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At least 19 recordsLinked to original sources

PubMed1979

Characterization of metronidazole-phosphate, a water-soluble metronidazole derivative, as a radiosensitizer of hypoxic cells.

A water-soluble derivative of metronidazole (Flagyl) was synthetized with the purpose to overcome some practical difficulties in the clinical administration of the drug. The derivative, a phosphate ester of metronidazole, was characterized for different physical-chemical properties. It had a low toxicity both in vitro and in vivo. In vitro, it retained a radiosensitizing effect specific for hypoxic cells which was, however, decreased in comparison with the parent compound. The decreased sensitization was related to a decreased one-electron reduction potential and octanol/water partition coefficient. In mice, metronidazole-phosphate had a prolonged blood life in comparison to metronidazole.

Animals↗

PubMed1979

[Radiosensitization with metronidazole. Pharmacocinetical comparison by means of blood level curves after administration of "metronidazol" in the form of tablets, suppositories, and enemas (author's transl)].

Severe acute gastrointestinal side-effects following high oral doses of metronidazole (6 g/m2) could be avoided by a combined oral and rectal application. With tablets and an enema (1 g metronidazole/2 ml) in a ratio 1:4 and an increased dosage of 10 g/m2, maximal serum concentrations of about 200 micrograms/ml are obtained like after an oral dosage of 6 g/m2. The maximal radiosensitizing effect on hypoxic tumor cells is seen five hours after oral application and seven hours after the combined oro-rectal application. No longterm toxicity was found following six high doses of metronidazole.

Administration, Oral↗

PubMed1979

Metronidazole in the prevention and treatment of anaerobic sepsis.

Clinical trials were carried out in order to determine the value of metronidazole in preventing the development of anaerobic infections after surgery. Following a successful controlled trial of hysterectomy patients, among whom the prophylactic use of oral metronidazole resulted in a reduction of the anaerobic sepsis rate from 25% to nil, further trials were carried out with patients having urgent appendicectomy, those having elective colonic surgery and pregnant women having delivery by the vaginal and caesarean routes. These studies were conducted as double-blind trials in which metronidazole was compared with a placebo; patients were randomly allocated to the two "drug" groups. Since completion of the hysterectomy trial over 618 hysterectomies have been performed under metronidazole cover, none of which were complicated by anaerobic sepsis. Among appendicectomy patients, anaerobic infection did not develop in any of the 49 patients who received prophylactic metronidazole, but bacteriologically confirmed clinical anaerobic infections developed in 9 (19%) of 46 control patients. Since completion of the trial over 1098 appendectomies have been performed under metronidazole cover, only two of which developed an anaerobic infection. Among colonic surgery patients, anaerobic infections did not develop in any of 27 patients who received prophylactic metronidazole, but bacteriologically confirmed clinical anaerobic infections developed in 11 (58%) of 19 control patients. Since completion of the trial over 126 colonic operations have been performed under metronidazole cover, none of which were complicated by anaerobic sepsis. Pregnant women having vaginal delivery were not especially prone to anaerobic infections so that metronidazole prophylaxis is not indicated in these patients. Delivery by caesarean section appears to carry a risk of post surgical anaerobic sepsis in about 20% of patients not protected with metronidazole prophylaxis. Metronidazole is regarded as the drug of choice for the treatment of those non-clostridial anaerobic infections that require antimicrobial therapy. It may be given orally, rectally, intravenously and topically, has virtually no side effects and its use is characterized by a strikingly rapid and sustained clinical and microbiological response.

Anaerobiosis↗

PubMed1977

Tinidazole and metronidazole in the treatment of intestinal amoebiasis.

