CN103040840A - Treatment application of composition and product of composition - Google Patents
Treatment application of composition and product of composition Download PDFInfo
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- CN103040840A CN103040840A CN2013100014048A CN201310001404A CN103040840A CN 103040840 A CN103040840 A CN 103040840A CN 2013100014048 A CN2013100014048 A CN 2013100014048A CN 201310001404 A CN201310001404 A CN 201310001404A CN 103040840 A CN103040840 A CN 103040840A
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Abstract
The invention relates to an application of a composition in preparing a drug for treating infection, in particular to moderate or severe infection, and a product of the composition.
Description
Technical field
The present invention relates to a kind of composition product and said composition in the application of preparation treatment urinary system infection, particularly moderate or severe urinary system infection medicine.
Background technology
Chemical compound 1 (structure is suc as formula shown in the I) is a kind of second filial generation semisynthetic antibiotics, uses as a kind of broad-spectrum sterilization antibiotic.
Formula I
Chemical compound 2 (structure is suc as formula shown in the II) is a kind of beta-lactamase inhibitor, and using with Antibiotic combination to increase antibiotic antibacterial activity.
Formula II
Along with clinically extensive use of chemical compound 1, the original responsive bacterial strain of part has produced drug resistance to chemical compound 1, and its antibacterial effect is descended.The drug tolerance of strain in numerous areas, the whole nation is researched and analysed the result and is shown, phenomenon to chemical compound 1 drug resistance has also been appearred in the sensitive organisms such as the escherichia coli of chemical compound 1 sensitivity, proteus mirabilis, hemophilus influenza in recent years.
Such as: Dan Xiaomei etc. are to the clinical separation pathogenic bacteria 772 strain drug resistance analysis of the 2001-2003 of Tianjin institute, antibacterial is to the resistant rate of chemical compound 1: golden Portugal bacterium (MRSA) 100%, escherichia coli 51.06%, Klebsiella 18.07%, Pseudomonas aeruginosa 91.53%, Enterobacter 55.22%, acinetobacter 69.74%.
No.1 Hospital Affiliated to Zhongshan Univ. ten thousand builds new grade during year January in January, 2003 to 2004, culture of isolated goes out various common bacteria 1910 strains from all kinds of specimen of this Out-patient Department and inpatient, it is carried out the drug resistance analysis result show, the escherichia coli that produces beta-lactamase and do not produce beta-lactamase is respectively 94%, 17% to the resistant rate of chemical compound 1; The Klebsiella Pneumoniae that produces beta-lactamase and do not produce beta-lactamase is respectively 94%, 23% to the resistant rate of chemical compound 1; The enterobacter cloacae that does not produce beta-lactamase is 76% to the resistant rate of chemical compound 1.
11 the hospital clinical Microbiological Labs in Shanghai City in 2003 collect 22158 strain antibacterials altogether, and wherein following antibacterial to the resistant rate of chemical compound 1 is: escherichia coli (40.6%); Klebsiella Pneumoniae (49.2%); Enterobacter cloacae (58.2%); Citrobacter freundii (51.2%); Root fungus (72.1%) rubs; Proteus vulgaris (43.4%); Serratia marcesens (66.2%); Hemophilus influenza (adult: 22.3%; Child: 10.1%).It is worth noting, the escherichia coli that produces beta-lactamase and do not produce beta-lactamase is respectively 94.9%, 12.4% to the resistant rate of chemical compound 1, the Klebsiella Pneumoniae that produces beta-lactamase and do not produce beta-lactamase is respectively 93.9%, 13.7% to the resistant rate of chemical compound 1, and the trend that significantly raises with the more non-beta-lactamase-producing strain of the beta-lactamase-producing strain resistant rate of In Guangzhou Area report is identical.
Therefore, improve the patient to the drug resistance of chemical compound 1 antibiotic medicine such as grade, particularly providing producing the good novel drugs of beta-lactamase bacterial drug resistance is the technical barrier that this area need to solve at present.
Clinical observation is found, often there is some difference on General Symptoms and local symptom for culture of patients with urinary system infection, and according to General Symptoms (raising or neutral classification raises etc. such as the mental status, shiver with cold, gastrointestinal reaction, heating, blood leukocytes) with local symptom (such as frequent micturition, urgent micturition, dysurea, urine color, lumbago, percussion tenderness over kidney region, urine microscopy etc.) can be divided into coincident with severity degree of condition slightly, moderate and severe.
For patients with mild, can be cured by the multi-medicament screening, but be needed long treatment time; And for moderate or severe patient, due to illness feelings at any time may threat to life, and any later treatment must not be arranged, and needs in time to select eutherapeutic medicine to be treated.At present, provide clinically alignment degree or severe state of an illness patient safety, effectively medicine also is the technical barrier that this area need to solve at present.
Find in the clinical practice, patient's the state of an illness shows as the patient of moderate or severe, part is to delay due to the state of an illness because of bacterial resistance, this some patients were is because the complexity of its mechanism of causing a disease and state of an illness situation, difficulty is cured by conventional medicine, therefore, provide good to bacterial drug resistance and to the effective medicine of the patient that is in a bad way, especially this area technical barrier that need solve at present.
