I. Listing at home and abroad
Belonging to the application of chemical drug 6+6.
At present, the domestic listed products are only produced by Harbin Pharmaceutical Group General Factory, and there are two manufacturers of preparations, namely: Harbin Pharmaceutical Group General Factory (specifications: 0.5g, 1.0g, 2.0g), with the trade name of Salanxin; Shanghai New Pioneer Pharmaceutical Co., Ltd. (specifications: 0.25g, 0.5g, 1.0g, 2.0g).
The importers of raw materials are Takeda Pharmaceutical Industry Co., Ltd. and Korea Hanmei Pharmaceutical Industry Co., Ltd.
The manufacturers of this preparation are: Korea Daxiong Pharmaceutical Co., Ltd. (0.5g, 1.0g) and Korea Hanmei Pharmaceutical Industry Co., Ltd. (0.5g, 1.0g).
Second, the ownership, administrative protection and legal protection of patent rights.
No patents related to this product were found, and there was no administrative protection.
Three. SFDA's acceptance of statement
Zhejiang Yongning Pharmaceutical Co., Ltd., four specifications and one raw material; Nanjing Haichen Pharmaceutical Co., Ltd., two specifications; The above is being reviewed by the drug testing center. The time is February 2009.
Imported by Jinyong Pharmaceutical Co., Ltd., and the information is under review. The time is February 2009.
Four. Description of the basic situation of drugs
It is a semi-synthetic second-generation cephalosporin. This product is a mixed powder preparation of cefotiam hydrochloride and buffered sodium carbonate, and a certain amount of anhydrous sodium carbonate (83: 17) is added.
Generic name: Cefotian Hydrochloride for Injection
English Name: Ceftian Hydrochloride for Injection
Hanyu pinyin: eye acid for injection through blasting body safety
The main component of this product is cefotiam hydrochloride, and its chemical name is (6R- trans) -7-[(2- amino -4- thiazolyl) acetyl] amino ]-3-[[ 1-[(2- (dimethylamino) ethyl ]- 1H- tetrazole-
Its chemical structural formula is:
Molecular formula: C 18H23N9O4S3? 2 hydrochloric acid
Molecular weight: 598.6
Description: This product is white or yellowish powder.
Indications: It is mainly used for the following infections caused by staphylococcus, streptococcus (except enterococcus), pneumococcus, influenza, Escherichia coli, Klebsiella, Enterobacter, Citrobacter, Proteus mirabilis, Proteus vulgaris, Proteus Redgerley and Proteus Morgan: septicemia, postoperative infection, burn infection, subcutaneous abscess and wife's furuncle. Tonsillitis (peritonsillitis, peritonsillar abscess), bronchitis, bronchiectasis complicated with infection, pneumonia, pulmonary suppuration, empyema, cholangitis, cholecystitis, peritonitis, pyelonephritis, cystitis, urethritis, prostatitis, myelitis, endometritis, pelvic inflammatory disease, periuterine tissue inflammation, adnexitis, vestibular adenitis, otitis media and sinusitis.
Usage and dosage:
Adults usually take 0.5-2g daily, divided into 2-4 times; Children should be given 40-80mg/kg daily by intravenous injection 3-4 times. This product can be appropriately increased or decreased with age and symptoms. The daily dose of adult septicemia can be increased to 4g, and the daily dose of children with severe refractory infections such as septicemia and encephalomyelitis can be increased to 160mg. For intravenous injection, it can be dissolved in normal saline or glucose injection. In addition, 0.25-2g of this product can be added into sugar solution, electrolyte solution or amino acid infusion, and it can be intravenously dripped within 30 minutes to 2 hours. For children, please refer to the above dosage, and add it into the rehydration solution for intravenous drip within 30 minutes to 1 hour.
Preparation method of this product injection: This product contains anhydrous sodium carbonate as buffer, which produces CO2 when dissolved, so the bottle body is made into negative pressure. 1g can be dissolved by injecting about 5ml of solution into the bottle. (1g When this product is used for intravenous drip, it can be dissolved by adding 100mL solution. ) For intravenous injection, 1g is generally diluted to 20ml before injection. Intravenous drip can't be diluted with water for injection, because it can't be an isotonic solution. When dissolving this product, please carefully read the instructions of dissolution method attached to this product. Contact measles will occur when preparing this injection. If your hands appear swelling, itching, redness, rash, itching, abdominal pain, nausea and vomiting during the preparation process, you should avoid touching the product in the future.
