sign in sign up
<<
Home , Carnidazole, Metronidazole, Nitrofuran, Nitrofurantoin, Nitroimidazole, Ornidazole

Br J Vener Dis: first published as 10.1136/sti.54.2.69 on 1 April 1978. Downloaded from

British Journal of Venereal Diseases, 1978, 54, 69-71

Editorial The family of drugs

In 1955 an complex isolated from a operative caused by susceptible anaerobes, strain of Streptomyces on the island of Reunion particularly in gynaecological surgery, appendi- was found by research workers of Rhone-Poulenc in cectomy, and colonic surgery. Paris to contain a trichomonacidal antibiotic- Real innovations in , such as azomycin. It had previously been isolated in Japan , always attract attention from other (Maeda et al., 1953) and identified as 2-nitroimi- research groups. Although interest was slow to dazole (Ia see Table) (Nakamura, 1955). At the develop, research workers have sought analogous, time, and for some years after, this remarkably structurally-modified compounds which might afford simple compound defied synthesis, but it stimulated some advantage in clinical use-for example, the workers at Rhone-Poulenc to prepare and test greater potency, better tolerance and freedom from the activity of the more readily accessible isomeric side effects, a broader spectrum of action, a longer 5- (II). It was their good fortune in duration of action, or in some other characteristic. 1957 to find that these isomers were more active This effort has been concerned with important agents than the natural product veterinary uses of 5-nitroimidazoles as well as the (Cosar and Julou, 1959). In a series of 150 related applications in human medicine. compounds, the one with a P-hydroxyethyl group Metronidazole has been a difficult target to in the 1-position gave the best compromise between improve upon, but several other drugs of this activity and toxicity and this brand of metroni- chemical family have been introduced to clinical dazole was introduced as Flagyl. practice and many more have been described in By the end of the decade, metronidazole was various stages of research. The main purpose of as the agent this editorial is briefly to review these newer drugs well established first systemically http://sti.bmj.com/ effective against and Tricho- and their relationships. monas foetus. In this subsequent period other It is worth noting that the first direct challenge to -such as, lamblia and metronidazole as a systemically effective tricho- histolytica-which share with trichomonad species monacide was not a 5-nitroimidazole. The Italian a parallel sensitivity to various drugs, were shown discovery (Magmilor), marketed in the to be susceptible. Through the 1960s the potential United Kingdom in 1960, is a , a series of the drug as treatment for the serious tropical that includes such drugs as and disease was explored and established in (but, as such, is outside the scope of on September 24, 2021 by guest. Protected copyright. both the intestinal and extra-intestinal forms, this article). including sy tnptomless cyst passers. The second nitroimidazole to be introduced was During this period, many additional therapeutic (lIb) (Naxogin), previously known as claims were made in an astonishing variety of nitrimidazine. This was also discovered in Italy, by conditions, ranging from alcoholism to haemor- the research workers of Carlo Erba (de Carneri rhoids, but of the few that stood the test of time the et al., 1969), and it was introduced in Britain in most significant was the treatment of acute ulcerative 1970. By the middle of 1977 no other member of gingivitis, Vincent's angina, after acute clinical this class had been marketed in this country for use observation by a British dental surgeon (Shinn, in human medicine. Two others are however in use 1962). on the Continent, these being (IIc) A much more recent development, which followed (Fasigyn, ) (Miller et al., 1969), which has the recognition of the importance of certain groups been available for about six years, and of non-sporing anaerobic and especially (IId) (Tiberal, Hoffmann-La Roche), a recent Bacteroidesfragilis in a wide range of , has introduction. Three other products which have been the establishment of metronidazole as a specific attracted recent interest are (IIe) (see highly effective drug for the treatment of these page 77), (lIf), and a 2-nitroimidazole, infections. It is also useful in preventing post- Ro 07-0582 or misonidazole (Ib), which has been 69 Br J Vener Dis: first published as 10.1136/sti.54.2.69 on 1 April 1978. Downloaded from