In view of above problems of the prior art, the research of related drugs is constantly being groped and verified, and is good, effective or drug resistance good and to the effective clinical use medicine of the serious state of an illness to the serious state of an illness in the hope of obtaining drug resistance.Relevant for example gropes research:
Chinese patent literature CN1513457A discloses a kind of free acid or the free acid of its salt and chemical compound 2 or compositions that its salt formed by weight 2: 1 to 8: 1 of chemical compound 1, it finds that from the In Vitro Bacteriostasis experiment is preliminary said composition has certain inhibition active to the bacterial strains such as staphylococcus aureus, staphylococcus epidermidis, streptococcus pneumoniae, colon bacillus, Klebsiella pneumonia, Pseudomonas aeruginosa, acinetobacter calcoaceticus, generation bacillus, shigella flexneri and enterobacter cloacae of the product beta-lactamase that separation obtains.
China's antibiotic magazine, 2009,34 (10): 621-631, studied compound formulation the acute toxicity LD50 Mice Body in of injection chemical compound 1 with chemical compound 2 (2:1)〉7.50g/kg, the gavage fatal dose of Beagle dog is 3.0g/kg, its toxicity is similar to the toxicity of compound alone 1, and animal experiment shows that injection chemical compound 1 is good with compound formulation toleration in experimental animals of chemical compound 2.
The analytical chemistry research notes, 2010,38 (6): 864-868, studied to 24 health volunteer's single dose intravenous instil low (1.5g), in the chemical compound 1 of (2.25g), high (4.5g) dosage or chemical compound 2 continuous 7 days, the pharmacokinetics of the compound injection of dosage chemical compound 1 and chemical compound 2 (2:1) in 3 intravenous drips every day, found that, chemical compound 1 and chemical compound 2 blood drug level increase with dosage, single and continuous several times administration concentration are without significant difference, and peak shape and peak time are basically identical.
China's antibiotic magazine, 2009,34 (11): 699-702, studied the compositions to 66 routine health volunteers' difference singles quiet 0.75g, 1.5g, 3.0g, 4.5g, 6.0g, 7.5g, 9.0g or continuous quiet 7.5g, 9.0g injection chemical compound 1 and chemical compound 2, after the medication experimenter is carried out clinical observation, lab testing and Electrocardioscopy found that, the safety of the compositions of single and continuous application injection chemical compound 1 and chemical compound 2, toleration is good.
Though above-mentioned research has confirmed the compositions of chemical compound 1 and chemical compound 2 and has had definitely external activity, the interior safety of animal and human's body body and toleration.Whether but these documents are not all reported said composition effective in vivo, whether can be prepared into the disease at which kind of position of Drug therapy, treats the disease of which kind of degree, and which kind of disease is had better therapeutic effect, and this is that technical problem to be solved is arranged.
In fact, infer that according to external activity effectiveness is very insecure in the body.According to " medicine registration management way " (version in 2007), new drug registration is declared listing except the experimental studies such as need study of pharmacy, external activity research, the anxious poison of animal, long malicious, carcinogenic, mutagenesis, also need carry out the test of clinical human safety and efficiency evaluation, observe human body for tolerance degree, untoward reaction, the pharmacokinetics of medicine, and medicine is on the impact of routine blood test, routine urinalysis, blood biochemistry etc., at the Clinical efficacy of guaranteeing the rear and further drugs of safety.Wherein, the researchs of clinical safety, particularly Clinical efficacy are only the most key stage in this complexity research.The chemical compound that the research of many external activities, animal experiment result of study well enter clinical research fails to be developed to medicine because of the factor such as safe, effective in the body, even the chemical compound of safety in the clinical research proof body also for want of effectively fails to be developed to medicine in the body.Illustrate in the external activity, body of chemical compound or compositions whether effectively not directly relatedly in the safety and body, do not have predictability.
Make progress such as pharmacy, 2004,28 (4): report in 163-168: at present, it not is a highly effective process that new drug comes into the market, and the medicine that wherein enters clinical research more than 90% is final owing to the factors such as safety, pharmacokinetics, drug effect fall short of success for lack of final effort.
In the research history of antibiotic medicine, good and the antibiotic Antibiotique composition that presents wide spectrum of multiple external activity is enough clinical safety and effectiveness and stop research for want of: Chinese antibiotic magazine for example, 2010,35 (12): report in 881-910, DQ-2556, CB-181963, FK-041, E1101, FR192752, S-3578 etc., wherein, CB-181963 is owing to only have very short post antibiotic effect (PAE), its administration frequency must be higher than the administration frequency (lacking enough effectiveness) of remaining beta-lactam, S-3578 stops clinical research because erythra side-effect problem (lacking enough safeties) occurring.
This shows, the medicine that embodies antibacterial activity in vitro is carried out sufficient activity in vivo research confirm that whether it still has or have what kind of pharmaceutically acceptable activity, remains those skilled in the art and need to pay the work that creative work just can be finished.
Acute cystitis is a kind of commonly encountered diseases, frequently-occurring disease, and the repeatedly characteristics of outbreak are arranged, and is mainly caused by antibacterials such as escherichia colis.Infect and often per urethram to drive in the wrong direction due to the bladder.The women is secondary to vaginitis, urethritis and acute pyelonephritis etc. more than the male more.At present, can adopt the effective cured by antibiotics of pathogenetic bacteria for conventional acute cystitis, but for the urinary system infection that shows as acute cystitis by bacterial antibiotic list medicine drug resistance, particularly beta-lactamase causes because producing, the state of an illness shows as the acute cystitis of moderate or severe, there are no the comparatively effective medicine of bibliographical information.
The applicant has carried out a large amount of experimentatioies, and has finished thus the present invention from the problem that prior art exists.