Sixty adult patients with symptomatic intestinal amoebiasis and with Entamoeba histolytica present in stools were allocated at random to treatment with tinidazole or metronidazole, both administered in a dose of 2 g once daily for 3 consecutive days. The treatment period was extended in patients with stools positive for Entamoeba histolytica on the day following the last treatment day. Fifty-six patients, 29 on tinidazole and 27 on metronidazole, completed the trial as per the protocol. Twenty-eight patients (96.5%) on tinidazole and 15 (55.5%) on metronidazole were cured. Parasitological cure with partial relief of symptoms was obtained in 1 (3.5%) and 5 (18.5%) patients on tinidazole and metronidazole, respectively. Seven patients (26%) on metronidazole were treatment failures. Treatment had to be extended beyond 3 day in 53% of patients (8/15) on metronidazole as opposed to 11% (3/28) on tinidazole (p less than 0.01). The total number of side-effects, their severity, and the types were more in the metronidazole group. No toxic effects due to either drug were recorded. Tinidazole provided significantly higher cure rates than metronidazole in the treatment of symptomatic intestinal amoebiasis (p less than 0.01), and was better tolerated than metronidazole.

Adult↗

PubMed1977

Metronidazole ("Flagyl") in dracunculiasis: a double blind study.

Two-hundred and twenty-nine cases dracunculiasis were selected for a double-blind trial of metronidazole against placebo. A cure rate of 85% was observed with metronidazole. A dosage of 400 mg metronidazole three times daily for 10-20 days appears suitable. Even with secondarily infected lesions, it was unnecessary to administer any other chemotherapeutic agent. In most cases symptomatic relief, especially of pain and pruritus, was obtained within two weeks. In patients with only subcutaneous worms, metronidazole did not apparently prevent the development of lesions and seemed to stimulate the worm to emerge quickly, with resultant less severe lesions. Complete cure was delayed in patients with multiple lesions, where worms reached the emergence state at different times. There did not appear to be any direct relationship between severity of the disease and response to metronidazole. If the worm was broken during treatment with metronidazole, no abscess formed nor was there any local inflammation. Metronidazole was very well tolerated even when administered for 20 to 25 days. No serious side-effects or toxic effects were observed.

Clinical Trials as Topic↗

PubMed1979

Changes in the fecal flora of patients with Crohn's disease during treatment with metronidazole. A preliminary report.

Six patients with Crohn's disease and three healthy volunteers were treated with metronidazole. Before and during metronidazole treatment quantitative and qualitative studies of the aerobic and anaerobic fecal bacterial flora were performed, and the minimal inhibitory concentration (MIC) values for metronidazole of the isolated bacteria were determined. There was no significant change in the fecal flora of the volunteers during metronidazole treatment, but three patients who clinically responded well to treatment had drastically changed their anaerobic flora. Two patients did not respond to the metronidazole therapy. The total anaerobic count for one of them was unchanged, and the number of isolated anaerobic species was high during the treatment. The total anaerobic counts of the other non-responder decreased, but metronidazole-resistant (MIC greater than or equal to 40 microgram/ml) Gram-negative rods remained in the fecal samples. Furthermore, after 2 months his condition worsened, and he was given corticosteroids and parenteral nutrition. The result in one patient with a moderate response to therapy was intermediate. Our observations may explain why some patients benefit from metronidazole therapy and others do not.

Adult↗

PubMed1979

Prophylactic peroperative intravenous metronidazole in elective colorectal surgery.

In a prospective double-blind randomised trial 83 patients undergoing elective colorectal surgery were given either preoperative intravenous metronidazole or intravenous normal saline. No other antimicrobials were given. Bowel preparation was the same for both groups. Deep post-operative wound sepsis occurred in 6 of 44 (13-6%) patients on metronidazole but in 20 of 39 (51-2%) control untreated patients. Anaerobes were responsible for all cases of deep sepsis in the metronidazole group (in 5 of the 6 cases aerobes were also isolated), and for 16 of the 20 cases of deep sepsis in the control group (all with aerobes). Superficial infection in the metronidazole group was caused by aerobes. Anastomotic leakage occurred in 5 of the 6 patients who developed deep sepsis on metronidazole and in 10 of 20 patients on placebo. Peroperative intravenous metronidazole dramatically reduced postoperative sepsis but failed to prevent infection in the presence of anastomotic breakdown.

Bacterial Infections↗

PubMed1978

Absence of strand breaks in deoxyribonucleic acid treated with metronidazole.

