Journal of Gastroenterology and Hepatology (1992) 7 , 533-537
REVIEW ARTICLE
Treatment of peptic ulcer disease with furazolidone Z - T . ZHENG AND Y-B. WANG
Digestive Disease Research Center, The Third Teaching Hospital of Beijing Medical University, Beijing, P R China
Abstract Furazolidone (FZ) has been used in China as a treatment of peptic ulcer disease for about 20 years. Clinical and experimental studies suggest that it has good short-term and long-term effects on both human and animal ulcers. The ulcer healing rate is related to the dosage and course of treatment. The healing rate of a high dose, 2 week course is about 70-75% and the relapse rate after 3 years is 9.5%. The adverse reactions to FZ are not severe, and are well tolerated in most patients. However the mutagenic studies of several biological systems indicate that it has a mutagenic effect, but the mutagenic and carcinogenic effects on humans and animals remain questionable, because FZ has been biotransformed into other metabolites. The mechanisms of F Z in the treatment of peptic ulcer disease are not fully understood, perhaps partly due to the monoamine oxidase (MAO) inhibitory reaction and partly to the antibacterial activity to Helicobacter pylori (HI’). T h e long-term effects of FZ are still not clear.
Key words: furazolidone, Helicobacter pylori, monoamine oxidase, peptic ulcer disease INTRODUCTION Furazolidone (FZ; N-5-nitro-2-furfurylideneamino-2oxazolidine) is a drug that was developed in the late 1940s for use as an antibiotic in the treatment of Gram-negative bacterial and protozoal diseases in man and animals. It has been used in China as an anti-ulcer agent for about 20 years and positive results have been obtained both in clinical and animal studies.’-4 In the treatment of bacterial disease, FZ relieved the symptoms of peptic ulcer disease in man and was used as a drug for the treatment of common peptic ulcer symptoms. Clinical and experimental studies carried out in China suggested that FZ has anti-ulcer efficacy both in human and animal ulcers. Furthermore, compared with other anti-ulcer agents it has a long-term anti-ulcer effect. T h e use of FZ as an anti-ulcer agent began in China and there are some reports of its use in the treatment of Helicobacter pylori (HP) related gastritis in foreign l i t e r a t ~ r e . ~ Recently, accumulated data suggested that HP has a close association with peptic ulcer disease. However, there were also some reports of its adverse reactions especially mutagenic and carcinogenic effect in several biological systems. There has been no report of a carcinogenic effect in animal and human studies. T h e reports of FZ in the treatment of peptic ulcer disease were very common in China, but the dosage and course were not unified and it was not possible to compare the therapeutic results of different authors.
This review will focus on the clinical effect of FZ and experimental studies of the mechanisms of its anti-ulcer efficacy.
CLINICAL USE OF FZ AS AN ANTIULCER AGENT The first report of FZ used in the treatment of peptic ulcer was published in 1972.6 Two other articles were published s~bsequently.’~~ Symptoms were used as diagnostic and therapeutic criteria. A fibre-optic gastroscope has been used to investigate the ulcer healing efficacy of FZ since 1978. The high dose 2 week regime (0.2 q.i.d. x 3 days, 0.2 t.i.d. x 4 days and 0.1 q.i.d x 7 days) was used. Patients diagnosed with peptic ulcer disease (including gastric ulcer, GU; duodenal ulcer, DU; and complex ulcer, CU) in an active stage, were enrolled in the authors’ studies. The diameter of the ulcer had to be larger than 0.3 cm. Ulcer healing was defined as red scar formation of the ulcer. The pilot study was published in 1979,’ 2 5 cases were treated with FZ and 21 were healed. T h e ulcer healing rate was 84% (21/25). An open trial study was then undertaken and gastropin was used as a control. One hundred and six cases were randomized into two groups: FZ and control. Gastropin was administered 1.0 t.i.d. for 2 weeks. Endoscopy was performed within 3 days at the end of the course of treatment. T h e ulcer healing rate was 74.7 (56/75) and
Correspondence: Zheng Zhi-Tian, Dept Gastroenterology, 3rd Teaching Hospital of Beijing Medical University, Beijing, 100083, PR China. Accepted for publication 16 August 1991.