Summary of the invention
When the described compositions of prior art is carried out studying in the body, the inventor finds, in external antibacterial experiment, embody more superior antibacterial activity although compare described compositions with compound alone 1, because external antibacterial experiment is not considered any organic factor, effect when infecting for interior therapeutic is unpredicted, and the effect during especially to the moderate of complexity or severe infection is difficult to calculate especially.Produce the reason of notable difference for this vivo and vitro result, may be because medicine must be through complicated transhipment, metabolic process in human body, meeting is so that medicine differs etc. at the aggregation extent of human body different parts, but the real concrete reason inventor also fails to understand fully.Yet, be not subjected to the restriction in theory, process is to a large amount of antibacterial research of various antibacterials at infection site, the inventor unexpectedly finds, described compositions is for because producing beta-lactamase and/or the compositions sensitive bacterial being caused that especially the urinary system infection of moderate or severe acute cystitis has very outstanding effect.This point will clearly show in the test below.
The object of the present invention is to provide a kind of medicinal application is the urinary system infection of acute cystitis in the clinical manifestation for the treatment of by bacterial chemical compound 1 single medicine drug resistance.Particularly be applied to because producing beta-lactamase and/or the compositions sensitive bacterial being caused, especially moderate or severe urinary system infection.
Among the present invention, the free acid structure of chemical compound 1 is suc as formula shown in the IB, and the free acid structure of chemical compound 2 is suc as formula shown in the IIB:
(formula IB) (formula IIB).
The technical barrier that exists in order to solve prior art, research worker of the present invention has been carried out a large amount of systematicness work to this:
1, Pharmacodynamics in vitro experiment
Adopt the plate doubling dilution to measure compositions In Vitro Bacteriostasis/antibacterial activity, experimental result shows: chemical compound 1 is (in free acid, structure is suc as formula IB) and chemical compound 2 (in free acid, structure is suc as formula IIB) weight ratio is that the compositions of 2:1～4:1 is to multiple beta-lactamase-producing strain, staphylococcus aureus for example, staphylococcus epidermidis, streptococcus pneumoniae, colon bacillus, Klebsiella pneumonia, Pseudomonas aeruginosa, acinetobacter calcoaceticus, aerobacteria, the In Vitro Bacteriostasis of shigella flexneri and enterobacter cloacae etc. is respond well, and fungistatic effect is better than compound alone 1 or chemical compound 2.
2, pharmacological toxicology research
General pharmacology is learned result of the test and is shown: in the chemical compound 1 of free acid and the compositions take the weight ratio of the chemical compound 2 of free acid as 2:1, under the dosage of mouse mainline 240mg/kg, 480mg/kg, 960mg/kg, compositions reaches mice autonomic movement, balance ability and all has no significant effect the length of one's sleep that pentobarbital sodium is induced; Under the dosage of anesthetized dog venoclysis 120mg/kg, 240mg/kg, 480mg/kg, compositions is to amplitude of respiration, respiratory frequency, heart rate, mean arterial pressure are showed no obvious impact, to being showed no obvious change before and after electrocardio S-T section, P ripple, QRS wave group, P-R interval, Q-T each administration group of interval and the matched group administration.Can find out that in animal experiment injection chemical compound 1 has no significant effect central nervous system, respiratory system, cardiovascular system with the compositions of chemical compound 2.
The tail vein injection single-dose is adopted in acute toxicity test, and carry out the maximum dosage-feeding experiment: chemical compound 1 reaches 5.00g/kg, is the maximum dosage under this medicine maximum dissolvable concentration 125.0mg/mL and the maximum administration volume 40mL/kg; Chemical compound 2 reaches 2.50g/kg, and chemical compound 1 reaches 7.50g/kg with the compositions of chemical compound 2 (2:1).Result of the test shows in the animal acute toxicity test, and the compositions of chemical compound 1 and chemical compound 2 and single medicine no significant difference on to the influence degree of animal meets preliminary security requirement.
Long term toxicity test is the result show: the compositions of chemical compound 1 and chemical compound 2 (2:1) and single medicine no significant difference on to the influence degree of animal meets preliminary security requirement.Chemical compound 1 is the safety non-toxic dosage of this medicine with (2:1) compositions 300mg/kg dosage of chemical compound 2, and this dosage is about 2.5 times of expectation human maximal dose.
Experiment shows, in the chemical compound 1 of free acid and compositions take the weight ratio of the chemical compound 2 of free acid as 3:1 or 4:1 with have consistent pharmacological toxicology result in the chemical compound 1 of free acid and the compositions take the weight ratio of the chemical compound 2 of free acid as 2:1.
In the above-mentioned experiment, the compositions of chemical compound 1 and chemical compound 2 (2:1) refers in the chemical compound 1 of free acid and the compositions take the weight ratio of the chemical compound 2 of free acid as 2:1.
3, biopharmaceutics research
Because acute toxicity, long term toxicity test result show the toxicity of chemical compound 1 and the compositions of chemical compound 2 (2:1), with single dose than no significant difference, toxicity does not increase.According to the regulations of medicine registration management, can remove clinical front animal pharmacokinetics test from.The intravenous injection peaking concentration time of the compositions of chemical compound 1 and chemical compound 2 (2:1) and chemical compound 1, chemical compound 2 single doses, half-life etc. approach, and metabolic chart is similar, meets the condition of making compound preparation.
In the above-mentioned experiment, the compositions of chemical compound 1 and chemical compound 2 (2:1) refers in the chemical compound 1 of free acid and the compositions take the weight ratio of the chemical compound 2 of free acid as 2:1.
