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The effects of metronidazole, which selectively sensitizes hypoxic cells, on the radiation response of C3H mouse mammary carcinoma and of mouse skin and jejunal epithelium have been investigated. A dose of 2.5 mg of metronidazole/mouse reduced the TCD50 from a control value of 6,360 rads to 5,310, 5,310 and 5,400 rads, at 3, 10 and 30 minutes after i.v. injection, respectively, in mice bearing tumors 8 mm in diameter. The skin response, as measured by the DD50, was also enhanced by metronidazole, the control value being 4,780 rads, compared to 3,980 rads in metronidazole-treated mice. The jejunal epithelium, however, was not sensitized by metronidazole, but conversely, a slight protective effect was observed at high radiation doses. This dose of metronidazole had no effect on tumor growth rate and was not toxic to the mice.

Serum IgE concentration is measured, according to the Rowe modification of the Mancini technique, in non-atopic patients suffering from various helminthic or protozoal infections. Our results indicate that the IgE level is often raised in parasitosis with prominent tissue phases and remains normal with helminths whose life is restricted to the lumen of the digestive tract. In addition, our observations show that, with helminthic or protozoal infestations, the serum IgE level tends to increase significantly and rapidly following a specific treatment of the parasitosis. Afterwards, the serum IgE level decreases slowly and may return to the normal in a few months. Thus, repetitive evaluations of serum IgE concentrations, before and after therapy, appear to be of a diagnostic value in the cases where a vague clinical picture is suggesting an helminthic parasitosis.

Four patients with well-documented amebic colitis had colonic deformities suggestive of ameboma. When barium enema examinations were performed, each of the 4 had cecal “coning,” and 1 had an additional sigmoid lesion. Only 1 patient with a cecal lesion had a palpable, tender mass in the right lower quadrant. After treatment with metronidazole (multiple courses in 1 case), there was clinical and parasitologic cure in each case and radiologic improvement in the 3 who were available for followup. Since ameboma may be confused with carcinoma, a search for amebae in stool and an indirect hemagglutination test for amebiasis may prevent unnecessary and potentially disastrous surgery.

A 21-year-old white male serviceman developed amebic dysentery in Vietnam which was cured clinically and parasitologically with metronidazole, 750 mg three times a day for 10 days. Eight months later (2 months after his return to the United States) he was hospitalized with fever and right upper quadrant pain and tenderness. A large hepatic abscess was detected on scan. Precystic forms of amebae were present in aspirates of the abscess. Cultures for bacteria and fungi were negative. Multiple stool specimens were negative for cysts or trophozoites of Entamoeba histolytica. Clinical cure with slow disappearance of the filling defect on liver scan followed chloroquine and uncomplicated prolonged metronidazole therapy. It is postulated that the liver abscess was present at the time of original infection and that the initial course of metronidazole therapy, though appropriate for colonic amebiasis, was not adequate for amebic hepatic abscess. It is recommended that liver function tests and radioisotopic scan of the liver be obtained in all cases of colonic amebiasis to detect early evidence of hepatic amebiasis.

A steroid danazol (17-alpha-Pregn-4-en-20-yno(23-d)-isoxazol-17-ol) possesses a marked separation of pituitary gonadotropin inhibitory activity from overt sex hormonal activities. The effect of danazol on fertility in the rat was determined. Danazol produced a dose-related decrease in the weights of ventral prostate seminal vesicles and testes of mature male rats when given orally at 80 mg/kg daily for 6 months - 1 year. It also produced highly significant decreases in the weights of sex accessory organs and testes. Mature female rats showed a similar dose-related effect on ovaries adrenals and thymus. Body weight and ovaries increased during treatment. Danazol was not progestational in the Clauberg assay when adminsitered orally at doses as high as 80Omg/kg. A dose of 20Omg/kg for 6 days following insemination was completely effective in preventing pregnancy.

A limited outbreak of giardiasis was observed in 5 families. Four of the families had been in direct contact with the presumed index case. The infection rate was estimated to 100%. The fifth family was infected indirectly by one of the mentioned families and infection occurred in 50%. Three infectious generations could thus be demonstrated and the index case was most likely a 3-year-old girl adopted from Israel.