Z-T. Zheng and Y-B. Wang
534 70.9% (22/31) in the FZ and control groups respectively. The difference between the two groups was insignificant (P> 0.6).* A double-blind controlled study was carried out from November 1982 to May 1983, to determine the therapeutic efficacy of FZ in the treatment of peptic ulcer disease. Seventy cases were randomized into two groups: FZ and placebo. The number of patients with GU, DU & CU were six, 30, one and four, 27, two in the FZ group and placebo group, respectively. The differences in age, sex, ulcer history, ulcer size, ulcer location, ulcer number and gastric acid examination between the two groups were insignificant. The 2 week ulcer healing rate was 72.8% (27/37) in the FZ group versus 24.2% (8/33) in the placebo group. The difference between the two groups was significant (P< 0.00 1).The three clinical trials suggest that FZ has good short-term effects on peptic ulcer disease. The 2 week ulcer healing rate was about 75Y0.~,~ Several thousand cases have been reported of peptic ulcer disease that were treated with FZ, but the healing efficacy varied. Clinical studies by the authors indicate that the ulcer healing efficacy of FZ was stable compared with other studies. Yang et al. used FZ 0.2 t.i.d. for 7 days and 0.1 q.i.d. for 7 days; the total dosage was 7.0 g. The 2 week ulcer healing rate was 91.7% (1l/12).9 The result was much better than in other studies but the number of cases were not enough. Liu et al. (unpubl. data) used a high dose 2 week regime in the treatment of DU; the ulcer healing rate was 75% (18/24). Tang et al. used FZ 0.2 t.i.d. for 4 weeks as a course. The total dosage was 16.8 g and the 4 week ulcer healing rate was 83.48% (96/115).” Zhang et al. used FZ 0.1 t.i.d. for 4 weeks as a course and the total dosage was 8.4 g; by the end of the course the ulcer healing rate was only 60% (30/50). l1 Zhao et al. used FZ 0.2 t.i.d. for 7 days, then after a 6 day interval, 0.2 t.i.d. was used again for 7 days. The 4 week ulcer healing rate was 68.8% (97/141) similar to the 2 week regime used by the authors.12 The results of the last two reports were not good enough probably because the dosage was lower and the course too long, and the serum level of FZ could not reach an adequate level. Pharmacological experiments suggest that the half-life increased and clearance rate decreased with the increasing dosage of FZ. Gan et al. used 0.2 t.i.d. for 7 days, 0.1 q.i.d. for 7 days and 0.1 t.i.d. for 14 days, over 4 weeks. T h e total dosage was 11.4 g. The ulcer healing rate was 80.0% (48/60).13 From studies mentioned it is concluded that FZ has anti-ulcer efficacy. The high dose 2 week regime ulcer healing rate was 73-75%, similar to the 4 week healing rate of cimetidine. If the doses were increased, the 4 week ulcer healing rate was 80-83%, but the adverse reactions were also increasing. The healing rate of ordinary doses (0.1 t.i.d.) was not good even over a 4 week course, this suggests that the therapeutic efficacy of FZ is related to the total dosage and length of course. Furazolidone not only has short-term effects but also has good long-term effects. A 2-4 year follow-up study was carried out from March 1978 to May 1981. Fifty-two cases were treated with FZ and 21 cases with gastropin (control). The relapse rates at 2 and 3 years were 7.7 and 9.5% in the FZ group versus 28.6 and 35.7% in the controls.2 The difference between the two groups was
significant. The 1 year relapse rate for peptic ulcer disease treated with cimetidine was almost 100%. Tang et al. carried out a 3-6 month follow-up study, they found the relapse rate of the FZ healed group was only 4.70% versus 22.22% in the cimetidine group.” This suggested that FZ is superior to cimetidine both in the short- and long-term. T h e adverse reactions of FZ have been observed by many author^'^-'^ and are mainly: dizziness; malaise; palpitation; nausea; and vomiting. These reactions are not severe and patients could tolerate them. They disappear or decrease with the lessening of the dose. Dermatological reactions are also common (such as skin eruption) and are dose-independent, probably related to an allergic reaction. Neurological reactions are dose-dependent, often exceed 10 g but are not common. It is reported that FZ 0.3 g per day for a month, the neurological toxicity is up to 5%. Altamirano and Bondari compared the adverse effect of FZ in the treatment of bacterial diarrhoea with other antibiotics. The 191 articles reviewed in this article have been published since 1950.15 It has been found that the total adverse reactions are only 8.3% including gastrointestinal reaction (8% occupied 5 1% of total reactions), neurological reaction (1.M%), systemic reactions (0.56%), dermatologic (0.54%), cardiovascular (0.1 ?l’~), pulmonary (0.1 YO), oral/pharyngeal (0.08%) and hepatic renal reactions (0.06Oh). Most of the reactions reported were not severe and treatment was rarely discontinued. FZ is no more dangerous than other antimicrobial agents. There have been some recent reports of its mutagenic and carcinogenic effect but all experiments were done on biological systems. Furazolidone is biotransformed in the human and animal body but it is not known whether the transformed metabolites have mutagenic and carcinogenic effects. No animal or human study has suggested that FZ has carcinogenic effects and further investigation is needed.16
T H E MECHANISMS OF FZ I N T H E T R E A T M E N T OF PEPTIC ULCER DISEASE Furazolidone is a drug that is easily absorbed in the gut and can be distributed to the whole body especially the gut and brain.’7~’8It can also penetrate the blood-brain barrier. Therefore, the mechanisms of FZ are not only topical, as indicated by previous studies, but also systemic.
