Effects of anti-inflammatory drugs on convulsant activity of quinolones: a comparative study of drug interaction between quinolones and anti-inflammatory drugs

Effects of anti-inflammatory drugs on convulsant activity of quinolones: a comparative study of drug interaction between quinolones and anti-inflammatory drugs

J Infect Chemother (2003) 9:314–320 DOI 10.1007/s10156-003-0275-1 © Japanese Society of Chemotherapy and The Japanese Association for Infectious Dise...

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J Infect Chemother (2003) 9:314–320 DOI 10.1007/s10156-003-0275-1

© Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 2003

ORIGINAL ARTICLE

Seiji Hori · Junko Kizu · Masahiro Kawamura

Effects of anti-inflammatory drugs on convulsant activity of quinolones: a comparative study of drug interaction between quinolones and anti-inflammatory drugs

Received: July 14, 2003 / Accepted: August 20, 2003

Abstract Quinolones have been reported to possess potent convulsant activity, which is enhanced when they are administered concurrently with anti-inflammatory drugs. To define the individual drug interactions of quinolones with anti-inflammatory drugs, we studied the convulsant activity of six quinolones with or without 13 anti-inflammatory drugs and 3 analgesic/antipyretic drugs in mice. Intraventricular injections of norfloxacin (NFLX), enoxacin (ENX), ciprofloxacin, lomefloxacin (LFLX), levofloxacin, and gatifloxacin induced convulsions in mice in a dosedependent manner. Concurrent administration of biphenylacetic acid strongly enhanced the convulsant activity of NFLX, ENX, and LFLX. Flurbiprofen also strongly enhanced the activity of NFLX and ENX, and ketoprofen strongly enhanced the activity of ENX. However, mefenamic acid, piroxicam, tenoxicam, meloxicam, etodolac, sulpyrine, isopropylantipyrine, and acetaminophen had no effect on the convulsant activity of quinolones. These results suggest that each quinolone has an individual drug interaction with each anti-inflammatory drug. It was suggested that we should know which anti-inflammatory drugs enhance the convulsant activity of individual quinolones, and which quinolone has no/weak drug interaction with different anti-inflammatory drugs when these drugs are used concurrently for the treatment of patients with infectious diseases. Key words Quinolones · Anti-inflammatory drugs · Drug interaction · Convulsion

S. Hori (*) · M. Kawamura First Department of Pharmacology, Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan Tel. ⫹81-3-3433-1111 (ext. 2251); Fax ⫹81-3-5473-1428 e-mail: [email protected] J. Kizu Department of Practical Pharmacy, Kyoritsu College of Pharmacy, Tokyo, Japan

Introduction Quinolones are now well-known to have potent convulsant (seizure-inducing) activity, and the activity is often enhanced by concurrent administration with anti-inflammatory drugs.1–4 In 1986, it was reported that the concurrent use of enoxacin (ENX) and fenbufen induced convulsions in seven patients.5 Moreover, the concurrent administration of some other quinolones and anti-inflammatory drugs has also been reported to induce convulsions in patients.6 Thus, the concurrent administration of quinolones with antiinflammatory drugs, specifically quinolones in combination with arylacetic acid-derived or propionic acid-derived antiinflammatory drugs, is contraindicated, or careful monitoring of patients is advised. However, the details of the drug interactions are still unclear. We previously reported that biphenylacetic acid, an active metabolite of fenbufen, enhanced the convulsant activity of ENX when the drugs were concurrently administered into lateral ventricle of mouse brain.7 We also reported that the convulsant activity of norfloxacin (NFLX) was strongly enhanced by the coadministration of biphenylacetic acid or flurbiprofen, but not by the coadministration of diclofenac sodium, mefenamic acid, aspirin, tenoxicam, ibuprofen, or acetaminophen.8 Our previous results suggest that individual anti-inflammatory drugs may have different drug interaction activity with different quinolones. Thus, it needs to be determined which quinolones exert weak convulsant activity and which anti-inflammatory drugs have weak or no drug interaction with the quinolones. Accordingly, we examined the convulsant activity of six quinolones with or without 13 anti-inflammatory drugs and three analgesic/antipyretic drugs by carrying out concurrent intraventricular injection in mouse brain.