4, the clinical toleration of compositions I phase of chemical compound 1 and chemical compound 2
The tolerance test result shows, in the chemical compound 1 of free acid and the maximum tolerated dose take the weight ratio of the chemical compound 2 of free acid as the compositions single-dose of 2:1 as 9.0g; Multiple dosing 2.25-3.0g, per 8 hours are once, intravenous drip, continuous 7 days are also safer, better tolerance.
Same experiment shows, shows as equally safety in the human body in the chemical compound 1 of free acid and the compositions take the weight ratio of the chemical compound 2 of free acid as 3:1 and 4:1, and toleration is good.
Can find out from above-mentioned Pharmacodynamics in vitro experiment, pharmacological toxicology research, biopharmaceutics research, toleration, in the chemical compound 1 of free acid and the compositions performance In Vitro Bacteriostatic take the weight ratio of the chemical compound 2 of free acid as 2:1～4:1, show as preferably safety, toleration at animal and human's body.But because medicine must be through complicated transhipment, metabolic process in human body, meeting so that medicine differ at the aggregation extent of human body different parts, can there be different therapeutic effect in corresponding medicine for the different parts disease, compositions by further human trial research chemical compound 1 and chemical compound 2 infects the curative effect situation to the partes corporis humani position, seeks the indication with optimum therapeuticing effect.
Toleration is because being to carry out in healthy population, selection to tested crowd in the experimentation is comparatively simple and easy, the Human Tolerance implementations that it is mainly investigated, the safety of drug dose that overall merit is used in human body, but this experiment has which kind of purposes and effect situation without any enlightenment and help to medicine in human body.
5, human body pharmacodynamics clinical trial
In order to determine that medicine has which kind of purposes and effect situation in human body, need carry out loaded down with trivial details and complicated human body pharmacodynamics clinical trial and could determine finally whether medicine has therapeutic effect to disease, this process of the test relates to the formulation of clinical trial protocol, the selection of indication, the selection of case, the formulation of dosage regimen, test grouping and method, test rating, therapeutic evaluation, the implementation of clinical trial protocol, statistical evaluation, the problems such as adverse reaction monitoring and strick precaution, the defective of arbitrary link will cause the inefficacy of evaluating drug effect, therefore, the human body effect experiment is for determining the most key link of drug effectiveness.
Research worker of the present invention, sum up by a large amount of early-stage preparations and Preliminary experiment results analysis, final formulation science, reasonable, effective clinical trial protocol, complex clinical trial by the several years is finally found: the clinical manifestation that the compositions of chemical compound 1 and chemical compound 2 is applied to by bacterial chemical compound 1 single medicine drug resistance is the culture of patients with urinary system infection of acute cystitis, particularly because producing beta-lactamase and/or the compositions sensitive bacterial being caused, especially the patient of moderate or severe urinary system infection has beyond thought effect.
Wherein, the order of severity of the state of an illness, can be according to patient's General Symptoms (raising or neutral classification raises etc. such as the mental status, shiver with cold, gastrointestinal reaction, heating, blood leukocytes) and local symptom (such as frequent micturition, urgent micturition, dysurea, urine color, lumbago, percussion tenderness over kidney region, urine microscopy etc.) etc., by the order of severity and/or have or not corresponding performance to give a mark, with higher moderate or the severe of being judged to be of comprehensive scores, this standard is science comparatively, both can be used for just checking the patient who treats, also can be used for the patient through Drug therapy.In the clinical practice, when the doctor finds patient's above-mentioned General Symptoms and/or local symptom as long as wherein there is a performance serious or outstandingly judge that namely the state of an illness is moderate or severe than ordinary circumstance, moderate of the present invention or severe had both comprised this type of patient, also comprise the patient by above-mentioned marking standard determination, also comprise the patient after having accepted the treatment of antibiotic or other antimicrobials, the situation that the state of an illness does not take a favorable turn or further increases the weight of.
Technical scheme of the present invention is screened the patient in the following manner, in the hope of study compositions of the present invention to its whether in the body effectively:
(1), inclusion criteria: 1. agree this clinical trial of participation and the patient who signs Informed Consent Form; 2. 18 one full year of life one full year of life to 70 of age, being in hospital or the out-patient of male or female; 3. be the patient of acute cystitis or complexity urinary tract infection to clinical manifestation, add up and give a mark by its General Symptoms that shows and local symptom,
The screening coincident with severity degree of condition is the patient of moderate or severe, concrete evaluation criteria such as following table:
If there is one of following situation in the patient, will be excluded, do not enter group and test:
1, cephalo-type and beta-lactam antibacterials there are allergies and allergic constitution person.
2, severe infections etc. needs antibacterials use in conjunction person.
3, severe cardiac, liver, kidney disease, or ALT, AST, BUN surpass 1.5 times of Upper Limit of Normal Values, and Cr surpasses the Upper Limit of Normal Value person.
4, hematopathy, late tumor, and central nervous system disease (such as epilepsy) or other system is serious or the PD person.
5, the spiritedness illness can not the partner.
6, the women of gestation or preparation gestation, women breast-feeding their children.
7, accepted the patient of any other trial drug in selected front 3 months.
(2), select that accumulative total appraisal result is that injection chemical compound 1 single therapy 72 hours are accepted in moderate or the unification of severe culture of patients with urinary system infection in (1), usage and dosage is specific as follows:
Grade and moderate infection--injection chemical compound 1 (1.0g) after normal saline 10mL dissolving, adds normal saline 100ml angular vein and instils 30 minutes time, per 8 hours 1 time.