FZ: An M A 0 inhibitor Monoamines especially dopamine (DA) have important implications in the regulation of gastrointestinal functions. Dopamine was found in enterchromaffin and enterchromaffin-like cells in the gut. It also found in gastroduodenal mucosa as well as in gastric juice. Animal studies have shown DA could inhibit gastric acid se cretion, gastrointestinal movement and dilate gastric mucosal blood vessels which enhance the blood flow of gastric mu~osa.’~-”So DA might be an endogenous protective factor of gastric mucosa. In the early 1960s,
Furazolidone for peptic ulcer disease
535
researchers found that there was a high incidence of peptic ulcer in Parkinsonism, it is known that Parkinsonism is associated with degeneration of the dopaminergic component of the nigrostriatal pathway, so the high prevalence of peptic ulcer disease in Parkinsonism might also be associated with DA depletion. In 1979 Szabo found that DA agonists could prevent cysteamine induced duodenal ulcer in rats, on the contrary, DA antagonists aggravate rat duodenal ulcer.23Hernandez et al. estimated the DA receptor binding site of duodenal mucosa in duodenal ulcer patients, they found the binding site are markedly elevated in D U patients.24 In our studies we found FZ could inhibit M A 0 activity in gut and brain. FZ and other M A 0 inhibitory agents such as nicotinamide, isoniazide and pargyline could cure acetic acid induced ulcer in rats more rapidly than control. So the anti-ulcer efficacy of FZ might relate to M A 0 inhibition (Table 1). Further studies of brain and gut monoamines in cysteamine induced ulcer, revealed that the monoamines, especially the DA content of the gut, are lowered before the ulcer forms. It was most prominent between 8 and 24 h after treatment with cysteamine and returned to normal at 48 h. It was found that the decrease in DA content in the gut correlates with the frequency and severity of ulcer formation. Furazolidone and other M A 0 inhibitors (N, I and P) given for 2 days before cystearnine injection could reduce the frequency and severity of the ulcer dose-dependently (Fig. 1). There were also changes of monoamines in the brain; 2, 4 and 8 h after cysteamine treatment, DA content in telencephalon was 58.30, 49.62 and 54.86% of the normal level. But there were only slight changes in stem brain and diencephalon. The DA content in the telencephalon was elevated after 4 h of FZ treatment and remained raised for 24 h (Figs. 2, 3). But it had little effect on the DA level in the diencephalon and stem brain. The brain and gut 5-HT and norepinephrine were affected slightly. If DA antagonists are given i.v. or i.p. simultaneously, the protective effect of FZ was blocked. However, DA agonists could enhance the protective effect of FZ (Fig. 4).25-27These results suggest that the anti-ulcer effect of FZ is associated with DA.
FZ and HP I n vitro and in viwo studies suggest that H P is highly susceptible to FZ.28-29I n witro studies showed that FZ is
3r
1
m 2 0 L
al
5 1
0 2.5 5 10 2.5 5 10 0.5 1 2 3 6 24 -
N
I
P
Control
FZ
Figure I The protective effect of FZ and other MA0 inhibitors (N, I and P) in cysteamine induced rat ulcer. * P < 0.05. **P< 0.01.
-8 100
-2 0 c
50
0 2
4
8
24
Hormonal resoonse
Figure 2 Furazolidone and cysteamine on rat telencephalon DA content *NS, **P< 0.02, ***P< 0.05.
active against HP at a concentration of only 3 ng/rnL. Since the discovery of HP, its relationship to peptic ulcer disease has been studied, but there was no confirming evidence to indicate that HP is an aetiological factor. However, we believe that HP probably relates to the relapsing of peptic ulcer disease.30 So the anti-HP efficacy of FZ was explained as one of the mechanisms responsible for its anti-ulcer effect. T h e H P clearance rate of FZ is about 80%. In the clinical studies carried out in our department, when FZ was administered 0.1 t.i.d for 4 weeks, H P clearance rate was 54.2% (1 5/24) versus 1% in the placebo group. T h e high dose 2 week regime H P clearance was 79.2% (19/24) in FZ group versus 3.4% (1/26) in cimetidine group. Gilman used FZ O.l/day for 2
Table 1 FZ, isoniazide, nicotinamide, isoniazide and pargyline in the treatment of acetic acid induced ulcer and the influence on duodenum and brain MA0 activity Drug
P FZ FZ FZ N I
P
10 50 100 100 100 20
28 76 83 76 56 64
< 0.005 < 0.001 < 0.001
< 0.020 < 0.020
Brain 15 65 59 43 36 46
MA0 inhibitory rate P Duodenum
< 0.005
< 0.001 < 0.001 < 0.001 < 0.002 < 0.002
8 28 16 20 16 12
P > 0.20 > 0.05 > 0.20 > 0.05 > 0.20 > 0.20
Z-T. Zheng and Y-B. Wung
536 40
200
*.
-s
-
-
?!
g 100
0
C
0
-3u
20
0 2
4
0
24
40
Hormonal response 0
Figure 3 Furazc ione and cysteamine on rat duodenum DA content P < 0.05.* Compared with control; ** compared with cysteamine. (0)FZ; ()I FZ + cys ( % ); cys (a); control.
FZ
Control
Figure 5 Stress induced rat ulcer after 45 days FZ discontinuation. *P < 0.05 (;%) FZ; (.:. ) Control. Tahle 2 The ulcer relapse rate of FZ and other anti-ulcer agents
3
L
Drug
0
( “ 2
0
6 months
10 months
2 years
3 years
(%)
(%)
(Oh)
(W
34.70 25.00 11.70 7.70 4.70
78.30 66.70
-
-
-
-
-
-
-
7.69
9.52
= I
1
0 Hormone
Figure 4 DA agonists and antogonistson cysteamine induced rat duodenal ulcer ( ) c = cysteamine; (0)c + H; ( V ) C + H + FZ; ( 8 ) C+M, ( w ) c + F Z + M + H ; ( m )C+B; ( ) C + B + FZ. C = cysteamine; B = bromocriptone M = Madopa; FZ = furazolidone; H = haloperidol.
weeks and the H P clearance rate was 93% (13/14) in the treatment group versus 13% (4/13) in the placebo group.5 It is doubtful whether the ulcer healing efticacy of FZ can be attributed to anti-HP efficacy, because H P positive peptic ulcer patients could also be healed by H2 blockers.
