Metronidazole (MT) is a widely used antimicrobial and antiparasitic drug [3–6]. Moreover, in clinical practice, the scope of its application is often associated not only with the effect on microorganisms, but also with its electron-acceptor property [7]. Its last property is most widely used in oncology to increase the effectiveness of radiotherapy for malignant tumors. Thus, to increase the effectiveness of radiation therapy for rectal tumors, 5-fluorouracil (5-FU) and MT are administered to patients during irradiation [8]. In addition, cancer patients after surgical treatment and against the background of adjuvant chemotherapy are prescribed MT to prevent local infectious complications [9]. At the same time, there is information in the literature about the effect of MT on the toxicity of cytostatics. In particular, MTX has been shown to increase the toxicity of methotrexate and 5-FU when administered together to tumor-inoculated mice [10]. Clinical studies found that the administration of the alkylating agent bisulfan against the background of MT led to a significant increase in liver enzymes compared to the control group that received the cytostatic alone [11]. It has also been shown that MT is able to influence the pharmacokinetics of the immunosuppressant tacrolimus, significantly increasing its biological activity and, at the same time, toxicity. Thus, in order to avoid drug overdose during the use of MTX, the course dose of the immunosuppressant tacrolimus had to be reduced by 4 times [12]. Although the very fact of increased toxicity of drugs when used together with MTX and the need to use MTX in cancer patients is beyond doubt. One of the promising directions to reduce the effect of MT on the toxic properties of cytostatics may be the development of optimal regimens for administering these drugs relative to each other [13].
The purpose of this work was to study the influence of different time intervals between the administration of MT and 5-FU on their biological effects. The choice of drugs is determined by the breadth of their use in oncological practice for various forms of cancer.
pharmachologic effect
Metronidazole is a broad-spectrum antiprotozoal and antibacterial agent.
Active against Trichomonas vaginalis, Entamoeba histolytica, as well as gram-negative anaerobes Bacteroides spp. (including B.fragilis, B.distasonis, B.ovatus, B.thetaiotaomicron, B.vulgatus), Fusobacterium spp. and some gram-positive anaerobes (susceptible strains of Eubacterium spp., Clostridium spp., Peptococcus spp., Peptostreptococcus spp.).
Aerobic microorganisms and facultative anaerobes are not sensitive to metronidazole, but in the presence of mixed flora (aerobes and anaerobes), metronidazole acts synergistically with antibiotics that are effective against common aerobes.
Pharmacokinetics
With intravenous administration of 500 mg of metronidazole over 20 minutes to patients with anaerobic infection, the concentration of the drug in the blood serum was 35.2 μg/ml after an hour, 33.9 μg/ml after 4 hours, 25.7 μg/ml after 8 hours .
The drug has high penetrating ability, reaching bactericidal concentrations in most tissues and body fluids, including lungs, kidneys, liver, skin, cerebrospinal fluid, brain, bile, saliva, amniotic fluid, abscess cavities, vaginal secretions, seminal fluid, breast milk. Binding to blood proteins is weak and does not exceed 10-20%. With normal bile formation, the concentration of metronidazole in bile after intravenous administration may significantly exceed the concentration of metronidazole in the blood plasma.
Metronidazole is excreted by the kidneys - 63% of the dose, 20% of the drug is excreted unchanged. The half-life of metronidazole is 6-7 hours. Renal clearance is 10.2 ml/min.
In patients with impaired renal function, after repeated administration of the drug, accumulation of metronidazole in the blood serum may be observed. Therefore, in patients with severe renal failure, the frequency of taking metronidazole should be reduced.
Metronidazole – powder, solution, suspension, tablets
Orally and parenterally.
Orally, during or after meals (or with milk), without chewing.
For trichomoniasis - 250 mg 2 times a day for 10 days or 400 mg 2 times a day for 5-8 days. Women must be additionally prescribed in the form of vaginal suppositories or tablets. If necessary, you can repeat the course of treatment or increase the dose to 0.75-1 g/day. Between courses you should take a break of 3-4 weeks with repeated control laboratory tests. An alternative treatment regimen is to prescribe 2 g once to the patient and his sexual partner.