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Materials and methods Materials Quinolones Levofloxacin (LVFX) and gatifloxacin (GFLX) were kind gifts from Daiichi Pharmaceutical (Tokyo, Japan) and Kyorin Pharmaceutical (Tokyo, Japan), respectively. NFLX, ENX, and lomefloxacin (LFLX) were purchased from Sigma Chemical (St. Louis, MO, USA), and ciprofloxacin (CPFX) was purchased from LKT Laboratories (St. Paul, MN, USA). Anti-inflammatory drugs Biphenylacetic acid, indomethacin, diclofenac, etodolac, flurbiprofen, ketoprofen, ibuprofen, loxoprofen, mefenamic acid, piroxicam, and tenoxicam were purchased from Sigma Chemical. Aspirin and acetaminophen were obtained from Nacalai Tesque (Kyoto, Japan). Sulpyrine and isopropylantipyrine were purchased from Wako Pure Chemical Industries (Osaka, Japan) and meloxicam was purchased from LKT Laboratories. Experimental animals Clean male albino mice (ddY strain, 6 weeks old) were supplied by Sankyo Labo Service (Tokyo, Japan). Mice were housed under conditions of a 12-h light/dark cycle, with free access to water and food. This study was carried out in accordance with the Helsinki Declaration and/or in accordance with the Guidelines for the Care and Use of Laboratory Animals (NIH and Jikei University). Methods Quinolones and anti-inflammatory drugs were dissolved in saline. Five-microliter aliquots containing suitable amounts of quinolone and each anti-inflammatory drug (5 nmol/ mouse) were administered in the right lateral ventricle of mouse brain, according to the method of Nakajima.9 Mice were under constant observation for 30 min after the injection to determine whether tonic or tonic/clonic convulsions were induced (5–10 mice for each dose). The effective dose for 50% (ED 50) values were calculated from the dose-response (convulsion) data, using GraphPad Prism software (GraphPad; San Diego CA, USA).

Results Convulsant activity of quinolones Intraventricular administration of NFLX, ENX, CPFX, LFLX, LVFX, and GFLX induced convulsions in mice in a

Fig. 1. Convulsant activity of quinolones. Quinolones were dissolved in saline in suitable concentrations, and a 5-µl aliquot containing the amount of quinolone shown on the horizontal axis was administered in the right lateral ventricle of mouse brain. Mice were kept under constant observation for 30 min (n ⫽ 10)

dose-dependent manner (Fig. 1). The convulsant activity was in the order of NFLX ⬎ CPFX ⬎ GFLX ⭌ LFLX ⭌ ENX ⬎ LVFX. ED 50 values of quinolones for their convulsant activity are listed in Table 1. Effects of anti-inflammatory drugs on the convulsant activity of quinolones Coadministration of flurbiprofen or biphenylacetic acid with NFLX or ENX in a lateral ventricle of mouse brain very strongly enhanced the convulsant activity of these quinolones alone. Both indomethacin and ketoprofen enhanced the convulsant activity of NFLX and ENX (Figs. 2 and 3, Table 1). Loxoprofen weakly enhanced the convulsant activity of NFLX (Fig. 2, Table 1). The convulsant activity of CPFX was enhanced by coadministration with biphenylacetic acid, flurbiprofen, or ketoprofen. The enhancing activity of these anti-inflammatory drugs on the convulsant activity of CPFX was weaker than that on the convulsant activity of NFLX or ENX (Fig. 4, Table 1). Coadministration with flurbiprofen or ketoprofen moderately enhanced the convulsant activity of LFLX, while indomethacin weakly enhanced it (Fig. 5, Table 1). The convulsant activity of LVFX was not affected by coadministration with any anti-inflammatory drugs (Fig. 6, Table 1). The convulsant activity of GFLX was weakly enhanced by concurrent administration with biphenylacetic acid (Fig. 7, Table 1). The other anti-inflammatory drugs did not affect the convulsant activity of the quinolones examined in this study (Figs. 2–7, Table 1).