Other effects of FZ Animal studies have also shown FZ could enhance gastric mucus secretion, DNA and protein synthesis, but human and animal studies showed no effect on prostaglandin synthesis. This could explain why FZ has no protective effect on indomethacin induced animal ~ l c e r . ’ ~ . ~ ~
Cimetidine Famotidine Amatadine Bromocriptine FZ
*No further relapse.
ance efticacy of FZ was not very good and the long-term ulcer healing effect could not be attributed to H P clearance. Recently, Sikiric et ul. used DA agonist (bromocriptine and amatadine) in the treatment of human peptic ulcer, H2 blockers (cimetidine and famotidine) were used as control. T h e ulcer healing rates in two groups were significantly different after a 4 week course. But the long-term effects in two groups were significantly different. T h e 6 month ulcer relapse rate of cimetidine and famotidine was 34.7 and 25% versus 7.7 and 11.7% in the bromocriptine and amatadine groups, respectively. After 10 months, there was no more relapse in DA agonist group but 78.3 and 66.7% in the cimetidine and famotidine groups.32 These data suggest that DA might be associated with the long-term ulcer healing effect of FZ.
CONCLUSIONS
The mechanisms of long-term effect Animal and human studies suggested that FZ had a long-term ulcer healing effect (Fig. 5, Table 2). In human ulcer the effect might be due to the anti-HP efficacy of FZ. But it could not explain the long-term effect on animal experiments. Gilman used FZ 0. l/day for 2 weeks and HP clearance rate was 92.8%, but after 6 weeks of discontinuation of FZ only 4 cases remained H P n e g a t i ~ e .This ~ suggested that the long-term H P clear-
Based on this review, we could conclude that FZ has good short- and long-term ulcer healing efficacy. The mechanizms might be due to its M A 0 inhibitory effect and its anti-HP action may play a minimal role. The formation and healing of peptic ulcer disease is associated with the change of DA, but how DA affects peptic ulcers and why DA agonists have good long-term ulcer healing effects still remain an enigma to researcher.
537
Furazolidone for peptic ulcer disease
REFERENCES 1. ZHENCZ. T. et al. The clinical and experimental study of
2.
3.
4.
5.
6. 7. 8. 9.
10. 11.
12. 13.
14.
15.
furazolidone in the treatment of peptic ulcer. Beijing Med. 1979; 1: 8-11. ZHENCZ. T. et al. Furazolidone in the treatment of peptic ulcer: long-term effect and experimental study. Chin. J. Digestion 1982; 2: 131-3. ZHENGZ. T. et al. The double blind controlled study of furazolidone in the treatment of peptic ulcer. Chin. J. Intern. Med. 1984; 23: 195-7. ZHENCZ. T. et al. Double-blind short-term trial of furazolidone in peptic ulcer. Lancet 1985; i: 1048-9. GILMAN R. et al. Efficacy of nitrofurans in the treatment of antral gastritis associated with campylobacter pyloridis. Gastroenterology 1987; 93: 1045 (abstract). ANON.A report of 12 cases of duodenal ulcer treated with furazolidone. Shandong Med. 1972; 5: 68 (in Chinese). CAOC. X. et al. Furazolidone in the treatment of gastroduodenal ulcer. Tianjing Med. 1976; 4: 44. CHENH. Y. 14 cases of peptic ulcer disease treated with furazolidone. Chin. J. Intern. Med. 1977; 16: 380. YANCH. T. et al. The role of Campylobacter pylori in gastritis and peptic ulcer. Nut1 Med. J. China 1988; 68: 366-70. TANG H. et al. 115 cases treatment of peptic ulcer using furazolidone. Hunan Med. 1983; 3: 5 . Z n m c M. Z. et al. Contrary study of furazolidone and cimetidine in the treatment of duodenal ulcer. Xijiang Med. Coll. J. 1985; 8: 38-9. ZHAOH. Y. et a / . Furazolidone in peptic ulcer (letter). Lancet 1985; ii: 276-7. GAN S. L. & DENG Y. Q. The therapeutic effect of furazolidone and cimetidine in the treatment of peptic ulcer. Chin. J. Digestion 1987; 7: 89. Su D. F. The adverse reactions of furazolidone in the treatment of peptic ulcer disease. Remin Jueyi 1982; 7 : 63-5. ALTAMIRANO A. & BONDARI A. Adverse reactions of furazolidone and other drugs; a comparative review. Scan. J. Gastroenterol. 1989; 24: (suppl. 169): 70-4.
16. ALI B. H. Pharmacology and toxicity of furazolidone in man and animals: Some recent research. Gen. Pharmacoi. 1989; 20: 557-63. 17. XUE Y. L. er al. T h e absorption and distribution of furazolidone in animal study. J. Beijing Med. Univ. 1987; 19: 435. 18. WHITEA. H. Absorption, distribution, metabolism and excretion of furazolidone: A review of the literature. Scan. J. Gastroenterol. 1989; 24: (suppl. 169): 4-10. 19. XINGL. P. et al. Research of the mechanisms of furazolidone in the treatment of peptic ulcer disease. Proceeding of the 3rd Congress Conference of Digestive Disease of China, Kunmin. 1987; 1. 20. DONGX. Y., Lu Q. H. Furazolidone on the acid secretion of rats. Beijing Med. 1980; 2: 183. Y. & URAKAWA T. Experimental studies on the 21. NACAHATA role of dopamine in stress ulcer. Jpn. J. Gastroenterol. 1986; 83: 1287-97. 22. CHENG. R. et al. Dopamine and haloperidol on the rat gastric mucosa. Chin. J. Digestion 1990; 10: 242. 23. SZABO S. Dopamine disorder in duodenal ulceration. Lancet 1979; ii: 880. 24. HERNANDEZ, D. E. er a[. Increasing dopamine receptor binding in duodenal ulcer patients. Dig. Dis. Sci. 1989; 34: 543-7. T. Furazolidone on the gut 25. XING L. P. & ZnENG. cotachalamine in cysteamine induce duodenal ulcer. Chin. J. Internal Med. 1988; 27: 282-5. 26. ZHENCZ. T., XINGL. P. Effect of furazolidone on gut catecholamine in cysteamine induced duodenal ulcer in the rat. Scan. J. Gastroenterol. 1988; 23: 1020-4. 27. HUANCC. W. & ZHENGZ. T. T h e effect of furazolidone on brain monoamines in the treatment of peptic ulcer. Natl Med. J. China 1989; 69: 195-7. 28. HOWDEN A. er al. I n virro susceptibility of Campylobacter pyloridis to furazolidone. Lancet 1986; 3: 1035 (letter). 29. GRAHAM D. Y. et al. In vivo susceptibility of Campylobacrer pylori. A m . J. Gastroenterol. 1989; 34: 233-8. 30. J I A B. Q. T h e possible role of Campylobacrer pylori in the peptic ulcer disease. Chin. J. Digestion 1990; 10: 1-2. 31. LI J. S. et al. Prostaglandin in the pathogenesis of peptic ulcer-the exploration of the mechanisms of furazolidone. Chin. J. Digestion 1988; 8: 18. 32. SIKIRIC P. et al. Dopamine agonists lessen DU relapse rate. Dig. Dis. Sci. 1990; 35: 1040.
