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ISSN 0976-111X

INTERNATIONAL JOURNAL OF PHARMA WORLD RESEARCH (An International Quarterly Published Online Research Journal)

www.ijpwr.com Title: Effect of ciprofloxacin on liver function enzymes in pulmonary tuberculosis

Kamlesh Kumar Swami*, P. R.Choudhary** *Asso.Prof.Department of Biochemistry, C.U.Shah Medical College, Surendranagr(Gujarat). **Astt.Prof. Department of Physiology, C.U.Shah Medical College, Surendranagr (Gujarat).

E-mail:[email protected]

Corresponding author:Dr. Kamlesh Kumar Swami Associate Professor Department of Biochemistry, C.U.Shah Medical College, Surendranagr, Gujarat, India

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ABSTRACT

Background: Ciprofloxacin is a second line antitubercular drug. It has invitro and in vivo antitubercular activity. Hepatotoxicity is a common adverse effect of antitubercular drugs that often present difficulty in management of treatment. Objective: To find out the effect of ciprofloxacin therapy on liver function enzymes Methods: The subjects were divided into four groups-Group I, patients receiving isoniazid, ethambutol (HE) (n=15); Group II, patients receiving isoniazid, ethambutol, rimfampin (HER) (n=15); Group III, patients receiving isoniazid, ethambutol, rimfampin and pyrazinamide (HERZ) (n=15); Group IV, (n=45) patients receiving ciprofloxacin with other antitubercular drugs (HE + Ciprofloxacin, HER + Ciprofloxacin, HERZ + Ciprofloxacin). The alanine tranasaminase (ALT), aspartate transaminase (AST) and lactate dehydrogenase (LDH) was estimated in serum. Results: In the present study, in patients receiving isoniazid, ethambutol (HE), serum alanine transaminase levels were 37±7, 54±3 and 66±5 units/ml on day 1, 15 and 30 respectively, whereas in other group receiving isoniazid, ethambutol and ciprofloxacin the levels were 36±16, 41±15 and 44±19 units/ml on corresponding days. Both on day 15 and 30 serum Alanine Transaminase levels were significantly lower in test group. Ciprofloxacin addition to the patients receiving isoniazid, ethambutol, rimfampin (HER) and isoniazid, ethambutol, rimfampin and pyrazinamide (HERZ) fluctuating trend were observed.

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Conclusion: It is concluded that ciprofloxacin may initially causes a non significant mild upset of the liver but the latter quickly adapts to itself therefore it may be used safely as second line antitubercular drug.

Key Words- Alanine transaminase, Aspartate transaminase, Ciprofloxacin, Lactate

dehydrogenase, Pulmonary tuberculosis,. INTRODUCTION Tuberculosis is a specific communicable disease caused by Mycobacterium Tuberculosis. It affects both pulmonary and extra-pulmonary tissues. Pulmonary tuberculosis remains one of the leading causes of morbidity and mortality worldwide. It is estimated that 1.7 million people died of tuberculosis in 2009. There were an estimated 9.4 million new cases of tuberculosis in 2009 of which the majority were in Asia and Africa. It is thought that the rates of new tuberculosis infections and deaths per capita have probably been falling globally for several years now. However, the total number of new tuberculosis cases is still slowly rising due to population growth1. There is mountain of evidence concerning use of combination chemotherapy in early cure of disease consequently adverse effects of individual drug may be enhanced or additive effects of individual drug may appear upon use of more than one drug. Second line antitubercular drugs are used when a primary chemotherapy fails due to any reason; reserve drugs are required to treat such patients2. Ciprofloxacin is a second line antitubercular drug. Chemically it is a fluorinated-4-quinolone bactericidal agent with a broad spectrum of activity. It has in vitro and in vivo antitubercular activity. It has been tried along with other second line drugs for multiresistent tuberculosis and for disease caused by mycobacterium avium complex in AIDS patients2,3,4.