Pharmacology and Toxicology:
1. Antibacterial effect:
(1) has a wide range of antibacterial effects on both gram-negative and positive bacteria. Especially for Escherichia coli, Klebsiella, Proteus mirabilis, influenza, etc. It shows strong antibacterial activity. It also showed good antibacterial activity against Enterobacter, Citrobacter, Indole-positive Proteus vulgaris, Proteus Redgerli and Proteus Morgan.
(2) The antibacterial function of this product is sterilization.
2. Action mechanism: The antibacterial mechanism of this product is to hinder the synthesis of bacterial cell walls. This product has strong antibacterial activity against Gram-negative bacteria, because it has good permeability to bacterial cell outer membrane, relatively stable to β -lactamase and high affinity to pbps 1B and 3, thus enhancing the inhibition of cell wall mucin cross-linking.
3. Toxicological study: In subacute and chronic toxicity experiments, this product was given by intramuscular injection at the dosage of 0. 1, 0.3, 1, 3g/kg/ day/month, and at the dosage of 0.03, 0. 1, 0.3,/kloc-respectively. Dogs were given intravenous injections of 0. 1, 0.3, 1g/kg/ day and intramuscular injections of 0.03, 0. 1 and 0.3g/kg/ day for 6 months. In the experiment of giving monkeys 0. 1, 0.3, 1g/kg/ day or intramuscular injection 1 month, it can be considered that the main findings caused by this product are as follows: (1) has an effect on the kidney, in the monkey 1g/kg administration group. In the experiments of rats 1g/kg/ day intramuscular injection 1 month and monkeys 1g/kg/ day intramuscular injection 1 month, it was also compared with cephalosporin I 1g/kg/ day group. The results showed that this product had the same effect on kidney as cephalosporin I. (3) In other animals, the high-dose intramuscular injection group showed local irritation and local vasoconstriction at the injection site, and there were no other abnormalities except specific skin flushing and swelling in dogs. Reproductive experiment In the experiment of intramuscular injection of cefotaxime and thiamethoxam in rats and rabbits during organogenesis, 0.03, 0. 1, 0.3g/kg/ day and 0.0 1, 0.03, 0.09g/kg/ day were not observed except for the female animals in the group of 0.09g/kg/ day. No abnormal changes were observed in the drug administration experiments of rats before and during pregnancy and during perinatal and lactation.
Pharmacokinetics:
After intravenous injection of 0.5g of this product, the blood concentration was 65mg/L immediately, and 20mg/L after half an hour. 30 minutes after intramuscular injection of 0.5g, the peak plasma concentration (Cmax) reached 20 mg/L ... The concentration of the drug in the internal organs was the highest in the lung, and there were some concentrations in other internal organs and muscle tissues. It is not easy to enter cerebrospinal fluid. The half-life (TL/2) of blood elimination is about 0.5 hours.
1g and 2g were given intravenously for 30 minutes, and the peak blood concentration was 75 and148 mg/l respectively. After intravenous injection of 0.5g of this product, the blood concentration is 5 1mg/L within 5 minutes, and the serum half-life of this product is 0.6- 1. 1 hour. After intravenous administration, this product can be widely distributed in various tissues in the body, with a high concentration in blood, kidney tissue and bile. The average drug concentration in bile was 702mg/L within 2 hours after intravenous infusion of 2g, and the drug concentration in kidney tissue exceeded 100mg/kg after intravenous injection of 0.5g g. Drugs can be distributed in tonsils, sputum, lung tissue, pleural effusion, gallbladder wall, ascites, kidney tissue, bladder wall, prostate, pelvic exudate, amniotic fluid and so on. , and there is a trace distribution in milk, but this product is difficult to penetrate the blood-brain barrier. This product has no accumulation in the body, and it is mainly excreted by the kidney in its original form, followed by bile excretion. The binding rate of serum protein is about 8%. 1 intravenous drip or intravenous injection of 0.5g, 1g, 2g, after 6 hours, 60-75% of the dose was excreted in urine. After intravenous injection of 0.5g, the urine drug concentrations reached 2000mg/L, 350mg/L and 66mg/L at 0-2 hours, 2-4 hours and 4-6 hours after administration, respectively. After the dosage of 1 intravenous injection 10, 20 or 40mg/kg, the urine excretion of children within 6 hours is similar to that of adults.