Severe infection--injection chemical compound 1 (1.5g) after normal saline 10mL dissolving, adds normal saline 100ml angular vein and instils 30 minutes time, per 8 hours 1 time.
Whether effectively to the patient judge by injection chemical compound 1 single therapy 72 hours, further give the compositions of chemical compound 1 of the present invention with chemical compound 2 to judging invalid patient.
(3), selecting to add up appraisal result in (1) is moderate or severe culture of patients with urinary system infection, 0～1 day collection mud-stream urine specimen is carried out antibacterial culturing, beta-lactamase detection and drug sensitive test before chemical compound 1 single therapy, the screening antibacterial culturing be the patient of " positive and to chemical compound 1 single medicine drug resistance, to the antibacterial of the product beta-lactamase of the compositions sensitivity of chemical compound 1 and chemical compound 2 ".
The patient of the urinary system infection that the compositions of chemical compound 1 and chemical compound 2 is applied to screen by the way, being surprised to find said composition is that the culture of patients with urinary system infection of acute cystitis has extraordinary effect for the clinical manifestation of the chemical compound 1 single medicine drug resistance that is caused (antibacterial culturing become positive) by antibacterial, and the complexity urinary tract infection with method screening and experiment has better effect.
The antibacterial further investigation is found compositions of the present invention is particularly to having extraordinary effect because of the urinary system infection that produces the bacterial acute cystitis of beta-lactamase.The antibacterial kind is identified: described antibacterial includes but not limited to Acinetobacter bauamnnii, staphylococcus epidermidis, escherichia coli, klebsiella pneumoniae, enterobacter cloacae.
In experimentation of the present invention, culture of patients with urinary system infection is carried out follow-up investigation, and the record of General Symptoms and local symptom and statistics, compositions of the present invention is effective to the patient of various coincident with severity degree of conditions, particularly the patient of moderate or severe.
Further the antibacterial further investigation is found that particularly drug sensitive test is more effective to the urinary system infection that the compositions sensitive bacterial causes for the compositions of chemical compound 1 and chemical compound 2.
Wherein, be the patient of acute cystitis or complexity urinary tract infection to the clinical manifestation by bacterial chemical compound 1 single medicine drug resistance, after giving the compositions of chemical compound of the present invention 1 with chemical compound 2 (in the chemical compound 1 of free acid with take the weight ratio of the chemical compound 2 of free acid as 2:1), antibacterial and whole body sign and local sign etc. are observed, study and add up, found that:
Its bacteria clearance to the patient of described acute cystitis is 90.9%, and clinical effective rate is 90.9%, and cure rate is 90.9%;
Its bacteria clearance to the patient of described complexity urinary tract infection is 83.3%, and clinical effective rate is 66.7%, and cure rate is 66.7%;
The compositions of described chemical compound 1 and chemical compound 2 to acute cystitis than the complexity urinary tract infection in bacteriology's curative effect-clearance rate, clinical efficacy-effective percentage, the aspects such as clinical efficacy-cure rate all have better effect, and beyond thought effect is arranged.
In addition, the compositions of described chemical compound 1 and chemical compound 2 is 66.7% to the patient's of described tracheaectasy concurrent infection clinical effective rate, and cure rate is 66.7%; The compositions that described chemical compound 1 and chemical compound 2 be described to the urinary system infection of acute cystitis than the respiratory system infection of tracheaectasy concurrent infection at clinical efficacy-effective percentage, the aspects such as clinical efficacy-cure rate all have better effect, and beyond thought effect is arranged.
Described " removing " for after treating, the specimen at former infection position is not turned out the pathogen of former infection again.
Described " effectively " shows clinical cure at least after treating, or antibacterial one of is removed.
Clinical cure when described " recovery from illness " follows up a case by regular visits to after treatment finishes for the patient, and antibacterial is removed.
Described clinical cure: symptom, the sign when all were selected when the patient followed up a case by regular visits to after treatment finishes all disappeared or recovered normal fully, the non-microorganisms such as lab testing are learned index and have all been recovered normally, and the imaging examination result has recovered normal or reached the degree that can judge healing; In some indication, may still can observe some clinical symptoms or sign when following up a case by regular visits to after treatment finishes, or still exist some non-microorganisms to learn the unusual of index.If above-mentioned situation is only to point out postinfectious state or underlying diseases, and inactive infection then also can be thought clinical cure.
Same experiment shows, uses in the chemical compound 1 of free acid with in the weight ratio of the chemical compound 2 of the free acid compositions as 3:1 or 4:1, has consistent experimental result.
According to above-mentioned a large amount of systematic experimental studies results, propose following technical scheme and realize the object of the invention: a kind of chemical compound 1 is preparing the application for the treatment of by the urinary system infection medicine of bacterial chemical compound 1 single medicine drug resistance with the compositions of chemical compound 2, and described urinary system infection clinical manifestation is acute cystitis.
Described Production by Bacteria beta-lactamase includes but not limited to Acinetobacter bauamnnii, staphylococcus epidermidis, escherichia coli, klebsiella pneumoniae, enterobacter cloacae.Described antibacterial drug sensitivity testing in vitro is responsive with the compositions of chemical compound 2 to chemical compound 1.
Described urinary system infection coincident with severity degree of condition is moderate or severe.
