Pharmacology and Toxicology of Xipule
1. pharmacological action ciprofloxacin is a synthetic broad-spectrum antibiotic. In vitro, it can effectively inhibit all gram-negative bacteria, including Pseudomonas aeruginosa, as well as gram-positive bacteria, such as staphylococcus and streptococcus. Usually anaerobic bacteria are not very sensitive. Ciprofloxacin has a rapid bactericidal effect not only in the proliferative phase but also in the stable phase. During the proliferation period of bacteria, some chromosomes curl and some don't, and DNA helicase plays a decisive role in this process. Ciprofloxacin inhibits DNA helicase, thus blocking bacterial metabolism, so that information can no longer be transcribed from bacterial chromosomes. The development of ciprofloxacin resistance is very slow and occurs step by step (multi-step process). Plasmid-mediated drug resistance, which is common in β-lactams, aminoglycosides and tetracycline antibiotics, is not found in ciprofloxacin, indicating that plasmid-carrying bacteria are also sensitive to ciprofloxacin. Because of its special mode of action, ciprofloxacin usually does not produce parallel drug resistance with other important active ingredients with different chemical components, such as β -lactam antibiotics, aminoglycosides, tetracyclines, macrolides or polypeptide antibiotics, sulfonamides, trimethoprim or furacilin derivatives. Ciprofloxacin is also completely suitable for pathogenic bacteria resistant to the above antibiotics. Parallel drug resistance can be seen in helicase inhibitors. However, because ciprofloxacin is highly sensitive to most pathogenic bacteria, parallel resistance to ciprofloxacin is rarely reported. Therefore, ciprofloxacin is still effective against pathogens that have developed resistance to helicase inhibitors. Because of its chemical structure, ciprofloxacin is completely effective against bacteria producing β -lactamase According to in vitro tests, the following pathogenic bacteria are considered to be sensitive: Escherichia coli, Shigella, Salmonella, Citrobacter, Klebsiella, Enterobacter, Serratia, Hafnia, Edwardsiella, Proteus (indole positive and indole negative), Providence, Morgan, Yersinia, Vibrio, Aeromonas, Aeromonas, Pseudomonas, Escherichia coli, Escherichia coli, Escherichia coli and Escherichia coli. Ciprofloxacin showed anti-anthrax activity in vitro, and serum concentration was used as a surrogate index. The following bacteria showed different degrees of sensitivity: Neisseria, Gardnerella, Flavobacterium, Alcaligenes, Streptococcus agalactiae, Enterococcus faecalis, Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus viridis, Mycoplasma hominis, Mycobacterium tuberculosis and Mycobacterium fortuitum. The following bacteria are usually resistant: Enterococcus faecalis, Ureaplasma urealyticum and Nocardia stellata. Drug resistance of digestive streptococcus: such as bacteroides. Ciprofloxacin is ineffective against Treponema pallidum. The acquired drug resistance rate of some bacteria may change with the change of region and time, so we should refer to the local drug resistance situation, especially when treating serious infections. The above in vitro drug sensitivity test results are only for reference when judging whether microorganisms are sensitive to ciprofloxacin. Ciprofloxacin can be used in combination with other antibiotics. In vitro, ciprofloxacin, β -lactam antibiotics and aminoglycoside antibiotics are used for common sensitive pathogens. The research shows that there are mainly additive effects or no interaction, and there are relatively few synergistic effects and antagonistic effects. Possible combination drugs include: Pseudomonas: azlocillin, Ceftazidime Streptococcus: mezlocillin, azlocillin, other effective β -lactam antibiotics, Staphylococcus: β -lactam antibiotics, especially isoxazoline, vancomycin anaerobic bacteria: metronidazole, clindamycin inhaled anthrax-It is also indicated that the concentration of ciprofloxacin in human serum can be used as a substitute index to reasonably predict the clinical efficacy and provide basic information for treatment. Using rhesus monkey as animal model of inhaled anthrax, when the survival rate is statistically significant, the average serum ciprofloxacin concentration reaches or exceeds the blood concentration of adults or children when administered orally or intravenously. The pharmacokinetics of ciprofloxacin in different populations was evaluated. When adults take ciprofloxacin 500mg orally every 65438 02 hours or take ciprofloxacin 400mg intravenously every 65438 02 hours, the average plasma concentration of ciprofloxacin is 2.97 and 4.56 μ g/ml, respectively. In the steady state, the average plasma concentration of the two administration methods was 0.2 μ g/ml. A study on 10 children aged 6 ~ 16 showed that ciprofloxacin 10 mg/kg was injected intravenously every 12 hours for 30 minutes, with an average peak plasma concentration of 8.3 μ g/ml and a valley concentration range of 0.09. After the second intravenous drip, ciprofloxacin 15 mg/kg was given to the patient every 12 hours, and the average peak blood concentration after the first oral administration was 3.6 μ g/ml. Including the effect on cartilage, the long-term safety data of children after using ciprofloxacin are limited. A placebo-controlled study was conducted on rhesus monkeys. The average inhalation of Bacillus anthracis spores (ranging from 5 to 30 times LD50) by experimental animals is 1 1 ld50 (~ 5.5×10 [sup] 5 [/sup]). The minimum inhibitory concentration (MIC) of ciprofloxacin against Bacillus anthracis strains used in this study was 0.08 μ g/ml. In this animal experiment, ciprofloxacin reached a steady-state plasma concentration in the range of 0.98 ~ 1.69mg/ml at the expected Tmax (65438+ 0 hour after exposure). The average steady-state valley concentration after exposure 12 hours ranged from 0. 12 to 0. 