Children 2-5 years old - 250 mg/day; 5-10 years - 250-375 mg/day, over 10 years - 500 mg/day. The daily dose should be divided into 2 doses. The course of treatment is 10 days.
For giardiasis - 500 mg 2 times a day for 5-7 days.
Children under 1 year old - 125 mg/day, 2-4 years old - 250 mg/day, 5-8 years old - 375 mg/day, over 8 years old - 500 mg/day (in 2 doses). The course of treatment is 5 days.
For giardiasis - 15 mg/kg/day in 3 divided doses for 5 days.
Adults: for asymptomatic amebiasis (if a cyst is detected), the daily dose is 1-1.5 g (500 mg 2-3 times a day) for 5-7 days.
For chronic amebiasis, the daily dose is 1.5 g in 3 divided doses for 5-10 days, for acute amoebic dysentery - 2.25 g in 3 divided doses until the symptoms stop.
For liver abscess, the maximum daily dose is 2.5 g in 1 or 2-3 doses, for 3-5 days, in combination with antibiotics (tetracyclines) and other methods of therapy.
Children 1-3 years old - 1/4 adult dose, 3-7 years old - 1/3 adult dose, 7-10 years old - 1/2 adult dose.
For balantidiasis - 750 mg 3 times a day for 5-6 days.
For ulcerative stomatitis, adults are prescribed 500 mg 2 times a day for 3-5 days; In this case, the drug is not indicated for children.
For pseudomembranous colitis - 500 mg 3-4 times a day.
For eradication of Helicobacter pylori - 500 mg 3 times a day for 7 days (as part of combination therapy, for example in combination with amoxicillin 2.25 g/day).
When treating anaerobic infection, the maximum daily dose is 1.5-2 g.
In the treatment of chronic alcoholism, 500 mg/day is prescribed for a period of up to 6 (not more than) months.
To prevent infectious complications - 750-1500 mg/day in 3 doses 3-4 days before surgery or 1 g once on the first day after surgery. 1-2 days after surgery (when oral administration is already allowed) - 750 mg/day for 7 days.
In case of severe renal dysfunction (creatinine clearance less than 10 ml/min), the daily dose should be reduced by 2 times.
Suspension for oral administration. Anaerobic bacterial infections: children - 7 mg/kg every 8 hours, course of treatment - 7-10 days; Giardiasis: children 2-5 years old - 200 mg/day, 5-10 years old - 300 mg/day, 10-15 years old - 400 mg/day. The duration of treatment for giardiasis is 5 days. The course of treatment can be repeated after 10-15 days
Parenterally. For adults and children over 12 years of age, an initial dose of 0.5-1 g IV drip (infusion duration is 30-40 minutes), and then every 8 hours, 500 mg at a rate of 5 ml/min. If well tolerated, after the first 2-3 infusions they switch to jet administration. The course of treatment is 7 days. If necessary, intravenous administration is continued for a longer time. The maximum daily dose is 4 g. According to indications, switch to maintenance oral administration at a dose of 400 mg 3 times a day. Children under 12 years of age are prescribed according to the same regimen in a single dose of 7.5 mg/kg.
For purulent-septic diseases, 1 course of treatment is usually carried out.
For preventive purposes, adults and children over 12 years of age are prescribed 0.5-1 g intravenously on the eve of surgery, on the day of surgery and the next day - 1.5 g / day (500 mg every 8 hours). After 1-2 days, they switch to maintenance therapy orally. For patients with chronic renal failure and creatinine clearance less than 30 ml/min and/or liver failure, the maximum daily dose is no more than 1 g, the frequency of administration is 2 times a day.