In a large amount of experimentatioies, find, give compositions of the present invention for above-mentioned patient, drug dose and corresponding form of medication can be selected according to injection routine dose and administering mode according to practical situation, wherein, in the compositions in the chemical compound 1 of free acid with take the weight ratio of the chemical compound 2 of free acid as 2:1～4:1, preferred weight ratio 2:1 or 3:1 or 4:1.
The compositions of chemical compound of the present invention 1 and chemical compound 2 is if clear its ratio of record refers to that all preferred weight ratio is 2:1 or 3:1 or 4:1 in the chemical compound 1 of free acid and the compositions take the weight ratio of the chemical compound 2 of free acid as 2:1～4:1.
In a preferred version of the present invention, the dosage form that includes but not limited in the chemical compound 1 of free acid and the compositions take the weight ratio of the chemical compound 2 of free acid as 2:1 has: 0.75g, 1.5g, 2.25g, 3.0g or 4.5g etc., wherein, 1.5g refer to compositions by the chemical compound 1 of counting 1.0g with free acid and count the forming of chemical compound 2 of 0.5g with free acid, the composition of other dosage forms can carry out corresponding calculating in this way.In addition, other are that the compositions of 3:1 or 4:1 contains identical or close dosage form such as weight ratio.
Medicine of the present invention can be by including but not limited to intravenous, subcutaneous, muscle, lumbar injection, or the mode of intravenous drip gives the patient, can select water for injection or injection normal saline etc. with composition dissolves and be adjusted to patient's acceptable drug level before the injection.
The present invention further comprises the product form of said composition, product is the pressed powder forms such as powder pin or lyophilizing, be stored in the ampuliform or bag-like container of sealing, such as cillin bottle, ampoule bottle, transfusion bag etc., product is with the carrier of record said composition composition and uses thereof in addition, for example, the label carrier such as pharmaceutical packing box and/or paper spare description.
Preferred but be not limited to following drug products form:
A kind of composition product, it comprises:
(a), in the chemical compound 1 of free acid and the compositions take the weight ratio of the chemical compound 2 of free acid as 2:1～4:1, preferred weight ratio is 2:1,3:1 or 4:1;
(b), the container of dress compositions;
(c), label, label character record or illustrate that described compositions is in the application of preparation treatment by bacterial chemical compound 1 single medicine drug resistance urinary system infection medicine.
The present invention relates to a kind of new purposes of compositions and contain the product of this new purposes; as long as the product that any mode has been put down in writing and/or used this purposes and had this purposes; all should be interpreted as identically with spirit of the present invention, all belong within protection scope of the present invention.
The specific embodiment
The present invention is described in further detail below in conjunction with embodiment, but the working of an invention mode is not limited to this.
Embodiment 1
Screen in such a way the patient:
(1), inclusion criteria: 1. agree this clinical trial of participation and the patient who signs Informed Consent Form; 2. 18 one full year of life one full year of life to 70 of age, being in hospital or the out-patient of male or female; 3. to clinical definite show as acute cystitis or complexity urinary tract infection the patient, add up and give a mark by its General Symptoms that shows and local symptom, the screening coincident with severity degree of condition is the patient of moderate or severe, concrete evaluation criteria such as following table:
If there is one of following situation in the patient, will be excluded, do not enter group and test:
1, cephalo-type and beta-lactam antibacterials there are allergies and allergic constitution person.
2, severe infections etc. needs antibacterials use in conjunction person.
3, severe cardiac, liver, kidney disease, or ALT, AST, BUN surpass 1.5 times of Upper Limit of Normal Values, and Cr surpasses the Upper Limit of Normal Value person.
4, hematopathy, late tumor, and central nervous system disease (such as epilepsy) or other system is serious or the PD person.
5, the spiritedness illness can not the partner.
6, the women of gestation or preparation gestation, women breast-feeding their children.
7, accepted the patient of any other trial drug in selected front 3 months.
(2), select that accumulative total appraisal result is that injection chemical compound 1 single therapy 72 hours are accepted in moderate or the unification of severe culture of patients with urinary system infection in (1), usage and dosage is specific as follows:
Grade and moderate infection--injection chemical compound 1 (1.0g) after normal saline 10ml dissolving, adds normal saline 100ml angular vein and instils 30 minutes time, per 8 hours 1 time.
Severe infection--injection chemical compound 1 (1.5g) after normal saline 10ml dissolving, adds normal saline 100ml angular vein and instils 30 minutes time, per 8 hours 1 time.
(3), selecting to add up appraisal result in (1) is moderate or severe culture of patients with urinary system infection, 0～1 day collection mud-stream urine specimen is carried out antibacterial culturing, beta-lactamase detection and drug sensitive test before chemical compound 1 single therapy, the screening antibacterial culturing be the patient of " positive and to chemical compound 1 single medicine drug resistance, to the antibacterial of the product beta-lactamase of the compositions sensitivity of chemical compound 1 and chemical compound 2 ".
Select in (2) chemical compound 1 single therapy 72 hours invalid, antibacterial culturing be " positive and to chemical compound 1 single medicine drug resistance; to the antibacterial of the product beta-lactamase of the compositions sensitivity of chemical compound 1 and chemical compound 2 " patient in (3) simultaneously, screen altogether 17 examples and meet the patient, wherein, acute cystitis 11 examples, complexity urinary tract infection 6 examples.
Embodiment 2
To give 17 routine patients of screening in above-described embodiment 1 in the chemical compound 1 of free acid and the compositions take the weight ratio of the chemical compound 2 of free acid as 2:1, carry out by a definite date 14 days treatment, wherein, the dosage of medicine and to give mode as follows:
The compositions (1.5g) of grade and moderate infection---injection chemical compound 1 and chemical compound 2 after normal saline 10mL dissolving, adds normal saline 100mL angular vein and instils 30 minutes time, per 8 hours 1 time.