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Hepatotoxicity is a common adverse effect of antitubercular drugs that often present difficulty in management of treatment. A reversible moderate increase in transaminases levels occurs about 15 to 30% of patients treated with first line antitubercular drugs5.A slight increase in the levels of transaminases should not lead to discontinuation of treatment, with a consequent increased risk of developing drug resistance of mycobacterial strain. However it is difficult to predict weather minor abnormalities of liver function conceal the initial stage of a severe hepatotoxic reaction. The standard procedure is to discontinue all antitubercular drugs if a patient develops a substantial increase in transaminases or clinical signs of liver damage6,7,8. In the present study we decided to assess the effect of ciprofloxacin on liver in patients receiving different anti-tubercular drug combinations. MATERIAL AND METHODS 90 patients (indoor and outpatient clinic of either sex) aged 10 to 80 years, suffering from pulmonary tuberculosis, were taken from T.B. and Chest hospital, attached to J.L.N.Medical College, Ajmer. All the patients were examined clinically and investigated. Sputum examination for acid fast bacilli and chest ski gram were carried out. The blood samples were collected on 1st, 15th and 30th days during the treatment and alanine tranasaminase (ALT), aspartate transaminase (AST) and lactate dehydrogenase (LDH) were estimated in serum. Results were compared with serum levels of ALT, AST and LDH of patients receiving ciprofloxacin group and non ciprofloxacin group. The subjects were divided into four groupsNON CIPROFLOXACIN GROUP Group I, patients receiving isoniazid, ethambutol (HE) (n=15); Group II, patients receiving isoniazid, ethambutol, rimfampin (HER) (n=15),

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Group III,patients receiving isoniazid, ethambutol, rimfampin and pyrazinamide (HERZ) (n=15) CIPROFLOXACIN GROUP Group IV, (n=45) patients receiving ciprofloxacin with other antitubercular drugs (HE + Ciprofloxacin, HER + Ciprofloxacin, HERZ + Ciprofloxacin). The alanine tranasaminase (ALT) and aspartate transaminase (AST) assay was performed in serum by method of Reitman and Frankel (1957) and LDH estimation was based on the method of Cabaud et al (1958). The results were compared with group IV and analyzed statistically by student t-test. RESULTS Ciprofloxacin is a fluorinated quinolone antibiotic with relatively low occurrence of adverse side effects. In the present study we observed a fluctuation in the serum level of AST, it was significantly higher on 1st and 30th day, in ciprofloxacin group as compared to the serum levels of AST in patients treated with antitubercular drugs. No significant rise was found on 15th day. On comparison ALT levels was found to be higher on 1st day as compared to the 15th and 30th day in ciprofloxacin group whereas the levels of LDH were significantly higher in ciprofloxacin group on 1st and 15th day but 30th day, values tend to return to the levels found in the other group of patients. Serum levels of AST were significantly higher on 1st, 15th and 30th day in Group-IV as compared to the Group-I, but the levels were higher on 1st and 15th day, no significant alteration was noticed on 30th day when Group-IV was compared to the Group-II, whereas

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AST levels were significantly higher on 1st and 30th day in Group-IV as compared to GroupIII. Serum levels of ALT were significantly higher on 15th and 30th day in patients treated with HE along with ciprofloxacin but no significant difference was observed on 1st day as compared to the ALT levels of patients treated with HE, whereas ALT levels were significantly raised on 1st and 15th day in HER + Ciprofloxacin treated patients as compared to the patients treated with only HER but no significant alteration was found on 30th day. Similar results were also observed in ALT levels on comparison of HERZ with HERZ + Ciprofloxacin treated patients. Serum levels of LDH in patients treated with HE along with ciprofloxacin were significantly higher on 1st and 15th day as compared to the serum levels of those patients who were receiving only HE, but no significant increase was observed on 30th day. There was no significant changes were found on 1st, 15th , 30th day in patients treated with HER and HER+ ciprofloxacin. Only a significant rise was observed on 1st day in HERZ + Ciprofloxacin receiving group as compared to HERZ receiving group. In patients receiving isoniazid, ethambutol (HE), serum Alanine Transaminase levels were 37±7, 54±3 and 66±5 units/ml on day 1st, 15th and 30th respectively, whereas in other group receiving isoniazid, ethambutol and ciprofloxacin the levels were 36±16, 41±15 and 44±19 units/ml on corresponding days. Both on day 15th and 30th serum Alanine Transaminase levels were significantly lower in test group. On the other hand, Lactate dehydrogenase levels were raised on day 1st and 15th but returned to normal on day 30th. Similarly ciprofloxacin addition to the patients receiving isoniazid, ethambutol, rimfampin (HER) and isoniazid, ethambutol, rimfampin and pyrazinamide (HERZ) fluctuating trend were observed.

