined as an increase in the SCr concentration equal to or more than 0.5 mg/L after cisplatin administration in comparison with the day before starting chemotherapy.

Exclusion criteria in our study included the patients who did not follow the study program, those who had used cisplatin at a dose of less than 50 mg/m 2 , patients who had received any type of non-steroidal anti-inflammatory drugs, aminoglycosides, radiocontrast agents or angiotensin-converting enzyme inhibitors in the recent 2 weeks or during the period of the study, patients with SCr more than 1.4 mg/dL (in men) and 1.2 mg/dL (in women) and/or serum potassium more than 5.5 mEq/L the day before chemotherapy administration, those who did not have stable vital signs before or during the period of study, for example blood pressure less than 90/60 mm Hg and/or pulse rate more than 100/min and patients who could not receive isotonic saline due to heart failure.


   Statistical Analysis Top


For data analysis, we were used the statistical package for social sciences (SPSS) version 15. Comparison of mean between two groups was performed by using the t test and statistical significance was considered at the P <0.05 level in all analyses.


   Results Top


In the period of the study, there were 87 patients for chemotherapy with cisplatin in our center. From them, 11 patients were excluded as per the exclusion criteria; therefore, 76 patients with a mean age of 51 ± 17.6 years were enrolled in the study. They were randomized to two groups; the placebo group (group 1) consisted of 38 patients - 22 males and 16 females and the theophyline group (group 2) also consisted of 38 patients - 26 males and 12 females. Overall, the mean age of our patients in groups 1 and 2 was 51 ± 18.7 and 50 ± 19.5 years, respectively, and there was no significant difference between the groups (P = 0.52).

The mean dose of cisplatin administration in the placebo and theophylin groups was 85.91 ± 44.48 and 87.11 ± 4 2.28, respectively, and there was no statistical difference between them (P = 0.57). Majority of the patients in both the groups (71% in the placebo group and 76.2% in the theophyline group) received 50-99 mg of cisplatin. The mean courses of cisplatin administration were 3.43 courses with a standard deviation of 3.31, and the majority of patients in both the groups (84.3% in the placebo group and the 73.8% in theophyline group) received one to four courses. The most common kind of malignancy in both the groups of patients was gastric cancer; in the placebo group, it was in 55.3% of the patients and in the theophyline group, it was in 65.8% of the patients.

Cisplatin nephrotoxicity occurred in three patients (7.9%) among the placebo group and in two patients (5.3%) among the theophyline group, and there was no significant difference between them (P = 1). There also were no significant association between cisplatin nephrotoxicity and different age (P = 0.1), males and females (P = 0.64), mean dose of cisplatin (P = 0.8) and mean previous courses of chemotherapy with cisplatin in patients with or without nephrotoxicity (P = 0.5).


   Discussion Top


Cisplatin has a well-established role in the treatment of many patients with solid cancers; however, its use is limited because of its toxicity to various organs including renal toxicity, gastrointestinal toxicity and ototoxicity. [14],[15] Nephrotoxicity, which evolves slowly and predictably after initial and repeated exposure, continues to raise major concerns and may result in transient or persistent renal failure. [16],[17]

Although the exact mechanisms contributing to renal dysfunction following exposure to cisplatin have not been fully elucidated, it appears that tubular epithelial cell toxicity, vasoconstriction in the renal microvasculature and pro-inflammatory effects contribute to cisplatin-induced nephrotoxicity.

There is only very little clear information available about the risk factors for cisplatin nephrotoxicity. However, those factors that appear to be most important include higher doses of cisplatin that result in high peak plasma-free platinum concentrations, previous exposure to cisplatin, concurrent treatment with other potential nephrotoxins, pre-existing kidney damage and inter-individual differences in cisplatin pharmacokinetics. [23],[24],[25],[26]

Although the standard approach for the prevention of cisplatin-induced nephrotoxicity is the administration of lower doses of cisplatin in combination with intensive intravenous isotonic saline with the resultant dieresis, a number of pharmacologic agents including theophyline, a known non-selective adenosine receptor antagonist, have also been proposed to prevent and/or decrease nephrotoxicity. [27]

It has been proposed that vasoconstriction in the renal microvasculature is mediated by the adenosine Ai receptor and appears to contribute to decreased renal blood flow after cisplatin injection; therefore, it can be blocked by theophylline. [28],[29]

In the present study, we evaluated the possible protective effect of theophyline in the prevention of cisplatin-induced nephrotoxicity, and our results indicate that it does not have a protective effect. However, a few studies have reported that cisplatin-induced nephrotoxicity was minimized by the use of theophylline and/or aminophylline. [30],[31]

Heidemann et al in a study in rats have demonstrated that when aminophylline was administered during the maintenance phase of acute tubular necrosis, it minimized nephrotoxicity. However, when the drug was administered only before the cisplatin administration, it did not have a protective effect. [28]