Summary In L URIA AND D ELBRUCK'S fluctuation test, with streptomycin-resistance and streptomycin-dependence as markers, certain derivatives 0f 5-nitroimidazole having an antiprotozoal activity increased the mutation rate of Klebsiella pneumoniae, Escherichia coli K12 and Citrobacter freundii 425. Among the substances tested, ronidazole showed the highest mutagenic activity, increasing the mutation rate of Klebsiella pneumoniae grown in 0.1 mM solutions by a factor 0f 26.5. The mutation frequency of bacteria grown in 0.1 mM solutions 0f metronidazole (Flagyl®), nimorazole (Naxogin®) and dimetridazole was increased between 3 and 7 times above the normal spontaneous mutation rate. The possible implications of these findings in the application of the substances as human antitrichomonal drugs (metronidazole and nimorazole) or preparations t0 prevent infections by Histomonas meleagridis in poultry (dimetridazole and ronidazole) are discussed.

A study was performed to determine the effect of miconazole on the occurrence of pathogenic yeasts after metronidazole treatment in 40 patients with vaginal trichomoniasis. The patients were randomly divided into two groups of 20. Group 1 received orally 250 mg of metronidazole b.i.d. for 10 days. Group 2 applied miconazole once daily for 14 days in addition to an identical metronidazole treatment. Microbiological examinations and pH determinations were done before and after treatment. Before treatment yeasts were found in six patients of the miconazole group and in three patients of the control group; after treatment two and seven occurrences were found, respectively. A significant decrease in vaginal pH was observed in both groups after treatment. After treatment trichomonads were still found in two patients of the control group and in none of the patients in the miconazole group. On the basis of these data it may be advisable to use miconazole along with trichomonacidal treatment in patients with vaginal trichomoniasis.

Various roentgen features of 19 cases of amebic colitis are analyzed and compared with granulomatous colitis, ulcerative colitis and other ulcerative diseases of the colon.The lesions of amebic colitis, in general, had a shaggy contour; the eccentric lesions were almost as common as the concentric lesions. The left-sided colitis was as common as the right-sided colitis and diffuse colitis was present only in the form of multiple skip lesions. Skip lesions were common. Deep and superficial ulcers of varying types were noted and had, in general, a ragged appearance. Various types of unspecific haustral and mucosal changes were noted. The annular lesions of amebomas were distinguished from carcinomas in most cases by their gradually tapering ends, relatively well preserved mucosa and response to antiamebic therapy.The diagnosis of amebic colitis was strongly considered when the cone-like cecum was accompanied by an intact terminal ileum and a skip lesion elsewhere in the colon. The shaggy contour of the lesi...

SummaryA total of 64 patients suffering from trichomoniasis were treated with a single oral dose of 2.0 g. tinidazole or 2.0 g. metronidazole in a comparative study. Forty-three patients received tinidazole, and 21 patients metronidazole. In the tinidazole group, 3 therapy failures occurred; in the metronidazole group, 1 therapy failure was observed. Even though there was a small number of patients, the tolerance of tinidazole seemed to be slightly better than that of metronidazole. These results seem to correspond with those of other authors with regard to the effectiveness and the tolerance of the single-dose treatment of tinidazole in treating trichomonal infections. The results with this new dosage schedule are at least equivalent and perhaps even superior to the usual 7-day treatment regime.

The radiosensitizing properties of metronidazole have been studied using bacteria, bean roots, and mammalian cells in vitro as test systems. Metronidazole has been shown to sensitize only anoxic cells in a concentration-dependent manner, a maximum enhancement ratio of 1·9 being obtained at 8 mmol/1. metronidazole concentration for mammalian cells. The effect of added SH compounds on the sensitizing effect of metronidazole was studied in bacteria and bean roots. Metronidazole sensitized bacteria to the effects of neutron irradiation by a factor of only 1·4. The mechanism of sensitization by metronidazole is discussed in the light of pulse radiolysis and ESR data, and its action compared with that of oxygen. Pharmacological data presented suggest that in vivo testing of metronidazole should be possible and that any radiosensitizing effects shown may be related to measured serum concentrations.

SummaryThe rates of reaction of ‘metronidazole’ [1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole] with e−aq, ·OH, ·CO−2, ·CH2OH, ·CHMeOH and ·CMe2OH have been measured by pulse radiolysis.E.s.r. data also show that metronidazole reacts rapidly with ·CH2OH, ·CMe2OH and ·CO2H; the spectrum of an intermediate in these reactions is attributed to the metronidazole radical-anion.