The deoxyribonucleic acid (DNA)-degrading potential of metronidazole was evaluated in vitro by three techniques: determination of melting curve, measurement of viscosity, and centrifugation in neutral or alkaline sucrose gradients. Studies were performed on calf thymus DNA and on (3)H-labeled or unlabeled pneumococcal and T7 phage DNA after treatment with metronidazole alone or metronidazole reduced by sodium dithionite in the presence of DNA. This latter process is known to elicit covalent binding of metronidazole to DNA. Reduced or unreduced metronidazole had no effect on the melting properties, viscosity, or sedimentation velocity of the nucleic acids studied. Sodium dithionite alone, however, caused a 25% decrease in the intrinsic viscosity of pneumococcal DNA, and decreased the sedimentation velocity of pneumococcal and T7 phage DNA in both neutral and alkaline sucrose gradients. These data suggest that degradation of DNA is not important in the interaction of metronidazole with nucleic acids, an interaction assumed relevant to the cytotoxic, radiosensitizing, and mutagenic activities of this compound.

Centrifugation, Density Gradient↗

PubMed1978

Single-dose oral treatment of vaginal trichomoniasis with tinidazole and metronidazole.

Sixty cases of trichomonal vaginitis were randomly allocated to treatment with tinidazole or metronidazole, both administered as a 2 g single dose. One patient on tinidazole did not complete her follow-up. Parasitological cure was obtained in all patients in both the treatment groups. A satisfactory clinical response was obtained in all 29 patients on tinidazole, and in 27 out of 30 (90%) on metronidazole. Complete relief of sumptoms was obtained in 62% (18/29) and 13% (4/30) of patients ontinidazole and metronidazole, respectively (p less than 0.01). Ten patients on tinidazole and 24 on metronidazole manifested side-effects. The frequency and severity of side-effects were much more in the metronidazole group (p less than 0.01). Tinidazole has distinct advantages over metronidazole in the one-dose treatment of trichomonal vaginitis.

Administration, Oral↗

PubMed1978

Treatment of amoebic liver abscess with tinidazole and metronidazole.

20 patients with amoebic liver abscess, confirmed by aspiration of typical amoebic 'pus', were treated in random order with either tinidazole or metronidazole in a dose of 2g once daily for 2 days. Clinical, radiological, and biochemical follow-up was done for 1 month. One patient, given metronidazole, absconded and 19 completed the trial. Complete recovery occurred in all 10 patients given tinidazole but in only 5 of the 9 given metronidazole (p = 0.05). Patients on tinidazole required repeat aspirations less frequently than those on metronidazole. Mild gastrointestinal side-effects occurred in 1 patient on metronidazole but in none on tinidazole. From the present study, tinidazole appears to be a more effective, better tolerated drug with a more rapid therapeutic effect than metronidazole.

Adult↗

PubMed1978

Metronidazole in anaerobic infections: a review of its activity, pharmacokinetics and therapeutic use.

Metronidazole which has been widely used for many years in the treatment of trichomoniasis, amoebiasis and giardiasis, has recently been shown to be active against anaerobic bacteria. Serum, cerebrospinal fluid and tissue concentrations bactericidal for Bacteroides species are attained after usual dosages given orally or intravenously or higher dosages given rectally (suppository). Prospective studies have demonstrated that the addition of metronidazole to regimens for pre-operative bowel preparation, decreases the frequency of postoperative infection and eliminates anaerobic infection. Similarly, anaerobic infection after acute appendicectomy or hysterectomy has been virtually eliminated by metronidazole given before and up to 1 week after surgery. Metronidazole has been successfully used in the treatment of anaerobic infections of the chest, head, gastrointestinal and female genitourinary tract, and of anaerobic septicaemia and bacteraemia. Metronidazole is the most active agent available against obligate anaerobes and is likely to be of major value in the treatment of serious infections due to these organisms. Although the absence of formal comparative trials in many areas of use makes it difficult to clearly state the relative therapeutic efficacy of metronidazole, compared with other drugs such as clindamycin, chloramphenicol or penicillin, it is nevertheless a very effective agent in the treatment and prevention of anaerobic infections.