z.
REVIEW ARTICLE
Treatment of peptic ulcer disease with furazolidone Z - T . ZHENG AND Y-B. WANG
Digestive Disease Research Center, The Third Teaching Hospital of Beijing Medical University, Beijing, P R China
Abstract Furazolidone (FZ) has been used in China as a treatment of peptic ulcer disease for about 20 years. Clinical and experimental studies suggest that it has good short-term and long-term effects on both human and animal ulcers. The ulcer healing rate is related to the dosage and course of treatment. The healing rate of a high dose, 2 week course is about 70-75% and the relapse rate after 3 years is 9.5%. The adverse reactions to FZ are not severe, and are well tolerated in most patients. However the mutagenic studies of several biological systems indicate that it has a mutagenic effect, but the mutagenic and carcinogenic effects on humans and animals remain questionable, because FZ has been biotransformed into other metabolites. The mechanisms of F Z in the treatment of peptic ulcer disease are not fully understood, perhaps partly due to the monoamine oxidase (MAO) inhibitory reaction and partly to the antibacterial activity to Helicobacter pylori (HI’). T h e long-term effects of FZ are still not clear.
Key words: furazolidone, Helicobacter pylori, monoamine oxidase, peptic ulcer disease INTRODUCTION Furazolidone (FZ; N-5-nitro-2-furfurylideneamino-2oxazolidine) is a drug that was developed in the late 1940s for use as an antibiotic in the treatment of Gram-negative bacterial and protozoal diseases in man and animals. It has been used in China as an anti-ulcer agent for about 20 years and positive results have been obtained both in clinical and animal studies.’-4 In the treatment of bacterial disease, FZ relieved the symptoms of peptic ulcer disease in man and was used as a drug for the treatment of common peptic ulcer symptoms. Clinical and experimental studies carried out in China suggested that FZ has anti-ulcer efficacy both in human and animal ulcers. Furthermore, compared with other anti-ulcer agents it has a long-term anti-ulcer effect. T h e use of FZ as an anti-ulcer agent began in China and there are some reports of its use in the treatment of Helicobacter pylori (HP) related gastritis in foreign l i t e r a t ~ r e . ~ Recently, accumulated data suggested that HP has a close association with peptic ulcer disease. However, there were also some reports of its adverse reactions especially mutagenic and carcinogenic effect in several biological systems. There has been no report of a carcinogenic effect in animal and human studies. T h e reports of FZ in the treatment of peptic ulcer disease were very common in China, but the dosage and course were not unified and it was not possible to compare the therapeutic results of different authors.
This review will focus on the clinical effect of FZ and experimental studies of the mechanisms of its anti-ulcer efficacy.
CLINICAL USE OF FZ AS AN ANTIULCER AGENT The first report of FZ used in the treatment of peptic ulcer was published in 1972.6 Two other articles were published s~bsequently.’~~ Symptoms were used as diagnostic and therapeutic criteria. A fibre-optic gastroscope has been used to investigate the ulcer healing efficacy of FZ since 1978. The high dose 2 week regime (0.2 q.i.d. x 3 days, 0.2 t.i.d. x 4 days and 0.1 q.i.d x 7 days) was used. Patients diagnosed with peptic ulcer disease (including gastric ulcer, GU; duodenal ulcer, DU; and complex ulcer, CU) in an active stage, were enrolled in the authors’ studies. The diameter of the ulcer had to be larger than 0.3 cm. Ulcer healing was defined as red scar formation of the ulcer. The pilot study was published in 1979,’ 2 5 cases were treated with FZ and 21 were healed. T h e ulcer healing rate was 84% (21/25). An open trial study was then undertaken and gastropin was used as a control. One hundred and six cases were randomized into two groups: FZ and control. Gastropin was administered 1.0 t.i.d. for 2 weeks. Endoscopy was performed within 3 days at the end of the course of treatment. T h e ulcer healing rate was 74.7 (56/75) and
Correspondence: Zheng Zhi-Tian, Dept Gastroenterology, 3rd Teaching Hospital of Beijing Medical University, Beijing, 100083, PR China. Accepted for publication 16 August 1991.