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DISCUSSION Standard anti-tuberculosis treatment with conventional regimens is still the mainstream therapeutic treatment. Unfortunately, if drug related adverse effects or drug resistance occurs, various second-line drugs make it difficult to choose which one is the optimal. Ciprofloxacin is a broad spectrum antibacterial agent used as second line antitubercular drug when a patient's primary chemotherapy fails due to any reason. Drug-induced hepatitis is an important issue in tuberculosis treatment. N.P. Thompson (1995) reported that antituberculosis chemotherapy is associated with abnormalities in liver function tests in 10­25% of patients and suggested a protocol for the practical management of this important clinical problem.9 Mohanty (1993) reported that ciprofloxacin was well tolerated during the period of treatment of pulmonary tuberculosis4. Ciprofloxacin provides a better option for second-line drug treatment for pulmonary tuberculosis when patients cannot use conventional antituberculosis agents.10 Dodding and Wileke (1996) measured the concentration of various enzymes during antituberculosis treatment and reported an increase in AST of more than twice the upper limit of normal. 5 During treatment of latent tuberculosis infection, alanine transaminase (ALT) monitoring is recommended for those who chronically consume alcohol, take concomitant hepatotoxic drugs, have viral hepatitis or other preexisting liver disease or abnormal baseline ALT. Treatment should be interrupted and, generally, a modified or alternative regimen used for those with ALT elevation more than three times the upper limit of normal in the presence of hepatitis symptoms and/or jaundice, or five times the upper limit of normal in the absence of symptoms. 11 An increase in serum ALT, is more specific for hepatocellular injury than an increase in aspartate transaminase (AST), which can also signify abnormalities in muscle, heart, or kidney 12, 13. Exposure to certain drugs may evoke

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physiologic adaptive responses18. The induction of survival genes, including those that regulate antioxidant, anti-inflammatory, and anti-apoptotic pathways, may attenuate toxin-related injurious responses. Such injury may also stimulate hepatocyte proliferation and protective adaptation. Asymptomatic, transient elevations of ALT may reflect slight, non progressive injury to hepatocyte mitochondria, cell membranes, or other structures. Such injury rarely leads to inflammation, cell death, or significant histopathologic changes.15, 16,17,18 The findings of the present study suggests that primarily ciprofloxacin, increases the levels of ALT,AST and LDH just after administration causes an hepatic dysfunctioning which could not be due to liver injury, but could be attributed to an adaptation to the drug. CONCLUSION The overall trend indicates that though ciprofloxacin may initially causes a non significant mild upset of the liver but the latter quickly adapts to itself therefore it is concluded that the use of ciprofloxacin as a better option of second-line drug to treat pulmonary tuberculosis when patients cannot use conventional anti-tuberculosis agents. REFERENCES 1. WHO Global tuberculosis report 2010. WHO 2010. 2. Richard J. O'Brien and Paul P. Nunn. Ciprofloxacin is not a component of first-line TB. Chest. October. 1994; 106(4):1312. 3. British thorasic association: a controlled trial of six months chemotherapy in pulmonary tuberculosis. Br.J.Dis.Chest.1981; 75:141-153. 4. Mohanty, K.C and Dhamgaye, T.M. Controlled trial of ciprofloxacin in short-term chemotherapy for pulmonary tuberculosis. Chest.1993; 104: 1194-1198.