The use of theophylline for the prevention of cisplatin-induced nephrotoxicity has also been suggested by Benoehr et al in a clinical trial in which 41 patients were randomly assigned to receive theophylline or placebo in conjunction with chemotherapy that included one dose of cisplatin at a dosage of 50 mg/m. [29] In this trial, they used theophylline, similar to our method in the present study, but in contrast to our study, renal function of each patient was assessed and compared by renal clearance of inulin, which is more sensitive and specific than our method, before and at Day 5 after cisplatin administration. Chemotherapy patients treated with theophylline in the study of Benoehr et al had no change in GFR measured by the renal clearance of inulin, while a significant decrease (21%) was observed in those receiving placebo. [29]

Today, the standard approach for prevention of nephrotoxicity is the administration of lower doses of cisplatin in combination with intensive hydration with isotonic saline. Although it has been proposed that theophyline, a known non-selective adenosine receptor antagonist, has a protective effect against cisplatin-induced nephrotoxicity, in our study, prophylactic use of aminophyline and theophyline compared with placebo did not decrease the prevalence of cisplatin-induced nephrotoxicity.


   Acknowledgments Top


This paper is issued from the thesis of Dr. Abdullah Khanzadeh no. U-88176 and financial support was provided by the Research Division of Ahvaz Joundishapur University of Medical Sciences. The authors would like to express their appreciation to the division head, the staff and of course to the chemotherapy patients in Shefa Hospital in the province of Khuzestan, Ahvaz, Iran, for their help.

 
   References Top

1.Muggia FM, Braly PS, Brady MF, et al. Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: A Gynecologic Oncology Group study. I Clin Oncol 2000;18:106-15.  Back to cited text no. 1
    
2.Reck M, von Pawel J, Zatloukal P, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAiL. I Clin Oncol 2009;27:1227-34.  Back to cited text no. 2
    
3.DeVita VT, Lawrence TS, Rosenberg SA. Principles & Practice of Oncology, 9 th ed. Wolters Kluwer/Lippincott Williams, Philadelphia, Pa, USA: 2011:2113-2122  Back to cited text no. 3
    
4.Filipski KK, Loops WJ, Verweij J, Sparreboom A. Interaction of cisplatin with the human organic cation transporter 2. Clin Pharmacol Ther 2008;14:3875-80.  Back to cited text no. 4
    
5.Yokoo S, Yonezawa A, Masuda S, Fukatsu A, Katsura T, Inui K. Differential contribution of organic cation transporters, OCT2 and MATE1, in platinum agent-induced nephrotoxicity. Biochem Pharmacol 2007;74:477.  Back to cited text no. 5
    
6.Luke DR, Vadiei K, Lopez-Berestein G. Role of vascular congestion in cisplatin-induced acute renal failure in the rat. Nephrol Dial Transplant 1992;7:1-7.  Back to cited text no. 6
    
7.lackson AM, Rose BD, Graff LG, et al. Thrombotic microangiopathy and renal failure associated with antineoplastic chemotherapy. Ann Intern Med 1984;101:41-4.  Back to cited text no. 7
    
8.Sutton RA, Walker VR, Halabe A, Swenerton K, Coppin CM. Chronic hypomagnesemia caused by cisplatin: Effect of calcitriol. I Lab Clin Med 1991;117:40-3.  Back to cited text no. 8
    
9.Cao L, Joshi P, Sumoza D. Renal salt-wasting syndrome in a patient with cisplatin-induced hyponatremia: Case report. Am J Clin Oncol 2002;25:344-6.  Back to cited text no. 9
    
10.10. Oeffinger KC, Hudson MM. Long-term complications following childhood and adolescent cancer: Foundations for providing risk-based health care for survivors. CA Cancer J Clin 2004; 54:208-36.  Back to cited text no. 10
    
11.Wu YJ, Muldoon LL, Neuwelt EA. The chemoprotective agent N-acetylcysteine blocks cisplatin-induced apoptosis through caspase signaling pathway. J Pharmacol Exp Ther 2005;312:424-31.  Back to cited text no. 11
    
12.Heyman SN, Spokes K, Egorin MJ, Epstein FH. Glycine reduces early renal parenchymal uptake of cisplatin. Kidney Int 1993;43:1226-8.  Back to cited text no. 12
    
13.Benoehr P, Krueth P, Bokemeyer C, Grenz A, Osswald H, Hartmann JT. Nephroprotection by theophylline in patients with Cisplatin chemotherapy: A randomized, single-blinded, placebo-controlled trial. J Am Soc Nephrol 2005; 16: 452-8.  Back to cited text no. 13
    
14.Hartmann JT, Lipp HP. Toxicity of platinum compounds. Expert Opin Pharmacother 2003; 4:889-901.  Back to cited text no. 14
    
15.Hartmann JT, Fels LM, Franzke A, et al. Comparative study of the acute nephrotoxicity from standard dose cisplatin/ifosfamide and high-dose chemotherapy with carboplatin and ifosfamide. Anticancer Res 2000;20:3767-73.  Back to cited text no. 15
    