As a radiosensitizing drug, it is administered intravenously at a rate of 160 mg/kg or 4-6 g/sq.m of body surface 0.5-1 hour before the start of irradiation. Apply before each irradiation session for 1-2 weeks. During the remaining period, radiation treatment is not used. The maximum single dose should not exceed 10 g, course dose - 60 g. To relieve intoxication caused by radiation, drip administration of a 5% dextrose solution, Hemodez or 0.9% NaCl solution is used.
For cervical and uterine cancer, skin cancer, they are used in the form of local applications (3 g dissolved in a 10% DMSO solution), moisten tampons, which are used topically, 1.5-2 hours before irradiation). In case of poor tumor regression, applications are carried out throughout the entire course of radiation therapy. If there is a positive dynamics of tumor clearance from necrosis - during the first 2 weeks of treatment.
Indications for use
Protozoal infections: extraintestinal amebiasis, including amoebic liver abscess, intestinal amebiasis (amoebic dysentery), trichomoniasis (including trichomonas vaginitis, trichomonas urethritis).
Infections caused by Bacteroides spp. (including B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus): infections of bones and joints, infections of the central nervous system, including meningitis, brain abscess, bacterial endocarditis, pneumonia, empyema and lung abscess, sepsis.
Infections caused by Clostridium spp., Peptococcus niger and Peptostreptococcus spp.: abdominal infections (peritonitis, liver abscess), pelvic infections (endometritis, fallopian tube and ovarian abscess, vaginal vault infections).
Prevention of postoperative complications (especially interventions on the colon, pararectal area, appendectomy, gynecological operations).
Contraindications
- hypersensitivity to metronidazole or other nitroimidazole derivatives;
— organic lesions of the central nervous system (including epilepsy);
- liver failure (in case of large doses);
— leukopenia (including history);
— I trimester of pregnancy,
- lactation period.
Carefully
Prescribe with caution for kidney and liver diseases (renal/liver failure).
II and III trimesters of pregnancy - only for health reasons.
Use during pregnancy and breastfeeding
Metronidazole should not be prescribed in the first trimester of pregnancy; in the future it should be used only if the potential benefit of the drug for the mother outweighs the possible risk to the fetus.
Since metronidazole passes into breast milk, reaching concentrations similar to those in plasma, it is recommended to stop breastfeeding during treatment with the drug.
special instructions
Long-term use of the drug should preferably be carried out under the control of peripheral blood parameters.
IV administration of a solution for infusion is indicated for patients in whom oral administration of the drug is impossible. For mixed infections, metronidazole infusion solution can be used in combination with parenteral antibiotics without mixing the drugs with each other.
When administered intravenously, it should not be mixed with other drugs. When using the drug, an exacerbation of candidiasis may occur.
Drinking alcohol during the course of therapy is strictly prohibited (a disulfiram-like reaction may develop: cramping abdominal pain, nausea, vomiting, headache, sudden rush of blood to the face).
When using the drug, slight leukopenia may occur, so it is advisable to monitor the blood picture (the number of leukocytes) at the beginning and at the end of therapy.
With leukopenia, the possibility of continuing treatment depends on the risk of developing an infectious process.
The appearance of ataxia, dizziness and any other deterioration in the neurological status of patients requires cessation of treatment.
May immobilize treponemes and lead to a false-positive Nelson test. When treating trichomonas vaginitis in women and trichomonas urethritis in men, it is necessary to abstain from sexual activity. Simultaneous treatment of sexual partners is mandatory. After treatment for trichomoniasis, control tests should be carried out during 3 consecutive cycles before and after menstruation.
When carrying out therapy for more than 10 days - only in justified cases, with strict monitoring of the patient and regular monitoring of laboratory blood parameters. If a longer course of therapy is necessary due to the presence of chronic diseases, the balance between the expected effect and the potential risk of complications should be carefully weighed.