9.8

Aspirin

Biphenylacetic acid Indomethacin Diclofenac Etodolac

Flurbiprofen Ketoprofen Ibuprofen Loxoprofen

Mefenamic acid

Piroxicam Tenoxicam Meloxicam

Sulpyrine Isopropylantipyrine

Acetaminophen

Arylacetic acid

Propionic acid

Fenamic acid

Oxicam

Pyrine

Para-aminophenol No

No No

No No No

No

Very strong Moderate No Weak

Very strong Moderate No No

No

36.1

43.8

53.4 30.2

30.8 30.8 53.4

65.3

1.2 4.7 24.7 32.4

2.4 8.6 27.6 37

24.7

No

No No

No No No

No

Very strong Strong No No

Very strong Strong No No

No

DI

30.8

37.0 20.8

14.5 14.5 17.3

20.8

6.9 6.7 24.2 23.3

5.0 18.2 25.2 18.9

29.0

17.0

ED 50

No

No No

No No No

No

Moderate Moderate No No

Moderate No No No

No

DI

Ciprofloxacin

25.2

30.8 25.2

25.2 36.6 53.4

43.8

11.3 8.3 43.8 25.2

5.5 19.0 43.8 30.8

22.9

30.8

ED 50

No

No No

No No No

No

Moderate Moderate No No

Moderate Weak No No

No

DI

Lomefloxacin

67.1

83.1 60.0

75.1 133.5 64.2

83.6

74.9 75.0 81.4 97.3

62.7 79.4 74.3 60.0

83.1

75.2

ED 50

No

No No

No No No

No

No No No No

No No No No

No

DI

Levofloxacin

34.6

20.8 25.2

25.2 25.2 36.6

20.8

33.4 29.9 20.8 25.2

17.3 25.2 25.2 37.0

25.2

27.5

ED 50

No

No No

No No No

No

No No No No

Weak No No No

No

DI

Gatifloxacin

Effective dose for 50% (ED 50) values were calculated from the data shown in Figs. 2–7, using GraphPad Prism software (GraphPad, San Diego CA, USA) DI, drug interaction (determined by the difference in dose-response curve from that of quinolone alone); very strong, ED 50 value without anti-inflammatory drugs/ED 50 value with antiinflammatory drug; strong ⭌10, 10⬎ ED 50 value without anti-inflammatory drugs/ED 50 value with anti-inflammatory drug ⭌5; moderate, 5 ⬎ ED 50 value without anti-inflammatory drugs/ED 50 value with anti-inflammatory drug ⭌2.5; weak, 2.5⬎ ED 50 value without anti-inflammatory drugs/ED 50 value with anti-inflammatory drug ⬉1.5; No, 1.5⬎ ED 50 value without antiinflammatory drugs/ED 50 value with anti-inflammatory drug

14.9

12.9 21.8

9.8 13.5 17.0

21.8

0.19 3.2 18.4 6.2

0.49 4.2 12.9 11.8

12.9

No anti-inflammatory drugs

ED 50

ED 50 DI

Enoxacin

Norfloxacin

Salicylic acid

Anti-inflammatory drugs (analgesic/antipyretic drugs)

Table 1. Convulsant activity (ED 50s, nmol) of quinolones with or without anti-inflammatory drugs

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317

Fig. 2A,B. Effects of anti-inflammatory drugs on the convulsant activity of norfloxacin. Norfloxacin was administered in the right lateral ventricle of mouse brain with anti-inflammatory drugs (5 nmol/mouse).