Adverse reactions:
Occasionally allergic reaction, gastrointestinal reaction, hemogram changes and transient serum transaminase increase. Can cause changes in intestinal flora, leading to vitamin B and K deficiency. I'll cause a second infection. A large number of intravenous injections can cause vascular pain and thrombophlebitis.
Taboo:
It is forbidden for those who are allergic to cephalosporins.
Precautions:
1. Cross allergic reaction: People who are allergic to one cephalosporin or cephamycin may also be allergic to other cephalosporins or cephamycin. People who are allergic to penicillin, penicillin derivatives or penicillamine may also be allergic to cephalosporins or cephamycin. In patients allergic to penicillin, 5% ~ 10% had allergic reaction when using cephalosporin; For example, when determining the immune response, 20% of patients who are allergic to penicillin are allergic to cephalosporins.
2. When patients with penicillin allergy apply this product, they should fully weigh the advantages and disadvantages according to the patient's situation before making a decision. Cephalosporin is not suitable for those who have allergic shock or immediate reaction to penicillin.
3. People with a history of gastrointestinal diseases, especially those with ulcerative colitis, localized enteritis or antibiotic-associated colitis (cephalosporins rarely produce pseudomembranous colitis), should use it with caution.
4. Renal insufficiency should be reduced and used with caution. Urine test should be carried out during medication, and the drug should be stopped if renal function is damaged.
5. This product can cause changes in blood picture, and should be stopped immediately when it is serious.
6. This product should be used immediately after dissolution, otherwise the color of the liquid medicine will become darker.
7. Interference with diagnosis: During the use of this product, false positive reaction may occur when urine sugar test is done with alkaline copper tartrate test solution; Direct antiglobulin (Coombs) test can produce false positive reaction.
Medication for pregnant and lactating women:
Although there are no problems in the application of cephalosporin in pregnant women and lactating women, the advantages and disadvantages of its application must be weighed.
Medication for children:
Medication for elderly patients:
Elderly patients with renal insufficiency need to adjust the dose.
Drug interaction:
1. Combined with aminoglycoside antibiotics, it is generally considered to have synergistic effect, but it may aggravate renal damage, and administration in the same container may affect the drug titer.
2. Combined with furosemide and other diuretics can cause renal damage.
An Analysis of the Market Cost of verb (the abbreviation of verb)
The market retail price of the specification 1.0g (finished drug) is about 100 yuan, and the market sales price is 3000 yuan/kg (API).
Cefotropin pivoxil
Which belongs to the application of chemical medicine 3+6. At present, the domestic listed product is imported by Meiji Fruit Co., Ltd. of Japan, with the trade name of Meiaike and the specification of 100mg. There are no domestic pharmaceutical companies.
AnnouncementNo. 172 of the US Food and Drug Administration on the administrative protection of drugs-Ceftorenpyrate from Meiji Fruit Co., Ltd. of Japan does not give administrative protection to drugs.
Only one patent named pharmaceutical composition was found, and the application number was CN94 108907. X. Abstract: The present invention provides a pharmaceutical composition with improved oral absorbability and reduced bitterness, which comprises (-)-(6R.7R)-2. 2- Dimethyl propionyloxymethyl 7-[(Z)-2-(2- amino-thiazole -4- yl) -2- methoxyimino-acetamido ]-3-[(Z)-2-(4- methylthiazole -5- yl) vinyl ]-8- oxo -5-. It is feasible to combine cefditoren pivoxil and hydroxypropyl cellulose to produce a pharmaceutical composition containing cefditoren pivoxil as an active ingredient, which has better oral absorption performance and reduced bitterness. The weight ratio of hydroxypropyl cellulose to cefditoren pivoxil is 0.4 or higher, preferably 0.8 to 4.