The compositions (2.25g) of severe infection---injection chemical compound 1 and chemical compound 2 after normal saline 10mL dissolving, adds normal saline 100mL angular vein and instils 30 minutes time, per 8 hours 1 time.
Treatment is added up therapeutic effect to above-mentioned patient after finishing: bacteriology's curative effect-clearance rate, clinical efficacy-effective percentage, and comprehensive therapeutic effect-cure rate.Concrete outcome is as follows:
From upper table as seen, the compositions of described chemical compound 1 and chemical compound 2 to acute cystitis than the complexity urinary tract infection in bacteriology's curative effect-clearance rate, clinical efficacy-effective percentage, and all there is better effect the aspect such as comprehensive therapeutic effect-cure rate, has beyond thought effect.
Wherein, the compositions (1.5g) of injection chemical compound 1 and chemical compound 2 refers to contain with free acid and counts the chemical compound 1 of 1.0g and count the chemical compound 2 of 0.5g with free acid; The compositions (2.25g) of injection chemical compound 1 and chemical compound 2 refers to contain with free acid and counts the chemical compound 1 of 1.5g and count the chemical compound 2 of 0.75g with free acid.
Same experiment shows, uses in the chemical compound 1 of free acid with in the weight ratio of the chemical compound 2 of the free acid compositions as 3:1 or 4:1, has consistent experimental result.
Illustrate that weight ratio of the present invention is that the compositions of chemical compound 1 and chemical compound 2 of 2:1～4:1 is at the culture of patients with urinary system infection for the treatment of by the acute cystitis of bacterial chemical compound 1 single medicine drug resistance, particularly because producing beta-lactamase and/or the compositions sensitive bacterial being caused, especially the patient of moderate or severe urinary system infection has beyond thought effect.
Embodiment 3
Screen in such a way patients with respiratory tract infections:
(1), inclusion criteria: 1. agree this clinical trial of participation and the patient who signs Informed Consent Form; 2. 18 one full year of life one full year of life to 70 of age, being in hospital or the out-patient of male or female; 3. clinical definite is shown as the patient of tracheaectasy concurrent infection, add up and give a mark by its General Symptoms that shows and local symptom, the screening coincident with severity degree of condition is the patient of moderate or severe, concrete evaluation criteria such as following table:
If there is one of following situation in the patient, will be excluded, do not enter group and test:
1, cephalo-type and beta-lactam antibacterials there are allergies and allergic constitution person.
2, severe infections etc. needs antibacterials use in conjunction person.
3, severe cardiac, liver, kidney disease, or ALT, AST, BUN surpass 1.5 times of Upper Limit of Normal Values, and Cr surpasses the Upper Limit of Normal Value person.
4, hematopathy, late tumor, and central nervous system disease (such as epilepsy) or other system is serious or the PD person.
5, the spiritedness illness can not the partner.
6, the women of gestation or preparation gestation, women breast-feeding their children.
7, accepted the patient of any other trial drug in selected front 3 months.
(2), select that accumulative total appraisal result is that injection chemical compound 1 single therapy 72 hours are accepted in moderate or the unification of severe patients with respiratory tract infections in (1), usage and dosage is specific as follows:
Grade and moderate infection--injection chemical compound 1 (1.0g) after normal saline 10ml dissolving, adds normal saline 100ml angular vein and instils 30 minutes time, per 8 hours 1 time.
Severe infection--injection chemical compound 1 (1.5g) after normal saline 10ml dissolving, adds normal saline 100ml angular vein and instils 30 minutes time, per 8 hours 1 time.
(3), selecting to add up appraisal result in (1) is moderate or severe patients with respiratory tract infections, 0～1 day collection sputum sample carries out antibacterial culturing, beta-lactamase detection and drug sensitive test before chemical compound 1 single therapy, the screening antibacterial culturing be the patient of " positive and to chemical compound 1 single medicine drug resistance, to the antibacterial of the product beta-lactamase of the compositions sensitivity of chemical compound 1 and chemical compound 2 ".
Select in (2) chemical compound 1 single therapy 72 hours invalid, antibacterial culturing be " positive and to chemical compound 1 single medicine drug resistance; to the antibacterial of the product beta-lactamase of the compositions sensitivity of chemical compound 1 and chemical compound 2 " patient in (3) simultaneously, screens altogether 6 routine tracheaectasy concurrent infection patients.
Will be in the chemical compound 1 of free acid and the compositions take the weight ratio of the chemical compound 2 of free acid as 2:1, give the 6 routine tracheaectasy concurrent infection patients that above-mentioned screening mode screens in above-described embodiment 3, carry out by a definite date 14 days treatment, wherein, the dosage of medicine and to give mode as follows:
The compositions (1.5g) of grade and moderate infection---injection chemical compound 1 and chemical compound 2 after normal saline 10mL dissolving, adds normal saline 100mL angular vein and instils 30 minutes time, per 8 hours 1 time.
The compositions (2.25g) of severe infection---injection chemical compound 1 and chemical compound 2 after normal saline 10mL dissolving, adds normal saline 100mL angular vein and instils 30 minutes time, per 8 hours 1 time.