Z-T. Zheng and Y-B. Wang
534 70.9% (22/31) in the FZ and control groups respectively. The difference between the two groups was insignificant (P> 0.6).* A double-blind controlled study was carried out from November 1982 to May 1983, to determine the therapeutic efficacy of FZ in the treatment of peptic ulcer disease. Seventy cases were randomized into two groups: FZ and placebo. The number of patients with GU, DU & CU were six, 30, one and four, 27, two in the FZ group and placebo group, respectively. The differences in age, sex, ulcer history, ulcer size, ulcer location, ulcer number and gastric acid examination between the two groups were insignificant. The 2 week ulcer healing rate was 72.8% (27/37) in the FZ group versus 24.2% (8/33) in the placebo group. The difference between the two groups was significant (P< 0.00 1).The three clinical trials suggest that FZ has good short-term effects on peptic ulcer disease. The 2 week ulcer healing rate was about 75Y0.~,~ Several thousand cases have been reported of peptic ulcer disease that were treated with FZ, but the healing efficacy varied. Clinical studies by the authors indicate that the ulcer healing efficacy of FZ was stable compared with other studies. Yang et al. used FZ 0.2 t.i.d. for 7 days and 0.1 q.i.d. for 7 days; the total dosage was 7.0 g. The 2 week ulcer healing rate was 91.7% (1l/12).9 The result was much better than in other studies but the number of cases were not enough. Liu et al. (unpubl. data) used a high dose 2 week regime in the treatment of DU; the ulcer healing rate was 75% (18/24). Tang et al. used FZ 0.2 t.i.d. for 4 weeks as a course. The total dosage was 16.8 g and the 4 week ulcer healing rate was 83.48% (96/115).” Zhang et al. used FZ 0.1 t.i.d. for 4 weeks as a course and the total dosage was 8.4 g; by the end of the course the ulcer healing rate was only 60% (30/50). l1 Zhao et al. used FZ 0.2 t.i.d. for 7 days, then after a 6 day interval, 0.2 t.i.d. was used again for 7 days. The 4 week ulcer healing rate was 68.8% (97/141) similar to the 2 week regime used by the authors.12 The results of the last two reports were not good enough probably because the dosage was lower and the course too long, and the serum level of FZ could not reach an adequate level. Pharmacological experiments suggest that the half-life increased and clearance rate decreased with the increasing dosage of FZ. Gan et al. used 0.2 t.i.d. for 7 days, 0.1 q.i.d. for 7 days and 0.1 t.i.d. for 14 days, over 4 weeks. T h e total dosage was 11.4 g. The ulcer healing rate was 80.0% (48/60).13 From studies mentioned it is concluded that FZ has anti-ulcer efficacy. The high dose 2 week regime ulcer healing rate was 73-75%, similar to the 4 week healing rate of cimetidine. If the doses were increased, the 4 week ulcer healing rate was 80-83%, but the adverse reactions were also increasing. The healing rate of ordinary doses (0.1 t.i.d.) was not good even over a 4 week course, this suggests that the therapeutic efficacy of FZ is related to the total dosage and length of course. Furazolidone not only has short-term effects but also has good long-term effects. A 2-4 year follow-up study was carried out from March 1978 to May 1981. Fifty-two cases were treated with FZ and 21 cases with gastropin (control). The relapse rates at 2 and 3 years were 7.7 and 9.5% in the FZ group versus 28.6 and 35.7% in the controls.2 The difference between the two groups was
significant. The 1 year relapse rate for peptic ulcer disease treated with cimetidine was almost 100%. Tang et al. carried out a 3-6 month follow-up study, they found the relapse rate of the FZ healed group was only 4.70% versus 22.22% in the cimetidine group.” This suggested that FZ is superior to cimetidine both in the short- and long-term. T h e adverse reactions of FZ have been observed by many author^'^-'^ and are mainly: dizziness; malaise; palpitation; nausea; and vomiting. These reactions are not severe and patients could tolerate them. They disappear or decrease with the lessening of the dose. Dermatological reactions are also common (such as skin eruption) and are dose-independent, probably related to an allergic reaction. Neurological reactions are dose-dependent, often exceed 10 g but are not common. It is reported that FZ 0.3 g per day for a month, the neurological toxicity is up to 5%. Altamirano and Bondari compared the adverse effect of FZ in the treatment of bacterial diarrhoea with other antibiotics. The 191 articles reviewed in this article have been published since 1950.15 It has been found that the total adverse reactions are only 8.3% including gastrointestinal reaction (8% occupied 5 1% of total reactions), neurological reaction (1.M%), systemic reactions (0.56%), dermatologic (0.54%), cardiovascular (0.1 ?l’~), pulmonary (0.1 YO), oral/pharyngeal (0.08%) and hepatic renal reactions (0.06Oh). Most of the reactions reported were not severe and treatment was rarely discontinued. FZ is no more dangerous than other antimicrobial agents. There have been some recent reports of its mutagenic and carcinogenic effect but all experiments were done on biological systems. Furazolidone is biotransformed in the human and animal body but it is not known whether the transformed metabolites have mutagenic and carcinogenic effects. No animal or human study has suggested that FZ has carcinogenic effects and further investigation is needed.16
T H E MECHANISMS OF FZ I N T H E T R E A T M E N T OF PEPTIC ULCER DISEASE Furazolidone is a drug that is easily absorbed in the gut and can be distributed to the whole body especially the gut and brain.’7~’8It can also penetrate the blood-brain barrier. Therefore, the mechanisms of FZ are not only topical, as indicated by previous studies, but also systemic.