Research results
In Fig. Figure 1 shows the growth dynamics of the CaO-1 ovarian carcinoma tumor in the control and against the background of exposure to 5-FU and M.T. Introduction by M.T. intraperitoneally at a dose of 1 g/kg on the 7th day after tumor transplantation did not have a significant effect on the dynamics of its growth. Subcutaneous administration of 5-FU at a dose of 100 mg/kg on the 7th day after tumor transplantation caused a delay in tumor release by more than 2 weeks. Subcutaneous administration of 5-FU 1 hour after intraperitoneal injection of MT enhanced the effect of the cytostatic agent, increasing the time of tumor emergence from 14 days when exposed to 5-FU alone to 17 days. A similar effect was observed when exposed to MT 20 min before injection of the cytostatic. However, with this scheme of administration of 5-FU and MT, the death of up to 40% of animals was observed. The death of animals suggests increased toxicity of this combination of drugs. Administration of the cytostatic after 4 and 12 hours did not affect the effect of the cytostatic.
Rice. 1. Influence of M.T. on the antitumor effect of 5-FU using the example of the growth dynamics of CaO-1 carcinoma. The x-axis shows days after tumor transplantation; the ordinate is the tumor volume in mm3.
In Fig. Figure 2 shows the dynamics of the growth of CaO-1 ovarian carcinoma in the control and against the background of drug exposure with an increase in the interval between the administration of the antimetabolite and MT to 12 hours. As can be seen from the above figure, in the control group there is rapid growth of the primary node. Introduction by M.T. intraperitoneally at a dose of 1 g/kg on the 7th day after tumor transplantation does not have any significant effect on tumor growth. Subcutaneous administration of 5-FU at a dose of 100 mg/kg on the 7th day after tumor grafting caused a shorter delay in tumor exit. Co-administration of MT and 12 hours later 5-FU did not increase the antitumor effect of the antimetabolite. However, increasing the administration interval to 12 hours led to the death of no more than 10% of the animals in this experimental group. The absence of animal death indicates a decrease in the toxicity of the drug combination with this administration regimen compared to the previous one.
Rice. 2. Influence of M.T. on the antitumor effect of 5-FU using the example of the growth dynamics of CaO-1 carcinoma at an interval of drug administration of 12 hours. The x-axis shows days after tumor transplantation; the ordinate is the tumor volume in mm3.
In Fig. Figure 3 shows the growth dynamics of B16 melanoma in the control group and against the background of drug exposure. Introduction by M.T. at a dose of 1 g/kg body weight of animals on the 7th day after tumor inoculation did not have a significant effect on tumor growth. 5-FU at a dose of 100 mg/kg on the 7th day after tumor transplantation did not inhibit tumor growth. Subcutaneous administration of 5-FU 20 minutes after MT also did not lead to the appearance of an antitumor effect of the antimetabolite. These data indicate that MT does not have a modifying effect on melanoma cells, which would overcome the initial tumor resistance to this antitumor drug.
Rice. 3. Influence of M.T. on the antitumor effect of 5-FU using the example of the growth dynamics of B16 melanoma. The x-axis shows days after tumor transplantation; the ordinate is the tumor volume in mm3.
In a special series of experiments, the effect of MT on the toxicity of 5-FU was assessed. In table Figure 1 presents the results of experiments to study the effect of the interval between the administration of 5-FU and MT on the death of animals. As follows from the data in table. 1,5-FU did not cause death in mice at a dose of 200 mg/kg. However, the introduction of the MT modifier 20 minutes before the injection of the antitumor drug led to the death of 70% of the animals, which indicates an increase in the toxicity of the chemotherapy drug under the influence of MT. 5-FU at a dose of 300 mg/kg led to lethal effects in 70% of individuals, and its application 20 minutes after administration of MT (1 g/kg) caused 100% death. At the same time, there is a significant decrease in the average life expectancy of dead animals from 14 to 9.9 days. Increasing the interval between the introduction of the modifier and 5-FU to 1 hour reduced the death of animals in this group by up to 90%. The decrease in toxicity of the drug combination can be explained by the rapid metabolism of MT in the mouse body. It is obvious that during this period the concentration of MT in the blood decreases and its effect on the toxicity of 5-FU decreases.