The above patents are all evasive.
Drug Name: Ceftazidime Tablets
English name: Cefditoren pivoxil tablets
Chinese Pinyin: Tou Bao Tuo Lun Pi Zhi Pian
The main component of this product is cefditoren pivoxil, and its chemical name is: (-)-(6R, 7r)-2,2- dimethyl propionyloxymethyl 7-[(Z)-2-(2- amino -4- thiazolyl) -2- methoxyiminoacetylamino ]-3-[(z) -2- (.
Molecular formula: C25H28N6O7S3
Molecular weight: 620.73
This product is a white film coated tablet.
1. pharmacological action
(1) antibacterial effect
1) cefditoren pivoxil is absorbed and metabolized into cefditoren on the intestinal wall, which exerts its antibacterial activity.
2) In vitro, cefditoren has broad-spectrum antibacterial effect on gram-positive bacteria and negative bacteria, especially gram-positive bacteria such as Staphylococcus, Streptococcus including Streptococcus pneumoniae, gram-negative bacteria such as Escherichia coli, Staphylococcus catarrhalis, Klebsiella, Proteus, Haemophilus influenzae, and anaerobic bacteria such as Streptococcus peptic, Propionibacterium acne and Bacteroides.
3) Ceftriaxone is stable to β -lactamase produced by various bacteria in the test tube, and also shows strong antibacterial activity to β -lactamase producing strains.
(2) Mechanism of action
The mechanism of cefditoren is to inhibit the synthesis of bacterial cell wall, and it has high affinity with various bacteria pbps (PBP), thus playing a bactericidal role.
(3) Therapeutic effect on experimental infection.
Ceftazidime has a good therapeutic effect on experimental infections caused by Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Klebsiella pneumoniae and Proteus. In addition, the therapeutic effect on the infection of β -lactamase producing strains is equal to or better than that of similar drugs.
(2) Long-term toxicity test
1) rats were given orally (based on cefditoren pivoxil) 125, 250, 500, 1000mg/kg/ day for 28 consecutive days; 3 1, 63,125,250 and 500mg/kg/day for 6 months. The main phenomena are cecal dilatation, slight increase of GOT and GPT, temporary increase of red blood cells in urine sediment, and increase of kidney weight. It is speculated that it is caused by the double influence of intestinal flora changes. In addition, no abnormalities of specific internal organs and tissues were found. The maximum tolerance is estimated to be 250 mg/kg.
2) dogs were given orally (calculated by cefditoren pivoxil) 1 25,250,500,11,000 mg/kg/day for 28 consecutive days; 1 25,250,500,11,000 mg/kg/day for 6 months. The main manifestations are the increase of total cholesterol, the increase of aspartate aminotransferase and GPT, the increase of liver and kidney weight, and a few cases of glassy drops on liver cells. The maximum tolerance is estimated to be 250mg/kg and125mg/kg, respectively.
(3) Reproductive toxicity test
The oral dose of cefditoren pivoxil to mice before pregnancy, early pregnancy and embryonic organ formation was 125, 250, 500, 1 1,000 mg/kg/day; Perinatal and lactation mice were 90,250 and 750 mg/kg/day; In addition, during embryonic organ formation, rabbits were given 2, 4, 7.5, 15 and 30mg/kg/ day. As a result, it has no effect on the reproductive function of female rats. Although the number of ossification of sacrococcygeal bone was observed to decrease during the formation of embryonic organs in the drug group above 500 mg/kg/day, it was not teratogenic. It has no effect on the growth, movement and reproductive function of newborns. Abortion and decreased embryo survival were observed in rabbits with a dose exceeding 7.5 mg/kg/day, but no teratogenic effect was found.