60 strains of Bacteroides fragilis were characterized by biochemical tests and by gaschromatographic analysis. In antibiotic sensitivity testing all strains were relatively resistant to β-lactamantibiotics, and many were resistant to tetracyclines. Of all the antibacterial drugs tested, clindamycin, chloramphenicol, tinidazole and metronidazole possessed the best activity.

Trichomonas vaginalis was first described byDonne (1836), who observed theorganism inpurulent secretions inbothwomen andmen, andstated that itwas not presentinnormalvaginal secretions. T.vaginalis was successfully cultured invitroby Lynch(1915), andthere havesince beenanumberof publications containing descriptions ofthemorpho- logical, epidemiological, andpathological aspectsof trichomonal infestation (Trussell, 1947; Whittington, 1957;Burch, Rees,andReardon, 1959a; Frostand Honigberg, 1962;Niekerk, 1963;Honigberg and King,1964;Nielsen, Ludvik, andNielsen, 1966). Therewas no effective therapy forTrichomonas infection untilthediscovery of metronidazole (Flagylg) by Durel,Roiron, Siboulet, andBorel (1960). Thisgreattherapeutic advanceledto the needforimprovedmethodsof demonstrating T.vaginalis insecretions. The simplest andmost rapid methodisdirect microscopy ofunstained wet preparations inwhichtheactively movingorganism isreadily recognized. However, sincethedevelop- mentofsuitable mediaithasbeenfoundthatculture isthemost sensitive method(Whittington, 1957; Burch,Rees,and Reardon, 1959b;Petri, 1962; Lowe,1965;Hess,1969). Routine culture ofT.vaginalis hasbeencarried out intheNeisseria Department oftheStatens Seruminstitut, Copenhagen, since1962,and a methodoftesting thesensitivity to metronidazole hasbeendeveloped concurrently.

Approximately 150 compounds are mentioned in the literature concerning the chemotherapy of trichinellosis. On the basis of a critical review of the data they have been placed in the following categories: 1. I. Compounds reported inactive. 2. II. Compounds for which efficacy has been claimed but which have not been shown to be clearly active at tolerated dosage. 3. III. Compounds with unequivocal efficacy, or with special significance in experimental or clinical trichinellosis. 3.1. A. Effective in the enteral phase 3.1.1. 1. Compounds that reduce worm burden 3.1.2. 2. Compounds that reduce worm fecundity 3.1.3. 3. Prophylactic compounds 3.2. B. Effective in the parenteral phase 3.2.1. 1. Compounds that are lethal to larvae 3.2.2. 2. Compounds that reduce viability or infectivity of larvae 3.2.3. 3. Drug types (benzimidazoles, organophosphates, tetramisole, diethylcarbamazine, antimitotics) 4. IV. Nonspecific drugs in clinical management. Many compounds have prophylactic or therapeutic activity in the enteral phase of trichinellosis in laboratory animals, but the only compounds active in the parenteral phase are certain benzimidazoles, certain organophosphates, tetramisole, diethyl-carbamazine, and, perhaps, certain antimitotic agents. In man, nonspecific agents, such as corticosteroids, have formed the traditional basis of treatment. There is evidence, however, that thiabendazole and diethylcarbamazine are effective in reducing the severity of the disease in man. In the case of thiabendazole the effect appears to be due, at least in part, to an anthelmintic effect directed against the muscle-dwelling larvae.

DOI: 10.3329/jcmcta.v20i2.5623Journal of Chittagong Medical College Teachers' Association 2009: 20(2):29-32

SummaryThe effect of Metronidazole upon alcohol consumption of two groups of rats has been measured. The first group of 11 animals was selected because they clearly showed a heightened preference for alcohol after a period of forced addiction. In these, a daily in-traperitoneal injection of Metronidazole was followed by a precipitous drop in alcohol consumption. In a second group, 18 animals selected because of their primary preference for alcohol, demonstrated the same substantial drop in alcohol consumption after the Metronidazole injections. No sex differences were found.

Subctaneous injection of suspension of odoriferous pus collected from the lesion of experimental Vincent's disease induced on a guinea pig was made in depilated back of another guinea pig weighing from 250 to 350 grams. The water solutions of Flagyl were injected subctaneously to the other portion on the back of the guinea pig, 10, 5 and 2.5mgs a day for 7 days respectively. The Flagyl group had a less production of pus and did not remain spirochaete or odour in the pus.Clinical trial:Clinical examination was made in 50 adults who were pointed out halitosis by means of double blind method. They were given 400mgs of either Flagyl or placebo tablets once a day for 5 days. Unexpectancy, disappearance of halitosis was not experienced only in the Flagyl group. The consideration of these results was discussed.