Anaerobiosis↗

PubMed1977

The contribution of metronidazole and two metabolites to the mutagenic activity detected in urine of treated humans and mice.

The urine of two patients receiving therapeutic doses of the trichomonacide, metronidazole, was analyzed for mutagenic activity using the histidine auxotroph TA1535 of Salmonella typhimurium. The activity detected in the urine was significantly higher than could be accounted for by the presence of the administered drug. Chromatographic analysis of the urine indicated the presence of the metabolite 1-(2-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole, which when tested in vitro with TA1535 was found to be ten times more active than metronidazole. An additional urinary metabolite, 1-acetic acid-2-methyl-5-nitroimadazole, was found to be inactive when similarly tested. The in vitro mutagenic activity of metronidazole and the two metabolites was unchanged by the addition of phenobarbital- or Aroclor-induced rat liver homogenate to the test system. In addition, metronidazole and the hydroxymethyl metabolite reverted S. typhimurium TA100 but not TA1537, TA1538, or TA98, and the acetic acid metabolite failed to revert any of the tester strains. In studies with mice, metronidazole was required in excess of the human dose in order for significant amounts of the hydroxymethyl metabolite to be detected in the urine. Urine from mice pretreated with the hepatotoxin, carbon tetrachloride, prior to the administration of metronidazole demonstrated approximately a 50% reduction in mutagenic activity, and the formation of the urinary metabolites was inhibited. These findings indicate the production of metabolites from the parent compound by the liver of the intact animal which could not be determined by use of the standard in vitro liver homogenate system.

Animals↗

PubMed1977

Bioavailability of metronidazole in fasting and non-fasting healthy subjects and in patients with Crohn's disease.

The possible influence of food intake on the bioavailability of metronidazole was examined in ten health volunteers by administration of a single dose of metronidazole on an empty stomach, and with a standardized breakfast. Food intake did not significantly alter the bioavailability of metronidazole. The interindividual variation in bioavailability appeared to be slight. In nine patients with Crohn's disease, the absorption of metronidazole appeared to be reduced and to be more variable than in healthy subjects. In both groups there was a clear relationship between the amount absorbed and dose/kg body weight. Thus, from the pharmacokinetic point of view, metronidazole can safely be given either with or between meals. The dose should be related to body weight.

Adult↗

PubMed1979

The differential action of metronidazole on nitrogen fixation, hydrogen metabolism, photosynthesis and respiration in Anabaena and Scenedesmus.

Metronidazole (2-methyl-5-nitroimidazole-1-ethanol) at 1--2 mM levels has been shown to be a selective inhibitor of nitrogenase activity in Anabanena. Two constitutive hydrogenases and photosynthesis are insensitive to metronidazole at these same concentrations. At higher concentrations metronidazole inhibits photosynthesis in Anabaena while photoreduction and to a lesser extent photohydrogen production are retarded in Scenedesmus. Respiration is slightly stimulated at high metronidazole levels in both algae. The reductant source for nitrogenase in Anabaena and photohydrogen production and photoreduction electron transport in Scenedesmus are discussed. Due to the activity to metronidazole as a selective inhibitor of ferredoxin-associated processes, it should prove to be useful in N2 fixation studies and in distinguishing between ferredoxin-linked reactions of different sensitivities and other activities not associated with low reduction potential components.

Cyanobacteria↗

PubMed1976

The stereoselective interaction of warfarin and metronidazole in man.

Because of the known interaction of warfarin and disulfiram and the "disulfiram effect" of metronidazole, the interaction with metronidazole of commercial racemic warfarin and its separated enantiomorphs was evaluated in eight normal subjects. Single oral doses of racemate, S(-)-warfarin, and R (+)-warfarin, were administered in the amounts of 1.5, 0.75 and 1.5 mg per kilogram of body weight, respectively, with and without metronidazole, 750 mg by mouth, beginning seven days before the warfarin dose and continuing seven days before the warfarin dose and continuing daily throughout the hypoprothrombinemia. Daily plasma samples were analyzed for warfarin in content and one-stage prothrombin time. A highly significant (P less than 0.01) augmentation of the mean warfarin level and hypoprothrombinemia with metronidazole occurred for racemic and S (-)-warfarin; none occurred with R (+)-warfarin. Thus, the interaction of racemic warfarin and metronidazole is stereoselective and can be lessened or even avoided by use of R (+)-warfarin alone for long-term therapy.