19 mg/ml. Oral ciprofloxacin treatment began 24 hours after inhalation of Bacillus anthracis for 30 days. Compared with the animals in the placebo group (9/ 10), the animal mortality was significantly reduced (1/9) [P = 0.00 1]. Ciprofloxacin treatment group 1 case died of anthrax after 30 days of drug treatment. 2. Toxicological study Acute toxicity study According to individual differences, the LD50 of intravenous infusion is 125 ~ 290 mg/kg. Subacute toxicity study with chronic toxicity exceeding 4 weeks In each experiment, the crystals containing ciprofloxacin appeared in the urine sediment of animals in the maximum dose group (rats 80 mg/kg, monkeys 30 mg/kg); The renal tubules of individual animals have also undergone pathological changes-a typical foreign body reaction caused by crystal deposits. The observed renal tubular lesion is not the result of the original toxic effect of ciprofloxacin (such as aminoglycosides), but the secondary inflammatory foreign body reaction caused by the precipitation of crystalline complex in the distal convoluted tubule. (See subchronic and chronic toxicity studies). The subchronic toxicity study over 3 months sometimes observed slight renal tubular injury, but this change existed in all dose groups of rats. However, only at the maximum dose (65,438+0.8 mg/kg) will the monkey have renal tubular lesions, accompanied by erythropenia and decreased hemoglobin content. After 6 months of chronic toxicity study, the concentration of urea and creatinine in the blood of monkeys in the maximum dose group (20 mg/kg) increased slightly, and the distal convoluted tubule was diseased. The carcinogenicity of mice (265,438+0 months) and rats (24 months) was studied. The maximum dose of mice was about 65,438+0,000 mg/kg/day, and that of rats was about 65,438+0.25 mg/kg/day (increased to 250mg/kg/ day after 22 weeks). There was no evidence that ciprofloxacin was used. Study on reproductive toxicity of rats' fertility ciprofloxacin has no effect on animal fertility, intrauterine development and postnatal development of offspring, and F 1 generation fertility. There is no evidence that ciprofloxacin is embryotoxic or teratogenic in the study of embryotoxicity. Study on Perinatal and Postnatal Development of Rats; Ciprofloxacin has no effect on the perinatal and postnatal development of animals. At the end of the feeding period, histological examination showed no signs of joint injury. Study on mutagenicity Eight in vitro mutagenicity tests of ciprofloxacin were conducted. The results are as follows: Salmonella: microsome test (negative) Escherichia coli: DNA repair test (negative) mouse lymphoma cell forward mutation test (positive) China hamster V79 cell HGPRT test (negative) Syrian hamster embryo cell transformation test (negative) Saccharomyces cerevisiae: point mutation test (negative) mitosis crossover and gene transformation test (negative) DNA repair test (UDS) in primary culture of rat hepatocytes (positive) Two of the eight in vitro tests were positive, but the results of the following four in vivo tests were all negative: rat hepatocyte DNA repair test, micronucleus test (mouse), dominant lethal test (mouse) and China hamster bone marrow test. Although two of the eight in vitro tests (namely, the forward mutation test of mouse lymphoma cells and the DNA repair test of primary culture of rat hepatocytes (UDS)) were positive, the four in vivo tests covering all the corresponding endpoints were negative. In a word, ciprofloxacin has no potential mutagenicity. Long-term carcinogenicity studies in mice and rats support this statement. The results of comparative studies on animals with special toxicity show that early helicase inhibitors (such as nalidixic acid and pipemidic acid) and some new helicase inhibitors (such as norfloxacin and ofloxacin) may cause some characteristic damages, such as kidney damage, weight-bearing articular cartilage damage and eye damage in young animals. The crystallization phenomenon observed in nephrotoxicity animal experiments usually occurs under specific pH conditions, so it is not suitable for humans. Compared with rapid injection, slow infusion of ciprofloxacin can reduce the occurrence of crystal precipitation. The appearance of crystalline precipitate in renal tubules will not cause renal damage immediately and spontaneously. In animal studies, this damage only occurs after high dose administration, and the level of crystallized urine is relatively high. For example, although it often causes crystallized urine, animals still show good tolerance after high-dose administration for more than 6 months, and the distal convoluted tubule has no renal damage and foreign body reaction. No renal damage without crystallized urine was observed. Therefore, the renal damage observed in animal experiments is definitely not the original toxic effect of ciprofloxacin on renal tissue (different from the renal tubular lesion caused by aminoglycoside antibiotics), but the typical secondary inflammatory foreign body reaction caused by the precipitation of crystalline complex of ciprofloxacin with magnesium and protein. The joint toxicity study is the same as other helicase inhibitors. Ciprofloxacin can cause damage to the large load-bearing joints of immature animals. The degree of cartilage injury varies with animal age, species and dose. Eliminating joint load can reduce cartilage injury. The research results of mature animals (rats and dogs) show no evidence of cartilage damage. According to the research results, from the toxicological point of view, it can be considered that ciprofloxacin treatment will not increase the risk of cataract. Study on the Toxicity of Ciprofloxacin to Retina Ciprofloxacin can bind to melanin-containing tissues including retina. The potential effect of ciprofloxacin on retina was evaluated in several animals with pigmented tissues. Ciprofloxacin treatment has no effect on the morphological structure and electroretinogram of retina.