Mice were kept under constant observation for 30 min (n ⫽ 5–10). NSAIDs, nonsteroidal anti-inflammatory drugs

Fig. 3A,B. Effects of anti-inflammatory drugs on the convulsant activity of enoxacin. Enoxacin was administered in the right lateral ventricle

of mouse brain with anti-inflammatory drugs (5 nmol/mouse). Mice were kept under constant observation for 30 min (n ⫽ 5–10)

Fig. 4A,B. Effects of anti-inflammatory drugs on the convulsant activity of ciprofloxacin. Ciprofloxacin was administered in the right lateral

ventricle of mouse brain with anti-inflammatory drugs (5 nmol/mouse). Mice were kept under constant observation for 30 min (n ⫽ 5–10)

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Fig. 5A,B. Effects of anti-inflammatory drugs on the convulsant activity of lomefloxacin. Lomefloxacin was administered in the right lateral

ventricle of mouse brain with anti-inflammatory drugs (5 nmol/mouse). Mice were kept under constant observation for 30 min (n ⫽ 5–10)

Fig. 6A,B. Effects of anti-inflammatory drugs on the convulsant activity of levofloxacin. Levofloxacin was administered in the right lateral

ventricle of mouse brain with anti-inflammatory drugs (5 nmol/mouse). Mice were kept under constant observation for 30 min (n ⫽ 5–10)

Fig. 7A,B. Effects of anti-inflammatory drugs on the convulsant activity of gatifloxacin. Gatifloxacin was administered in the right lateral

ventricle of mouse brain with anti-inflammatory drugs (5 nmol/mouse). Mice were kept under constant observation for 30 min (n ⫽ 5–10)

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Discussion Various quinolones are currently used for the treatment of infectious diseases. The adverse effects induced by quinolones were once considered not to be so severe. However, convulsions associated with quinolone administration were reported,1–4 and, thus, quinolones are currently considered to have potent convulsant activity. In 1986, seven cases of convulsions associated with the concurrent administration of ENX and fenbufen were reported by Japanese Ministry of Health and Welfare (now the Japanese Ministry of Health, Labour, and Welfare).5 Since that report, information in many package inserts states that combination therapy with quinolones and anti-inflammatory drugs is contraindicated, or careful monitoring of patients with such combination therapy is advised. In our previous report, we demonstrated that the intraventricular injection of ENX with biphenylacetic acid enhanced the convulsant activity of ENX alone in mice.7 Also, Nozaki et al.10 reported that intraperitoneally administered biphenylacetic acid enhanced the convulsant activity of NFLX or ENX. However, the details of the drug interactions between quinolones and anti-inflammatory drugs still remain unclear. It needs to be determined which antiinflammatory drugs exert potent enhancing activity on quinolone-induced convulsions, and which quinolones are not significantly influenced by anti-inflammatory drugs. In this study, we have demonstrated that the convulsant activity of LVFX alone was weak, and it was not enhanced by the concurrent administration of anti-inflammatory drugs. The convulsant activity of GFLX was weakly enhanced by biphenylacetic acid, but not by other antiinflammatory drugs. On the other hand, the convulsant activity of NFLX and ENX was strongly enhanced by concurrent administration with biphenylacetic acid or flurbiprofen. These results suggest that each quinolone has individual characteristics of drug interaction with each antiinflammatory drug (Table 1). Biphenylacetic acid strongly enhanced the convulsant activity of NFLX and ENX, while etodolac failed to do so. Both biphenylacetic acid and etodolac are classified in the same group of anti-inflammatory drugs, i.e., arylacetic acid derivatives. Flurbiprofen, which is classified as a propionic acid derivative, strongly enhanced the convulsant activity of NFLX and ENX, whereas loxoprofen, which belongs to the same group as flurbiprofen, weakly affected the activity of NFLX. Ibuprofen, a propionic acid derivative, had no significant enhancing effect on the convulsant activity of the quinolones. These results suggest that each antiinflammatory drug has unique characteristics in drug interactions with quinolones, even if the anti-inflammatory drugs are classified in the same group (Table 1). Mefenamic acid, piroxicam, tenoxicam, meloxicam, sulpyrine, isopropylantipyrine, and acetaminophen did not modify the convulsant activity of any of the six quinolones examined in the study. These results indicate that these anti-inflammatory and analgesic/antipyretic