Adult↗

PubMed1978

Use of high-pressure liquid chromatography to determine plasma levels of metronidazole and metabolites after intravenous administration.

A rapid and sensitive high-pressure liquid chromatography assay for metronidazole and its two principle metabolites, 1-(2-hydroxyethyl-2-hydroxymethyl)-5-nitro-imidazole [hydroxy metabolite] and 1-acetic acid-2-methyl-5-metronidazole [acid metabolite], was developed. The retention times observed were 5.7, 3.3, and 4.5 min, respectively. A reverse-phase muC(18) Bondapak column using a solvent system of methanol, acetonitrile, and 0.005 M pH 4 potassium dihydrogen phosphate (4:3:93, vol/vol) was used to achieve separation of the three compounds. Patients receiving metronidazole therapy were given a loading dose of 13.6 mg of drug per kg intravenously over 1 h, followed by a maintenance dose of 1.43 mg/kg per h. The range of metronidazole concentrations observed was 6.8 to 47.5 mug/ml. These levels are well above the minimal inhibitory concentrations of most clinically significant anaerobic bacteria including Bacteroides fragilis. Little of the acid metabolite was observed in the plasma. The concentration of hydroxy metabolite ranged from 1.6 to 16 mug/ml. The latter may represent an additional source of antimicrobial activity since the hydroxy metabolite has approximately 30% the biological activity of metronidazole.

Chromatography, High Pressure Liquid↗

PubMed1978

Antimicrobial activity of metronidazole in anaerobic bacteria.

The antimicrobial activity of metronidazole was investigated in anaerobic bacteria by use of time-viability studies. This antimicrobial agent has a rapid onset of bactericidal activity under proper reducing conditions. The bactericidal rates were not affected by inoculum size or nutritional requirements, nor by inhibition of growth and protein synthesis by chloramphenicol. Using supernatant fractions of actively growing cultures of susceptible organisms, we observed a disappearance of metronidazole and a loss of biological activity, but there was no significant change in preparations from resistant bacteria. The decrease in drug concentration with susceptible cells occurred during the time that its bactericidal action was being exerted. Extracts from susceptible organisms rapidly reduced the concentration of metronidazole, confirming previous observations which suggest that the drug acts as a terminal electron acceptor. Radioisotope experiments with [14C]metronidazole revealed that the compound was taken up by both resistant and susceptible bacteria, although there was a difference in rate and extent of accumulation. These studies demonstrate that metronidazole's antimicrobial activity against anaerobic bacteria is bactericidal and independent of growth rate, and that it involves the uptake and metabolism of the compound.

Bacteria, Anaerobic↗

PubMed1978

Inactivation of metronidazole by anaerobic and aerobic bacteria.

The rate of inactivation of metronidazole in vitro was determined during the course of time-kill curves against anaerobic and aerobic bacteria in the stationary phase of growth. Metronidazole at a concentration of 10 mug/ml, as measured by bioassay, was rapidly inactivated in broth culture by susceptible anaerobic bacteria (minimum bactericidal concentration </= 3 mug/ml), and this correlated closely with its bactericidal activity. In contrast, the drug was neither inactivated nor had any bactericidal activity against a resistant strain of Propionibacteriumacnes (minimum bactericidal concentration > 1,500 mug/ml). Three of four aerobic bacteria also inactivated metronidazole, although at generally slower rates than the anaerobes, but this was not associated with a bactericidal effect against these organisms. The presence of aerobic bacteria in mixed cultures with Bacteroides fragilis did not, moreover, inhibit the bactericidal activity of metronidazole against the latter organism. However, the possibility still remains that, in vivo, aerobic bacteria capable of inactivating metronidazole could inhibit the action of the drug against anaerobes in mixed infections.

Bacteria↗