The chemotherapeutic activity and the toxicity of some nitroheterocycles used in antiparasitic therapy (aminitrozole, 2-α-thenoylamino-5-nitrothiazole, niridazole, furazolidone, nifuratel and metronidazole) were compared in laboratory tests. Metronidazole appeared as the most active compound against trichomoniasis and amoebiasis and had in addition the widest safety margin; it also had the highest therapeutic index against lambliasis. Niridazole while showing activity against these protozoa had a less favourable therapeutic index but was the only one which was very active against bilharziasis. Furazolidone appeared as a specially good antibacterial agent with a good activity against Iambliasis. Aminitrozole showed a wide spectrum of activity; its safety margin was slightly lower, however. The other two (2-α-thenoylamino-5-nitrothiazole and nifuratel) were less active and showed a narrower spectrum of activity.

Euthyroid rats given metronidazole for30 days had no significant alteration in body or thyroid weight, but had a significant depression of pituitary weight. However, the pituitary TSH content was not affected. Hypothyroid rats given metronidazole developed smaller goiters than controls, but the difference was not statistically significant. The serum TSH level of rats receiving metronidazole was significantly less than controls being 0.12 mU/ml. vs. 0.44 mU/ml. When net TSH synthesis was measured (see Method) metronidazole treatment significantly reduced synthesis from 212 mU/24 hrs. to 145 mU/24 hrs. These findings in rats are consistent with the claim that metronidazole inhibits TSH secretion and thyroid function in man.

Seven of 8 patients with hypogammaglobulinemia and gastrointestinal symptoms were infected with Giardia lamblia. This parasite was not detected by multiple stool examinations in 4 of the 7 infected patients but was diagnosed correctly by small intestinal biopsy. Abnormalities of the small intestinal mucosa were found in all 8 patients. Two patients had nodular lymphoid hyperplasia and 3 the flat lesion of hypogammaglobulinemic sprue. The remaining 3 patients had mixed lesions; that is, the lesions varied both in severity of the villus abnormality and in the frequency of lymphoid nodules. All patients lacked plasma cells in the lamina propria. Because of the variation in the severity of the small intestinal abnormalities within individual patients, multiple small bowel biopsies were needed to evaluate the effects of treatment on mucosal morphology. After eradication of Giardia lamblia in 7 patients, the abnormalities in villus structure returned towards normal in all. No change occurred after a course of metronidazole (Flagyl) in the 1 patient who had a severe intestinal lesion but no evidence of giardiasis. Four patients with steatorrhea and giardiasis gained weight and their fecal fat excretion returned to normal. Diarrhea disappeared after treatment in the remaining 3 patients.

Giardiasis was diagnosed in three of five children by means of small intestinal biopsy and smears of biopsy mucus when stool examinations failed to demonstrate the parasite. In a fourth patient the biopsies and smears were positive for the trophozoites, but one of three stools examined contained cysts. Biopsies were not taken from a fifth patient who had cysts in the stool. All the children had gastrointestinal symptoms; two had steatorrhea. Chronic intractable vomiting occurred in one patient; another had chronic intermittent diarrhea. Treatment with metronidazole for ten days reversed the symptoms and malabsorption completely in all but one patient who had granulomatous colitis.

SUMMARY As reported in the literature, there is a potentially wide spectrum of antiparasitic and antibacterial activity in the chemical group of nitroheterocyclic compounds. The schistosomicide Ambilhar (niridazole) is an example of a single compound exhibiting anthelminthic, antiprotozoal, and antibacterial properties. A description is given of some of these properties, as revealed in laboratory experiments. The antiamoebic activity of Ambilhar is superior to that of emetine and chloroquine. This statement applies not only to its curative effect against amoebic liver infection, but also to its amoebicidal activity in the rat intestine. With regard to trichomonicidal activity, reference is made to metronidazole as the chemotherapy of choice in trichomoniasis. When mice are used as test models, however, Ambilhar proves active at the same dosage level as metronidazole. In mice, Ambilhar also displays a distinctive spectrum of antibacterial activity; its effect on various types of Enterobacteriaceae, including Salmonella and Shigella species, is of particular interest.