Table 1. The influence of various modes of administration of the MT modifier on the toxicity of 5-FU Table 1. The influence of various modes of administration of the MT modifier on the toxicity of 5-FU
This assumption is confirmed by data indicating that a further increase in the interval between drug administration to 4 hours leads to an even greater reduction in the toxicity of the combined action of MT and 5-FU. The modifier itself in mono mode did not cause the death of animals.
In table Figure 2 presents the results of experiments studying the effect of an antitumor drug and MT, as well as their combination on the number of leukocytes in the peripheral blood of mice. In the control group of animals, the number of leukocytes in the peripheral blood was stable throughout the entire observation period with average values from 9.6 to 11.2∙103 cells/μl. The introduction of the MT modifier at a dose of 1 g/kg caused a decrease in the number of leukocytes in the peripheral blood to 7.6∙103 cells/μl on the 4th day after the administration of MT. In the following days, there was a restoration of the number of cells in the peripheral blood almost to the initial levels. In the group of animals that received 5-FU at a dose of 100 mg/kg, there was also a decrease in the number of leukocytes in the peripheral blood to 7.0∙103 cells/μl on the 4th day after administration of the antitumor drug. In the following days, there was also a restoration of the number of cells in the peripheral blood almost to the initial levels. In the group of animals that were administered the modifier 2 hours before the injection of the antitumor drug, there was also a decrease in the number of leukocytes in the peripheral blood to 6.1∙103 cells/μl on the 4th day after the administration of the antitumor drug. In the following days, a restoration of the number of cells in the peripheral blood was observed. However, there was no restoration to the original number of cells in the peripheral blood of mice during the studied period of time. The latter circumstance can be explained by the increased toxicity of this combination of drugs compared to their separate use. Increasing the interval between the administration of the modifier and the antitumor drug to 4 hours led to the fact that the dynamics of changes in the number of leukocytes in the peripheral blood was similar to that in the group of mice that received 5-FU alone.
Table 2. Effect of 5-FU and its combination with MT on the average number of leukocytes in the peripheral blood of mice (∙103 cells/μl) Note. Here and in the table. 3:* — p<0.05 significant differences between experimental groups and control (M±m).
As follows from table. 3, in the control group of animals, the average body weight was stable throughout the entire observation period. The introduction of the MT modifier at a dose of 1 g/kg causes a decrease in weight by approximately 5% (from 21.5 to 20.5 g). In the group of animals that received 5-FU at a dose of 100 mg/kg, there was also a decrease in animal body weight by approximately 5%. In the group of animals that received the modifier 2 hours before the administration of the antitumor drug, there was a significant decrease in the body weight of the animals, reaching 16.1 g by the 7th day (25% decrease), which indicates an increase in the general toxic effect of the drug combination compared to their separate use. When the interval between the administration of the modifier and the antitumor drug is increased to 4 hours, the loss of animal body weight does not differ from this indicator in groups of animals with separate use of these drugs.
Table 3. Effect of 5-FU and its combination with MT on the average body weight of mice, g
Directions for use and doses
Intravenous infusion.
Intravenous administration of metronidazole is indicated for severe infections, as well as in the absence of the possibility of taking the drug orally.
For adults and children over 12 years of age, the single dose is 500 mg, the rate of intravenous continuous (jet) or drip administration is 5 ml per minute. The interval between injections is 8 hours. The duration of treatment is determined individually. The maximum daily dose is no more than 4 g. According to indications, depending on the nature of the infection, a transition to maintenance therapy with oral forms of metronidazole is carried out.
For children under 12 years of age, metronidazole is administered at 7.5 mg/kg body weight in 3 doses at a rate of 5 ml per minute.
To prevent anaerobic infection before planned surgery on the pelvic organs and urinary tract for adults and children over 12 years of age, metronidazole is prescribed as an infusion at a dose of 500-1000 mg, on the day of surgery and the next day - at a dose of 1500 mg / day (500 mg every 8 ocloc'k). After 1-2 days, they usually switch to maintenance therapy with oral forms of metronidazole.