70 British Journal of Venereal Diseases the subject of recent investigations in a different The comparative trichomonacidal activity of field, that of radiosensitisation. these drugs in experimental animals differs with the The close structural relationships of these com- host and infecting species used; ornidazole has an pounds are demonstrated in the Table, which shows ED50 of 3 mg/kg against T. foetus but 37 mg/kg that the above products, apart from misonidazole, against T. vaginalis in the mouse (Grunberg et al., differ only in the groups attached to the ring nitrogen 1970). It has been shown in some reports that adjacent to the nitro group. Secnidazole is a simple nimorazole and tinidazole have lower ED50, than homologue of metronidazole; orinidazole differs metronidazole but other reports have not substan- from it only by having a hydrogen replaced by tiated this. It is doubtful whether differences in the chlorine. These modest changes in structure, as well values are often of much therapeutic significance. as the basic substituent, morpholine, in nimorazole, All these drugs are absorbed efficiently from the the sulphone group in tinidazole, and the thio- digestive tract after , but they carbamate system in carnidazole may be expected differ in their pharmacokinetic properties in humans. to modify various physicochemical and biochemical The serum half-life of tinidazole (12-5 h) is nearly characteristics-such as, distribution between twice that for metronidazole (713 h), while that of aqueous and lipid media, transport across mem- secnidazole (17 h) is half as long again. Nimorazole branes, metabolic pathways, tissue distribution, is more rapidly absorbed and excreted than metroni- routes of , and other properties. They dazole and it may be some advantage that its two probably have little effect on the essential anti- main urinary metabolites retain antiprotozoal protozoal or antibacterial action, which appears to activity. It is also claimed that this compound is be a function of the nitro group associated with the more effectively absorbed from pessaries (de ring. Carneri et al., 1969). Comparisons of the anti-infective activity of Are these modest differences of practical relevance related drugs are notoriously misleading when they in clinical practice? Again it is not easy to draw are based on results from different laboratories clear-cut conclusions by a review of published work. using different strains of pathogen and different Cure rates for are usually good experimental techniques. Broad generalisations (85 to 95 %) but they are complicated by the number alone are possible from a review of the literature. of relapses and by whether or not these are re- The first is that activities of the five 5-nitro infections: the concomitant treatment of consorts drugs against T. vaginalis or T. foetus are of the always gives better results. When studies on metro- same order, and minimal inhibitory concentrations nidazole and on each of the other drugs have been http://sti.bmj.com/ range from 0-12 to 60 jig/ml. There are minor compared, using similar dosage schedules, the variations in activity against G. lamblia and E. results have been similar. histolytica, metronidazole being among the most The subject of dosage schedules has received potent; and somewhat more variation against much attention, with shorter schedules being sought Gram-negative anaerobic bacteria, where nimor- for the newer drugs which would be an advantage azole is slightly less active than the others. in the type of patient often seeking treatment. on September 24, 2021 by guest. Protected copyright. Table Structures of nitroimidazoles studied in human medicine 02N I I

Rx - N1 N R- N + N

NO2 R2 (I) (11) (la) R'=H (Ila) R=-CH2CH2 OH; R2 = CH3 OH 2 (llb) Rq=-CH2CH2N 0; R =H nimorazole (Ib) R=-CH2.2CH.CH2.OCH3 misonidazole (lic) R!_ - CH2CH2.SO2.CH2 CH3;R=CH3 tinidazole OH (lid) R=-CH2.CH.CH2 Cl; R=CH3 ornidazole OH 1 ~~~~~~2 (lie) Rl=-CH2.CH.CH3; R = CH3 secnidazole (lIf) RW=-CH2CH2 NH-CS-OCH3 R2= CH3 carnidazole Br J Vener Dis: first published as 10.1136/sti.54.2.69 on 1 April 1978. Downloaded from