FZ: An M A 0 inhibitor Monoamines especially dopamine (DA) have important implications in the regulation of gastrointestinal functions. Dopamine was found in enterchromaffin and enterchromaffin-like cells in the gut. It also found in gastroduodenal mucosa as well as in gastric juice. Animal studies have shown DA could inhibit gastric acid se cretion, gastrointestinal movement and dilate gastric mucosal blood vessels which enhance the blood flow of gastric mu~osa.’~-”So DA might be an endogenous protective factor of gastric mucosa. In the early 1960s,
Furazolidone for peptic ulcer disease
535
researchers found that there was a high incidence of peptic ulcer in Parkinsonism, it is known that Parkinsonism is associated with degeneration of the dopaminergic component of the nigrostriatal pathway, so the high prevalence of peptic ulcer disease in Parkinsonism might also be associated with DA depletion. In 1979 Szabo found that DA agonists could prevent cysteamine induced duodenal ulcer in rats, on the contrary, DA antagonists aggravate rat duodenal ulcer.23Hernandez et al. estimated the DA receptor binding site of duodenal mucosa in duodenal ulcer patients, they found the binding site are markedly elevated in D U patients.24 In our studies we found FZ could inhibit M A 0 activity in gut and brain. FZ and other M A 0 inhibitory agents such as nicotinamide, isoniazide and pargyline could cure acetic acid induced ulcer in rats more rapidly than control. So the anti-ulcer efficacy of FZ might relate to M A 0 inhibition (Table 1). Further studies of brain and gut monoamines in cysteamine induced ulcer, revealed that the monoamines, especially the DA content of the gut, are lowered before the ulcer forms. It was most prominent between 8 and 24 h after treatment with cysteamine and returned to normal at 48 h. It was found that the decrease in DA content in the gut correlates with the frequency and severity of ulcer formation. Furazolidone and other M A 0 inhibitors (N, I and P) given for 2 days before cystearnine injection could reduce the frequency and severity of the ulcer dose-dependently (Fig. 1). There were also changes of monoamines in the brain; 2, 4 and 8 h after cysteamine treatment, DA content in telencephalon was 58.30, 49.62 and 54.86% of the normal level. But there were only slight changes in stem brain and diencephalon. The DA content in the telencephalon was elevated after 4 h of FZ treatment and remained raised for 24 h (Figs. 2, 3). But it had little effect on the DA level in the diencephalon and stem brain. The brain and gut 5-HT and norepinephrine were affected slightly. If DA antagonists are given i.v. or i.p. simultaneously, the protective effect of FZ was blocked. However, DA agonists could enhance the protective effect of FZ (Fig. 4).25-27These results suggest that the anti-ulcer effect of FZ is associated with DA.
FZ and HP I n vitro and in viwo studies suggest that H P is highly susceptible to FZ.28-29I n witro studies showed that FZ is
3r
1
m 2 0 L
al
5 1
0 2.5 5 10 2.5 5 10 0.5 1 2 3 6 24 -
N
I
P
Control
FZ
Figure I The protective effect of FZ and other MA0 inhibitors (N, I and P) in cysteamine induced rat ulcer. * P < 0.05. **P< 0.01.
-8 100
-2 0 c
50
0 2
4
8
24
Hormonal resoonse
Figure 2 Furazolidone and cysteamine on rat telencephalon DA content *NS, **P< 0.02, ***P< 0.05.
active against HP at a concentration of only 3 ng/rnL. Since the discovery of HP, its relationship to peptic ulcer disease has been studied, but there was no confirming evidence to indicate that HP is an aetiological factor. However, we believe that HP probably relates to the relapsing of peptic ulcer disease.30 So the anti-HP efficacy of FZ was explained as one of the mechanisms responsible for its anti-ulcer effect. T h e H P clearance rate of FZ is about 80%. In the clinical studies carried out in our department, when FZ was administered 0.1 t.i.d for 4 weeks, H P clearance rate was 54.2% (1 5/24) versus 1% in the placebo group. T h e high dose 2 week regime H P clearance was 79.2% (19/24) in FZ group versus 3.4% (1/26) in cimetidine group. Gilman used FZ O.l/day for 2
Table 1 FZ, isoniazide, nicotinamide, isoniazide and pargyline in the treatment of acetic acid induced ulcer and the influence on duodenum and brain MA0 activity Drug
P FZ FZ FZ N I
P
10 50 100 100 100 20
28 76 83 76 56 64
< 0.005 < 0.001 < 0.001
< 0.020 < 0.020
Brain 15 65 59 43 36 46
MA0 inhibitory rate P Duodenum
< 0.005
< 0.001 < 0.001 < 0.001 < 0.002 < 0.002
8 28 16 20 16 12
P > 0.20 > 0.05 > 0.20 > 0.05 > 0.20 > 0.20
Z-T. Zheng and Y-B. Wung
536 40
200
*.
-s
-
-
?!
g 100
0
C
0
-3u
20
0 2
4
0
24
40
Hormonal response 0
Figure 3 Furazc ione and cysteamine on rat duodenum DA content P < 0.05.* Compared with control; ** compared with cysteamine. (0)FZ; ()I FZ + cys ( % ); cys (a); control.