For patients with severe renal impairment (creatinine clearance less than 30 ml/min) and/or liver, the daily dose of metronidazole is 1000 mg; (multiplicity of administration is 2 times).
Material and methods
Animals
. Mice of the CBA/Lac male and C57Bl/6 female line weighing 18–20 g at the age of 1.5 months were obtained from the Stolbovaya nursery in the Moscow region. MT and 5-FU are official drugs. The doses used were the maximum tolerated or were close to those, which was due to the need to register the effect of increasing the toxicity of the combined use of drugs. MT was used once at a dose of 1 g per 1 kg of animal body weight (maximum tolerated dose 1.4 g/kg). The antitumor efficacy of the combined action of the drugs was studied in the following regimens: 5-FU was administered at a dose of 100 mg/kg subcutaneously, and MT was administered at a dose of 1 g/kg intraperitoneally 20 minutes, 1 hour, 4 hours, 12 hours before the administration of 5-FU. There were 10 animals in each group. When assessing the toxicity of the studied combination, MT was administered intraperitoneally at a dose of 1 g/kg 20 minutes, 1 and 4 hours before subcutaneous administration of 5-FU. Treatment began 7 days after tumor cell transplantation. Each group contained 10 CBA/Lac mice. The death of animals was recorded within 30 days after administration of the drugs, assessing the reliability of differences in their life expectancy in the groups that received one antimetabolite and an antimetabolite with a modifier. There were 10 animals in each group. In control groups, mice were administered 5-FU or M.T. alone. The “pure” control group received isotonic sodium chloride solution.
Transplantable tumors
.
Melanoma B16 and mucinous ovarian cancer CaO-1 were obtained from the bank of tumor strains of the Russian Cancer Research Center named after. N.N. Blokhin" of the Russian Ministry of Health. Transplanted CaO-1 ovarian carcinoma has been described as highly sensitive to the action of 5-FU [1, 2]. Melanoma B16 is resistant to 5-FU. The experiments used the 3rd passage of the tumor in vivo
.
A suspension of tumor tissue was performed at 105 cells in 0.1 ml of nutrient medium 199. B16 melanoma cells were transplanted into C57Bl/6 mice, CaO-1 ovarian carcinoma cells were transplanted into CBA/Lac mice. The antitumor effect was assessed by tumor volume and tumor growth inhibition (TGR). The volume of the tumor over time (in mm3) was determined by the formula V=a
2
b
, where
a
is the smallest linear size of the tumor in millimeters;
a, b
—the largest linear size of the tumor in millimeters.
Tumor growth inhibition was calculated using the formula: TPO = V
avg.
experience – V
average control /
V
average control. The toxic effect of drugs and their combinations was assessed by the number of leukocytes in the peripheral blood of animals, changes in their body weight and the dynamics of their death.
Side effect
Gastrointestinal disorders:
epigastric pain, nausea, vomiting, diarrhea, glossitis, stomatitis, “metallic” taste in the mouth, loss of appetite, anorexia, dry oral mucosa, constipation, pancreatitis (reversible cases), change in tongue color/“coated tongue” (from - for the growth of fungal microflora).
Immune system disorders:
angioedema, anaphylactic shock.
Nervous system disorders
: peripheral sensory neuropathy, headache, convulsions, dizziness, the development of encephalopathy and subacute cerebellar syndrome (impaired coordination and synergism of movements, ataxia, dysarthria, gait disturbances, nystagmus, tremor) has been reported, which are reversible after discontinuation of metronidazole, aseptic meningitis.
Mental disorders:
psychotic disorders, including confusion, hallucinations; depression, insomnia, irritability, increased excitability.
Visual disorders:
transient visual impairments, such as diplopia, myopia, blurred outlines of objects, decreased visual acuity, impaired color perception; neuropathy/optic neuritis.