Treatment is added up therapeutic effect to above-mentioned patient after finishing: bacteriology's curative effect-clearance rate, clinical efficacy-effective percentage, and comprehensive therapeutic effect-cure rate.Concrete outcome is as follows:
From upper table as seen, the compositions of described chemical compound 1 and chemical compound 2 to the culture of patients with urinary system infection of acute cystitis than the patients with respiratory tract infections of tracheaectasy concurrent infection at clinical efficacy-effective percentage, all there is better effect the aspects such as comprehensive therapeutic effect-cure rate, have beyond thought effect.
Wherein, the compositions (1.5g) of injection chemical compound 1 and chemical compound 2 refers to contain with free acid and counts the chemical compound 1 of 1.0g and count the chemical compound 2 of 0.5g with free acid; The compositions (2.25g) of injection chemical compound 1 and chemical compound 2 refers to contain with free acid and counts the chemical compound 1 of 1.5g and count the chemical compound 2 of 0.75g with free acid.
Same experiment shows, uses in the chemical compound 1 of free acid with in the weight ratio of the chemical compound 2 of the free acid compositions as 3:1 or 4:1, has consistent experimental result.
Above-mentioned result of study explanation weight ratio of the present invention is that the compositions of chemical compound 1 and chemical compound 2 of 2:1～4:1 is at the culture of patients with urinary system infection for the treatment of by the acute cystitis of bacterial chemical compound 1 single medicine drug resistance, particularly because producing beta-lactamase and/or the compositions sensitive bacterial being caused, especially the patient of moderate or severe urinary system infection has beyond thought effect with respect to other clinical symptoms of urinary system infection and respiratory system infection.
Above-described embodiment is the better embodiment of the present invention; but embodiments of the present invention are not restricted to the described embodiments; other any do not deviate from change, the modification done under spirit of the present invention and the principle, substitutes, combination, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (10)
1. chemical compound 1 is preparing the application for the treatment of by the urinary system infection medicine of bacterial chemical compound 1 single medicine drug resistance with the compositions of chemical compound 2, described urinary system infection clinical manifestation is acute cystitis, wherein, chemical compound 1 and chemical compound 2 are respectively suc as formula shown in (I) and the formula (II):
Formula I formula II.
2. the application of the compositions of chemical compound 1 as claimed in claim 1 and chemical compound 2 is characterized in that: described antibacterial is for producing the beta-lactamase antibacterial.
3. the application of the compositions of chemical compound 1 as claimed in claim 1 and chemical compound 2, it is characterized in that: described urinary system infection is moderate or severe urinary system infection.
4. the application of the compositions of chemical compound 1 as claimed in claim 2 and chemical compound 2, it is characterized in that: described urinary system infection is moderate or severe urinary system infection.
5. such as the application of the described chemical compound 1 of the arbitrary claim of claim 1 to 4 with the compositions of chemical compound 2, it is characterized in that: described antibacterial is responsive to described compositions.
6. such as the application of the described chemical compound of the arbitrary claim of claim 1 to 41 with the compositions of chemical compound 2, it is characterized in that: in the described compositions in the chemical compound 1 of free acid with take the weight ratio of the chemical compound 2 of free acid as 2:1～4:1.
7. the application of chemical compound as claimed in claim 51 and the compositions of chemical compound 2 is characterized in that: in the described compositions in the chemical compound 1 of free acid with take the weight ratio of the chemical compound 2 of free acid as 2:1～4:1.
8. such as the application of the described chemical compound of the arbitrary claim of claim 1 to 71 with the compositions of chemical compound 2, it is characterized in that: in the described compositions in the chemical compound 1 of free acid with take the weight ratio of the chemical compound 2 of free acid as 2:1,3:1 or 4:1.
9. composition product, it comprises:
(a), in the chemical compound 1 of free acid and the compositions take the weight ratio of the chemical compound 2 of free acid as 2:1～4:1;
(b), the container of dress compositions;
(c), label, the compositions of the described chemical compound 1 of label character record or explanation as the arbitrary claim of claim 1 to 8 and chemical compound 2 is treated application by the urinary system infection medicine of bacterial chemical compound 1 single medicine drug resistance in preparation.
10. a kind of composition product as claimed in claim 9 is characterized in that: in the described compositions in the chemical compound 1 of free acid with take the weight ratio of the chemical compound 2 of free acid as 2:1,3:1 or 4:1.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1543958A (en) * | 2003-11-25 | 2004-11-10 | 郭东宇 | Antibiotic action enhancing medicinal composition |
| CN1729987A (en) * | 2005-08-19 | 2006-02-08 | 夏中宁 | Cefuroxime sodium and sulbactam sodium composition for injection |
| CN1850047A (en) * | 2006-06-01 | 2006-10-25 | 济南帅华医药科技有限公司 | Slow-release preparation containing beta-lactamase inhibitor and cephalosporin and its use |
| CN101648016A (en) * | 2008-08-11 | 2010-02-17 | 广州威尔曼新药开发中心有限公司 | Medicinal composition with high stability |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1543958A (en) * | 2003-11-25 | 2004-11-10 | 郭东宇 | Antibiotic action enhancing medicinal composition |
| CN1729987A (en) * | 2005-08-19 | 2006-02-08 | 夏中宁 | Cefuroxime sodium and sulbactam sodium composition for injection |
| CN1850047A (en) * | 2006-06-01 | 2006-10-25 | 济南帅华医药科技有限公司 | Slow-release preparation containing beta-lactamase inhibitor and cephalosporin and its use |
| CN101648016A (en) * | 2008-08-11 | 2010-02-17 | 广州威尔曼新药开发中心有限公司 | Medicinal composition with high stability |
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