FZ
Control
Figure 5 Stress induced rat ulcer after 45 days FZ discontinuation. *P < 0.05 (;%) FZ; (.:. ) Control. Tahle 2 The ulcer relapse rate of FZ and other anti-ulcer agents
3
L
Drug
0
( “ 2
0
6 months
10 months
2 years
3 years
(%)
(%)
(Oh)
(W
34.70 25.00 11.70 7.70 4.70
78.30 66.70
-
-
-
-
-
-
-
7.69
9.52
= I
1
0 Hormone
Figure 4 DA agonists and antogonistson cysteamine induced rat duodenal ulcer ( ) c = cysteamine; (0)c + H; ( V ) C + H + FZ; ( 8 ) C+M, ( w ) c + F Z + M + H ; ( m )C+B; ( ) C + B + FZ. C = cysteamine; B = bromocriptone M = Madopa; FZ = furazolidone; H = haloperidol.
weeks and the H P clearance rate was 93% (13/14) in the treatment group versus 13% (4/13) in the placebo group.5 It is doubtful whether the ulcer healing efticacy of FZ can be attributed to anti-HP efficacy, because H P positive peptic ulcer patients could also be healed by H2 blockers.
Other effects of FZ Animal studies have also shown FZ could enhance gastric mucus secretion, DNA and protein synthesis, but human and animal studies showed no effect on prostaglandin synthesis. This could explain why FZ has no protective effect on indomethacin induced animal ~ l c e r . ’ ~ . ~ ~
Cimetidine Famotidine Amatadine Bromocriptine FZ
*No further relapse.
ance efticacy of FZ was not very good and the long-term ulcer healing effect could not be attributed to H P clearance. Recently, Sikiric et ul. used DA agonist (bromocriptine and amatadine) in the treatment of human peptic ulcer, H2 blockers (cimetidine and famotidine) were used as control. T h e ulcer healing rates in two groups were significantly different after a 4 week course. But the long-term effects in two groups were significantly different. T h e 6 month ulcer relapse rate of cimetidine and famotidine was 34.7 and 25% versus 7.7 and 11.7% in the bromocriptine and amatadine groups, respectively. After 10 months, there was no more relapse in DA agonist group but 78.3 and 66.7% in the cimetidine and famotidine groups.32 These data suggest that DA might be associated with the long-term ulcer healing effect of FZ.
CONCLUSIONS
The mechanisms of long-term effect Animal and human studies suggested that FZ had a long-term ulcer healing effect (Fig. 5, Table 2). In human ulcer the effect might be due to the anti-HP efficacy of FZ. But it could not explain the long-term effect on animal experiments. Gilman used FZ 0. l/day for 2 weeks and HP clearance rate was 92.8%, but after 6 weeks of discontinuation of FZ only 4 cases remained H P n e g a t i ~ e .This ~ suggested that the long-term H P clear-
Based on this review, we could conclude that FZ has good short- and long-term ulcer healing efficacy. The mechanizms might be due to its M A 0 inhibitory effect and its anti-HP action may play a minimal role. The formation and healing of peptic ulcer disease is associated with the change of DA, but how DA affects peptic ulcers and why DA agonists have good long-term ulcer healing effects still remain an enigma to researcher.
537
Furazolidone for peptic ulcer disease
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16. ALI B. H. Pharmacology and toxicity of furazolidone in man and animals: Some recent research. Gen. Pharmacoi. 1989; 20: 557-63. 17. XUE Y. L. er al. T h e absorption and distribution of furazolidone in animal study. J. Beijing Med. Univ. 1987; 19: 435. 18. WHITEA. H. Absorption, distribution, metabolism and excretion of furazolidone: A review of the literature. Scan. J. Gastroenterol. 1989; 24: (suppl. 169): 4-10. 19. XINGL. P. et al. Research of the mechanisms of furazolidone in the treatment of peptic ulcer disease. Proceeding of the 3rd Congress Conference of Digestive Disease of China, Kunmin. 1987; 1. 20. DONGX. Y., Lu Q. H. Furazolidone on the acid secretion of rats. Beijing Med. 1980; 2: 183. Y. & URAKAWA T. Experimental studies on the 21. NACAHATA role of dopamine in stress ulcer. Jpn. J. Gastroenterol. 1986; 83: 1287-97. 22. CHENG. R. et al. Dopamine and haloperidol on the rat gastric mucosa. Chin. J. Digestion 1990; 10: 242. 23. SZABO S. Dopamine disorder in duodenal ulceration. Lancet 1979; ii: 880. 24. HERNANDEZ, D. E. er a[. Increasing dopamine receptor binding in duodenal ulcer patients. Dig. Dis. Sci. 1989; 34: 543-7. T. Furazolidone on the gut 25. XING L. P. & ZnENG. cotachalamine in cysteamine induce duodenal ulcer. Chin. J. Internal Med. 1988; 27: 282-5. 26. ZHENCZ. T., XINGL. P. Effect of furazolidone on gut catecholamine in cysteamine induced duodenal ulcer in the rat. Scan. J. Gastroenterol. 1988; 23: 1020-4. 27. HUANCC. W. & ZHENGZ. T. T h e effect of furazolidone on brain monoamines in the treatment of peptic ulcer. Natl Med. J. China 1989; 69: 195-7. 28. HOWDEN A. er al. I n virro susceptibility of Campylobacter pyloridis to furazolidone. Lancet 1986; 3: 1035 (letter). 29. GRAHAM D. Y. et al. In vivo susceptibility of Campylobacrer pylori. A m . J. Gastroenterol. 1989; 34: 233-8. 30. J I A B. Q. T h e possible role of Campylobacrer pylori in the peptic ulcer disease. Chin. J. Digestion 1990; 10: 1-2. 31. LI J. S. et al. Prostaglandin in the pathogenesis of peptic ulcer-the exploration of the mechanisms of furazolidone. Chin. J. Digestion 1988; 8: 18. 32. SIKIRIC P. et al. Dopamine agonists lessen DU relapse rate. Dig. Dis. Sci. 1990; 35: 1040.
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