(4) Other special toxicity
antigenicity
Using rats and guinea pigs to review the results, although cefditoren pivoxil and adjuvant were found to be immunogenic in subcutaneous sensitization experiments in guinea pigs, they were not found to be immunogenic in intraperitoneal sensitization experiments in mice. The allergic reaction of oral administration in guinea pigs and mice was the same as that of clinical administration, and no immunogenicity was found. For the active mother cefditoren, there is almost no immunogenicity and induced antigenicity
As for the cross reaction with similar drugs, weak cross antigenicity with cefteram and cefotaxime was observed. In addition, the positive effect of cefditoren in Combs test is also very weak.
pharmacokinetics
1. absorption and distribution
1) plasma concentration
When healthy adults take orally 100 mg, 200mg and 300mg 1 time on an empty stomach, the plasma concentration of cefditoren is shown in Figure 1, which is dose-dependent. In addition, the absorption of drugs after meals is better than that on an empty stomach.
2) Concentration of body fluids and tissues
Sputum, tonsil tissue, maxillary sinus mucosa, skin tissue, breast tissue, gallbladder tissue, uterus and vagina, cervix, meibomian gland tissue, wound surface after tooth extraction, etc. But it is not distributed in milk.
2. Metabolism and excretion
Cefotoulon pivoxil was transformed into cefditoren with antibacterial activity in the absorption era.
Ceftriaxone is mainly excreted from urine and bile without metabolism. When healthy adults take orally 100 mg, 200mg and 300mg/time after meals, the urinary excretion rate of cefditoren (0-24 hours) is about 20%. After continuous application of the drug (200mg q 12h, ***7 days), no accumulation was found.
3. Serum concentration and urine excretion when renal function is impaired.
Patients with decreased renal function (especially CCR)
indicate
The following infections are caused by bacteria sensitive to this agent, including Staphylococcus, Streptococcus, Streptococcus Gastrodiae, Brandenburg cocci, Propionibacterium acnes, Escherichia coli, Citrobacter, Klebsiella, Enterobacter, Serratia, Proteus (Proteus mirabilis, Proteus vulgaris), Morganella, Providence, Haemophilus influenzae and Bacteroides.
Folliculitis, furuncle, carbuncle, infectious impetigo, erysipelas, cellulitis, lymphangitis, pyogenic paronychia, carbuncle, subcutaneous abscess, sweat, infectious powder tumor, chronic pyoderma.
Shallow secondary infections such as mastitis, perianal abscess, trauma and surgical wound.
Pharyngolaryngitis (laryngeal abscess), acute bronchitis, tonsillitis (peritonsillitis, peritonsillar abscess), chronic bronchitis, bronchiectasis (when infected), secondary infection of chronic respiratory diseases, pneumonia, and pulmonary suppuration.
Pyelonephritis, cystitis.
Cholecystitis and cholangitis.
Uterine adnexitis, intrauterine infection, vestibular adenitis.
Otitis media and sinusitis.
Blepharitis, stye, eyelid abscess, dacryocystitis, meibomian adenitis.
Periodontitis, pericoronitis, jaw inflammation.
dosage
Oral. Dosage: 200mg(2 tablets) once, twice a day 1, after meals. Increase or decrease with age and symptoms.
counteraction
1. allergic reactions: rash, itching, urticaria and fever.
2. Digestive system: nausea, vomiting, diarrhea, like other broad-spectrum antibiotics, pseudomembranous enteritis, there will be rare records.
3. Blood system: eosinophilia, leukopenia, etc. It is reported that when treated with cephalosporin, Combs reaction was positive.
4. Renal function: occasionally urea nitrogen and serum creatinine increase.
5. Liver function: Sometimes GOT, GPT and Al-P are elevated.
taboo
Patients with previous history of shock are prohibited.
Matters needing attention
1. General note: According to the report, most β -lactam antibiotics can cause serious reactions (including anaphylactic shock). Therefore, you should consult carefully before taking the medicine.
2. Other precautions: There are reports of lowering serum carnitine.
Medication for pregnant and lactating women
Medication for pregnant women: The safety of medication during pregnancy has not been determined. Therefore, pregnant women or women who may become pregnant can only take drugs when the benefits of treatment outweigh the risks.
drug interaction
Attention to combination: combination with antacid will reduce its absorption rate, and combination with probenecid will reduce its urine excretion rate.
The price of imported raw materials is 35 thousand yuan/kg, and the domestic cost is about 6,000-7,000 yuan/kg; The price of imported film is 9.9 yuan/film, and the specification is 0.1g.