The Nitroimidazole Family of Drugs
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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 nitroimidazole family of drugs In 1955 an antibiotic complex isolated from a operative infection 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 chemotherapy, such as azomycin. It had previously been isolated in Japan metronidazole, 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-nitroimidazoles (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 antiprotozoal 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 Trichomonas vaginalis and Tricho- and their relationships. monas foetus. In this subsequent period other It is worth noting that the first direct challenge to protozoa-such as, Giardia lamblia and Entamoeba 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 nifuratel (Magmilor), marketed in the to be susceptible. Through the 1960s the potential United Kingdom in 1960, is a nitrofuran, a series of the drug as treatment for the serious tropical that includes such drugs as nitrofurantoin and disease amoebiasis was explored and established in nitrofurazone (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 nimorazole (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 tinidazole (IIc) A much more recent development, which followed (Fasigyn, Pfizer) (Miller et al., 1969), which has the recognition of the importance of certain groups been available for about six years, and ornidazole of non-sporing anaerobic bacteria and especially (IId) (Tiberal, Hoffmann-La Roche), a recent Bacteroidesfragilis in a wide range of infections, has introduction. Three other products which have been the establishment of metronidazole as a specific attracted recent interest are secnidazole (IIe) (see highly effective drug for the treatment of these page 77), carnidazole (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 oral administration, 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 excretion, 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 imidazole 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 trichomoniasis 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 in vitro 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).