drugs may not affect the convulsant activity of quinolones (Table 1). To show the drug interactions between quinolones and anti-inflammatory drugs, a single dose (5 nmol/mouse) of anti-inflammatory drug was used in this study. Clinically, anti-inflammatory drugs are administered at various doses. It is important to determine the accumulation or penetration of anti-inflammatory drugs and quinolones in the central nervous system. Further examination of the pharmacokinetics of these drugs in the central nervous system is necessary. The combinations of quinolones and antiinflammatory drugs which showed no drug interaction in this study may have no drug interaction in patients. Thus, when a physician is obliged to administer an antiinflammatory drug concurrently with a quinolone, we suggest that it would be better to choose a combination of these agents that showed no drug interaction according to our present results (Table 1). In this study, we demonstrated that each individual quinolone has different convulsant activity and drug interaction with different anti-inflammatory drugs. Moreover, we also demonstrated that an individual anti-inflammatory drug has different drug interactions with quinolones. Thus, it is clearly suggested that we should know which quinolones have weak convulsant activity, which quinolones have weak/no drug interaction with anti-inflammatory drugs, and which anti-inflammatory drugs have a weak enhancing effect on the convulsant activity of each quinolone. To use these drugs safely, prior to the prescribing of these drugs, it is recommended that doctors become familiar with the individual drug interactions of particular quinolones and anti-inflammatory drugs. Acknowledgments We thank Daiichi Pharmaceutical Co. and Kyorin Pharmaceutical Co. for their kind gifts of levofloxacin and gatifloxacin, respectively.

References 1. Simpson K, Brodie MJ. Convulsions related to enoxacin. Lancet 1985;II:161. 2. Arcieri GE, Griffith G, Gruenwaldt A, Heyd S, O’Brien S, Beccker N, et al. Ciprofloxacin: an update on clinical experience. Am J Med 1987;82(Suppl 4A):381–94. 3. Anastasio GD, Menscer D, Little JM. Norfloxacin and seizures. Ann Intern Med 1988;109:169–70. 4. Reiter C, Pfeiffer M, Hullman RN. Brief report: safety of ciprofloxacin based on phase IV studies (“Anwendungsbeobachtung”) in the Federal Republic of Germany. Am J Med 1989;87(Suppl 5A):103S–6S. 5. Japanese Ministry of Health and Welfare. Report of clinical adverse reactions, no. 81 (in Japanese). Japanese Ministry of Health and Welfare, Tokyo, Japan; 1986. 6. Hori S, Kageyama S. Quinolones and their central nervous system toxicities (in Japanese). Ryoikibetsu Shokogun Shirizu 1999;27: 552–7. 7. Hori S, Shimada J, Shiba K, Yoshida M, Saito A, Sakai O. A study on convulsive effect of sparfloxacin with or without non-steroidal anti-inflammatory drugs (in Japanese). Chemotherapy 1991; 39(Suppl 4):161–6. 8. Hori S, Kawamura M. Convulsant activity of norfloxacin and gatifloxacin and interaction with anti-inflammatory drugs (in Japanese). Jpn J Chemother 2002;50:460–3.

320 9. Nakajima S. Convulsions induced by vitamin B6 antagonists and their prevention (in Japanese). Showa Igakukai Zasshi 1972;22: 193–202. 10. Nozaki M, Takeda N, Tanaka K, Niwa M, Inazumi K, Kaida K, et al. Convulsions induced by concomitant use of new quinolone

antibacterial and NSAID (in Japanese). Jpn J Inflammation 1991;11:343–8.