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5. Dossing M, Wilckle J.T.R, Askgarad DS. Liver injury during antituberculosis treatment. Tuber. Lung.Dis.1996; 77: 335-340. 6. Smith J, Tyrell WF, Gow A, Allan GW, Lees AW. Hepatotoxicity in rifampinisoniazid treated patients related to their rate of isoniazid inactivation. Chest.1972; 61(6):587-588. 7. Gonzalez ML, Dambrosi. Adverse effects of antitubercular drug causing changes in treatment. Tubercle.1982; 63: 291-294. 8. Baghaei, Parvaneh, Tabarsi, Payam; Chitsaz, Ehsan; Saleh, Masoumeh. Incidence, clinical and epidemiological risk factors, and outcome of drug-induced hepatitis due to antituberculous agents in new tuberculosis cases. American Journal of Therapeutics.2010; 17 (1): 17-22. 9. Thompson, N.P. Caplin, M.E. Hamilton, M.I. Anti-tuberculosis medication and the liver dangers and recommendations in management. Eur. Respir. J.1995; 8: 1384­ 1388. 10. Chao-Kai Yang, Horng-Chyuan Lin, Kang-Yun Lee. The effects of ciprofloxacin on chest radiographic regression in patients with drug intolerance or resistant tuberculosis. Chang Gung Med J. 2004; 27: 292-299. 11. Jussi J. Saukkonen, David L. Cohn, Robert M. Jasmer. An official ATS statement: hepatotoxicity of antituberculosis therapy. American Journal of Respiratory and Critical Care Medicine. 2006; 174: 935-952, 12. Kaplowitz N. Biochemical and cellular mechanisms of toxic liver injury. Semin Liver Dis. 2002; 22: 137­144.

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13. Dufour DR, Lott JA, Nolte FS, Gretch DR, Koff RS, Seeff LB. Diagnosis and monitoring of hepatic injury. I. Performance characteristics of laboratory tests. Clin Chem. 2000; 46: 2027­2049. 14. Sukhesb Rao. Ciprofloxacin in retreatment of pulmonary tuberculosis: Experience with 16 patients. Ind. J. Tub. 1994; 41: 83. 15. Dufour DR, Lott JA, Nolte FS, Gretch DR, Koff RS, Seeff LB. Diagnosis and monitoring of hepatic injury: II. Recommendations for use of laboratory tests in screening, diagnosis, and monitoring. Clin Chem 2000; 46: 2050­2068. 16. American Gastroenterologic Association Clinical Practice Committee. AGA technical review on the evaluation of liver chemistry tests. Gastroenterology. 2002; 123:1367­ 1384. 17. Rosenzweig P, Miget N, Brohier S. Transaminase elevation on placebo during phaseI trials: prevalence and significance. Br J Clin Pharmacol. 1999; 48: 19­23. 18. Williams GM, Iatropoulos MJ. Alteration of liver cell function and proliferation: differentiation between adaptation and toxicity. Toxicol Pathol. 2002; 30: 41­53.

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Table: 1

AST/ALT/LDH levels (mean±SD) in ciprofloxacin group and non-ciprofloxacin group

Enzyme

DURATION OF TREATMENT 1 Day 15th Day 30th Day Group-A Group-B Group-A Group-B Group-A Group-B

st

AST (Units/ml) ALT (Units/ml) LDH (IU/L)

29±7

43±18 *** 35±16 *** 132±35 ***

46±10

49±14 NS 41±14 NS 158±46

49±14

69±25 *** 53±18 NS 145±52

24±5

33±6

52±11

92±34

128±45

145±23

** NS Group-A: Non-ciprofloxacin treatment group [Antitubercular drugs (HE/HER/HERZ)] (n=45) Group-B: Ciprofloxacin treatment group [Antitubercular drugs+Ciprofloxacin] (n=45)

* Significant (p 0.05), ** Very Significant (p 0.01),*** Highly significant (p 0.001)

Table:2

AST/ALT/LDH levels (mean±SD) in ciprofloxacin groups and non-ciprofloxacin groups DURATION OF TREATMENT Group studied 1st Day 15th Day 30th Day Serum aspartate transaminase levels [AST] Units/ml (Mean±SD) Group-I 30±9 38±14 41±10 Group-II 33±10 57±8 68±11 Group-III 25±4 43±7 45±21 Group-IV 43±18 49±14 69±25 Serum alanine transaminase levels [ALT] Units/ml (Mean±SD) Group-I 37±7 54±3 66±5 Group-II 22±6 27±6 45±19 Group-III 18±2 32±9 47±10 Group-IV 36±16 41±15 44±19 Serum Lactate dehydrogenase levels [LDH] IU/L (Mean±SD) Group-I 64±45 70±33 137±9 Group-II 140±33 165±69 161±22 Group-III 74±23 151±34 138±38 Group-IV 132±35 158±46 145±52 Non-ciprofloxacin treatment group (Group-I,II,III) Ciprofloxacin treatment group (Group-IV)

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