Blood and lymphatic system disorders
: agranulocytosis, leukopenia, neutropenia, thrombocytopenia.
Disorders of the liver and biliary tract
: increased activity of “liver” enzymes (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase), development of cholestatic or mixed hepatitis and hepatocellular liver damage, sometimes accompanied by jaundice; In patients treated with metronidazole in combination with other antibacterial agents, cases of liver failure requiring liver transplantation have been observed.
Skin and subcutaneous tissue disorders
: rash, itching, skin flushing, urticaria, pustular skin rash, Stevens-Johnson syndrome, toxic epidermal necrolysis.
Renal and urinary tract disorders
: staining of urine in a brownish-reddish color, caused by the presence of a water-soluble metabolite of metronidazole in the urine, dysuria, polyuria, cystitis, urinary incontinence, candidiasis.
General and administration site disorders
: fever, nasal congestion, arthralgia, weakness, thrombophlebitis (pain, hyperemia or swelling at the injection site).
Laboratory and instrumental data
: flattening of the T wave on the electrocardiogram.
Interaction with other drugs
Metronidazole for intravenous infusion is not recommended to be mixed with other medications!
When using metronidazole for injection, there is little interaction with other drugs, but caution should be exercised when used simultaneously with certain drugs.
Warfarin and other indirect anticoagulants.
Metronidazole enhances the effect of indirect anticoagulants, which leads to an increase in the time of prothrombin formation.
Disulfiram.
Concomitant use may lead to the development of various neurological symptoms, so metronidazole should not be prescribed to patients who have taken disulfiram within the last two weeks.
Cimetidine
inhibits the metabolism of metronidazole, which may lead to an increase in its concentration in the blood serum and an increased risk of side effects.
Simultaneous use of drugs that stimulate microsomal oxidation enzymes in the liver ( phenobarbital, phenytoin
) may accelerate the elimination of metronidazole, resulting in a decrease in its plasma concentration.
In patients receiving long-term treatment with lithium
in high doses, when using metronidazole, it is possible to increase the concentration of lithium in the blood plasma and develop symptoms of intoxication.
The antimicrobial effect of metronidazole is enhanced in combination with sulfonamides and antibiotics.
With the combined use of metronidazole and cyclosporine
An increase in the concentration of cyclosporine in the blood plasma may be observed.
Metronidazole reduces the clearance of fluorouracil,
which may cause an increase in the toxicity of the latter.
When used concomitantly, metronidazole may increase plasma concentrations of busulfan.
It is not recommended to combine with non-depolarizing muscle relaxants (vecuronium bromide).
Metronidazole is incompatible with ethanol (disulfira-like reactions develop when used together).
Discussion
This study provides data on the effect of MT on the specific activity of the antitumor drug 5-FU. The therapeutic effect of the drug and its combination with MT was assessed by its effect on the dynamics of tumor growth in mice - B16 melanoma and CaO-1 ovarian carcinoma.
5-FU inhibited the growth of CaO-1 ovarian carcinoma. Influence of M.T. The antitumor efficacy of 5-FU depended on the interval between the administration of MT and the cytostatic agent. An increase in the antitumor effect of 5-FU was observed when the modifier was administered 20 minutes and 1 hour after the cytostatic agent. MT and the synergistic effect of the combination decreased with increasing interval between administrations of these drugs.
The lack of enhancement of the antitumor effect of the combination in mice engrafted with B16 melanoma resistant to 5-FU indicates that MT is not a modifier of B16 melanoma resistance to 5-FU. The above suggests that MT has an effect on 5-FU metabolism. This position is confirmed by a series of experiments devoted to the study of the toxicity of the combination depending on the dose of 5-FU and the time interval between administrations of MT and cytostatic. According to the data obtained, the time interval of 5-FU should be at least 4 hours. With a shorter interval (in particular, after 2 hours), the toxicity of the cytostatic increases 1.5-2 times, which leads to an increase in the death of animals.