16.Lipp HP, Bokemeyer C, Hartmann JT, Stanley A. Cytostatic drugs. In: Side Effects of Drugs Annual 26, Aronson JK, ed. Oxford: Elsevier; 2003. p. 490-511.  Back to cited text no. 16
    
17.Hartmann JT, Kollmannsberger C, Kanz L, Bokemeyer C. Platinum organ toxicity and possible prevention in patients with testicular cancer. Int J Cancer 1999;83:866-9.  Back to cited text no. 17
    
18.Yokoo S, Yonezawa A, Masuda S, Fukatsu A, Katsura T, Inui K. Differential contribution of organic cation transporters, OCT2 and MATE1, in platinum agent-induced nephrotoxicity. Biochem Pharmacol 2007;74:477-87.  Back to cited text no. 18
    
19.Choi MK, Song IS. Organic cation transporters and their pharmacokinetic and pharmacodynamic consequences. Drug Metab Pharmacokinet 2008;23:243-53.  Back to cited text no. 19
    
20.Luke DR, Vadiei K, Lopez-Berestein G. Role of vascular congestion in cisplatin-induced acute renal failure in the rat. Nephrol Dial Transplant 1992;7:1-7.  Back to cited text no. 20
    
21.Ramesh G, Reeves WB. TNF-alpha mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity. J Clin Invest 2002;110:835-42.  Back to cited text no. 21
    
22.Ramesh G, Reeves WB. MAP kinase inhibition ameliorates cisplatin nephrotoxicity in mice. Am J Physiol Renal Physiol 2005;289: F166-74.  Back to cited text no. 22
    
23.Hartmann JT, Kollmannsberger C, Kanz L, Bokemeyer C. Platinum organ toxicity and possible prevention in patients with testicular cancer. Int J Cancer 1999;83:866-9.  Back to cited text no. 23
    
24.Siegert W, Beyer J, Strohscheer I, et al. High-dose treatment with carboplatin, etoposide, and ifosfamide followed by autologous stem-cell transplantation in relapsed or refractory germ cell cancer: A phase I/II study. The German Testicular Cancer Cooperative Study Group. J Clin Oncol 1994;12:1223-31.  Back to cited text no. 24
    
25.Kemp G, Rose P, Lurain J, et al. Amifostine pretreatment for protection against cyclophosphamide-induced and cisplatin-induced toxicities: Results of a randomized control trial in patients with advanced ovarian cancer. J Clin Oncol 1996;14:2101-12.  Back to cited text no. 25
    
26.De Jongh FE, van Veen RN, Veltman SJ, et al. Weekly high-dose cisplatin is a feasible treatment option: Analysis on prognostic factors for toxicity in 400 patients. Br J Cancer 2003;88:1199-206.  Back to cited text no. 26
    
27.Didier Portilla, Mazin Safar, Melissa Shanon , Richard Penson, Paul Palevsky, Alice Sheridan. Cisplatin nephrotoxicity. UP to date version 18.2.  Back to cited text no. 27
    
28.Osswald H, Vallon V. Tubuloglomerular feedback and its role in acute renal failure. In: Ronco C, Bellomo R, eds. Critical Care Nephrology. Kluwer Academic Publishers, Dordrecht; The Netherlands 1998:613-22.  Back to cited text no. 28
    
29.Benoehr P, Krueth P, Bokemeyer C, Grenz A, Osswald H, Hartmann JT. Nephroprotection by theophylline in patients with Cisplatin chemotherapy: A randomized, single-blinded, placebo-controlled trial. J Am Soc Nephrol 2005;16:452-8.  Back to cited text no. 29
    
30.Osswald H. Renal effects of adenosine and their inhibition by theophylline in dogs. Naunyn Schmiedebergs Arch Pharmacol 1975;288:79-86.  Back to cited text no. 30
[PUBMED]    
31.Heidemann HT, Muller S, Mertins L, Stepan G, Hoffmann K, Ohnhaus EE. Effect of aminophylline on cisplatin nephrotoxicity in the rat. Br J Pharmacol 1989;97:313-8.  Back to cited text no. 31
    

Top
Correspondence Address:
Marzieh Beladi Mousavi
Department of chemistry, Islamic Azad University, Omidiyeh branch, Omidiyeh
Iran
Login to access the Email id


DOI: 10.4103/1319-2442.128528

PMID: 24626000

Rights and Permissions




 

Top
   
 
 
    Similar in PUBMED
    Search Pubmed for
    Search in Google Scholar for
    Email Alert *
    Add to My List *
* Registration required (free)  
 


 
    Abstract
   Introduction
    Materials and Me...
   Statistical Analysis
   Results
   Discussion
   Acknowledgments
    References
 

 Article Access Statistics
    Viewed2168    
    Printed25    
    Emailed0    
    PDF Downloaded472    
    Comments [Add]    

Recommend this journal