Editorial-The nitroimidazole family of drugs 71 Whereas the standard course originally established 1973). This has been confirmed by clinical trials at for metronidazole was 200 mg thrice daily for Mount Vernon Hospital, Northwood (Deutsch seven days, nimorazole was introduced in regimens et al., 1975) and also by North American investi- of three 1 g doses at 12-hourly intervals or even as a gators (Urtasun et al., 1975, 1976). In a search for single 2 g dose. Metronidazole has since been shown related compounds with higher electron-affinity, to be effective in these regimens. 2-nitroimidazoles were found to be promising The single-dose treatment has obvious clinical and misonidazole was selected for its high potency. attractions and there is evidence that all five drugs Unfortunately the doses used were still very large: give a good cure rate after such a schedule. Orni- this experimental drug shows signs of being too toxic dazole has been shown to give successful cures in for regular use for this radiosensitising purpose. 870 of cases after a single course of four 500 mg pes- In this special field therefore there is much scope saries (Hillstrom et al., 1977; Skold et al., 1977). The for a more satisfactory compound; in the traditional high success rate after a single 2 g dose of secnidazole fields significant improvement on existing agents is reported, see page 77, but it is perhaps too early will probably be extremely difficult to attain. to say the longer the half-life in serum the higher the cure rate after a single dose. The only information References on carnidazole is that given by Notowicz et al. Cosar, C., and Julou, L. (1959). Activity of 1-(21-hydroxyethyl)-2- (1977) who showed that a high cure rate was methyl-5-nitroimidazole (8823 RP) against experimental Tricho- achieved in women with a single 2 g dose. monas vaginalis infection. Annales de l'Institut Pasteur, 96, 238-241. de Carneri, I., Cantone, A., Emanueli, A., Giraldi, P. N., Logemann, Resistance to metronidazole among tricho- W., Meinardi, C., Monti, G., Nannini, G., Tosolini, G., and monads has been induced in laboratory experiments Vita, G. (1969). In Progress in and Anticancer Chemo- if for therapy-Proceedings of the Sixth International Congress of Chemo- but it has very rarely, ever, been responsible therapy, Tokyo, 1969. therapeutic failure of which the commonest cause is Deutsch, G., Foster, J. L., McFadzean, J. A., and Parnell, M. (1975). reinfection. Cross-resistance in trichomonads is Human studies with high dose metronidazole. A non-toxic radio- sensitiser of hypoxic cells. British Journal of Cancer, 31, 75-80. shown in the laboratory between nitroimidazoles, Foster, J. L., and Willson, R. L. (1973). Radiosensitisation of anoxic as might be expected between drugs probably cells by metronidazole. British Journal of Radiology, 46, 234-235. Grunberg, E., Cleeland, R., Prince, H. N., and Titsworth, E. (1970). acting by the same mechanism, but it may be oc-Chloromethyl-2-methyl-5-nitro-l-imidazoleethanol (Ro 7-0207) incomplete. a substance exhibiting activity against amoebae, the newer in amoebiasis have trichomonads and pinworms. Proceedings of the Society for Studies of products Experimental Biology and Medicine, 133, 490-492. been limited and conclusions must be tentative. Hillstrom, L., Pettersson, L., Palsson, E., and Sandstrom, S. 0. Powell and Elsdon-Dew (1972), of the amoebiasis (1977). Comparison of ornidazole and tinidazole in single-dose treatment of trichomoniasis in women. British Journal of Venereal http://sti.bmj.com/ research unit in Durban, compared four of these Diseases, 53, 193-194. drugs in the treatment of amoebic . Maeda, K., Osato, T., and Umezawa, H. (1953). A new antibiotic azomycin. Journal of , 6A, 182. Ornidazole came nearest to the performance of Miller, M. W., Howes, H. L., and English, A. R. (1969). Tinidazole, metronidazole, but tinidazole was slower in action, a potent new antiprotozoal agent. Antimicrobial Agents and and nimorazole failed to eradicate the intestinal Chemotherapy, 9, 257-260. Misra, N. P., and Laiq, S. M. (1974). Comparative trial of tinidazole infection, as shown by the number of cyst passers and metronidazole in intestinal amoebiasis. Current Therapeutic after treatment. Insufficient activity in the gut is a Research, 16, 1255-1263. Nakamura, S. (1955). Structure of azomycin, a new antibiotic. on September 24, 2021 by guest. Protected copyright. weakness of all the 5-nitroimidazoles. Indian Pharmaceutical Bulletin (Tokyo), 3, 379. workers however obtained equal results with Notowicz, A., Stolz, E., and De Koning, G. A. J. (1977). First experiences with single-dose treatment of vaginal trichomoniasis metronidazole and tinidazole when they compared with carnidazole (R 25831). British Journal of Venereal Diseases, five-day courses of 400 mg three times a day of the 53, 129-131. with 600 a the latter Powell, S. J., and Elsdon-Dew, R. (1972). Some new nitroimidazole former mg twice day of (Misra derivatives: clinical trials in amoebic . American and Laiq, 1974; Prakash et al., 1974). Journal of Tropical Medicine and Hygiene, 21, 518-520. In clinical reports, the effectiveness of metroni- Prakash, C., Bansal, B. C., and Bansal, M. R. (1974). A comparative study of tinidazole and metronidazole in symptomatic intestinal dazole against Gram-negative anaerobic infections amoebiasis. Journal of the Association of Physicians of India, 22, is well established. While there is no reason to doubt 527-529. Shinn, D. L. S. (1962). Metronidazole in acute ulcerative gingivitis. the potential efficacy of the newer drugs, clinical Lancet, 1, 1191. evidence has not yet been published. Skold, M., Gnarpe, H., and Hillstrom, L. (1977). Ornidazole: a new The 2-nitroimidazole, also deve- anti-protozoal compound for treatment of Trichomonas vaginalis misonidazole, infection. British Journal of Venereal Diseases, 53, 44-48. loped by Hoffmann-La Roche, is of interest in a Urtasun, R. C., Band, P., Chapman, J. D., Feldstein, M. L., Mielke, different connection. In 1973, Dr R. L. Willson of B., and Fryer, C. (1976). Radiation and high dose metronidazole in supratentorial glioblastomas. New England Journal of Medicine, Brunel University demonstrated that metronidazole, 294, 1357-1364. probably because of its marked electron-affinity Urtasun, R. C., Chapman, J. D., Band, P., Rabin, H., Fryer, C., and Sturmwind, J. (1975). Phase I study of high dose metronidazole. character, was able to render hypoxic tumour cells An in vivo and in vitro specific radiosensitizer in hypoxic cells. more sensitive to radiotherapy (Foster and Willson, Radiology, 117, 129-133.