CN101612149A - Hematoporphyrin monomethyl ether is in the new purposes of field of medicaments - Google Patents
Hematoporphyrin monomethyl ether is in the new purposes of field of medicaments Download PDFInfo
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Abstract
The present invention relates to several new purposes of hematoporphyrin monomethyl ether, comprise diseases such as treatment atherosclerosis, acne, condyloma acuminatum, laryngeal papillomatosis, verruca vulgaris, wart of toe, verruca plana, bowenoid papulosis, Kaposi sarcoma that people's acquired immune deficiency syndrome (AIDS) is relevant, periodontitis, mouthful gingivitis at field of medicaments.Hematoporphyrin monomethyl ether has absworption peak at the 630nm place, is a kind ofly in the photodynamic therapy to form novel photosensitive agent single, stable performance.It can be rapidly removed from tissue, and is very low to the light toxic action of normal structure, can effectively treat various disease, atherosclerosis and the acnes that cause because of antibacterial, virus.
Description
Technical field
The present invention relates to field of medicaments, relate more specifically to utilize hematoporphyrin monomethyl ether, treat the application of the relevant Kaposi sarcoma of atherosclerosis, acne, condyloma acuminatum, laryngeal papillomatosis, verruca vulgaris, wart of toe, verruca plana, bowenoid papulosis, people's acquired immune deficiency syndrome (AIDS), periodontitis, mouthful gingivitis by the affected part being applied optical dynamic therapy (PDT).
Background technology
Photodynamic therapy (photodynamic therapy, PDT) be to impose Photoactive compounds (photosensitizer) to the patient, comprise and being administered systemically and topical, photosensitizer is in the lesions position enrichment, again with the low-intensity laser irradiation of specific wavelength, excite photosensitizer to make it to produce the photodynamics reaction, position in the photodynamics reaction produces free radicals such as singlet oxygen, can kill and wound the histiocyte of this diseased region, mainly produce therapeutic effect by direct cytotoxicity and sealing lesions position blood vessel thereof, be characterized in selectively acting in diseased region, and the therapeutic dose may command, be the most promising a kind of new technique that grew up in nearly 20 years.PDT has obtained on tumor treatment and has broken through progress since 20th century, entered clinical research the seventies.At present, it not only is confined to the treatment of malignant tumor, also shows good prospect in other multiple treatment of diseases.
(atherosclerosis is a mid-aged population cardiovascular and cerebrovascular disease important pathologic basis occurred frequently As) to atherosclerosis, is commonly encountered diseases and the frequently-occurring disease that directly influences human health.Conventional Therapeutic Method such as low fat diet and lipid lowerers etc. to the stable of As speckle with disappear and have certain curative effect, but all have side effect in various degree, and to the restenosis unsatisfactory curative effect due to the percutaneous coronary angioplasty postoperative.Local treatment such as gene therapy, novel vascular stent and intravascular irradiation therapy etc. still are in conceptual phase, and the curative effect instability, seek new Therapeutic Method and remain clinical important topic.
Acne (acne) is a kind of pilosebaceous chronic inflammatory disease dermatoses that involves, and good sending out in the seborrhea position can show as skin lesion such as acne, pimple, pustule, tuberosity, cyst and cicatrix.Its sickness rate 70%～87% has surpassed asthma, epilepsy to the influence of teen-age emotion and social function, and the factors such as obstruction, bacterial infection and inflammatory reaction of the main and hypersteatosis of its morbidity, pilosebaceous duct have substantial connection.Acne treatment is main treatment means with oral tretinoin medicines, antibiotic, gonadal hormone, external tretinoin cream, anti-inflammatory ointment, benzoyl peroxide, sulfur preparation at present.But the especially long-term oral retinoid medicine of traditional method, antibiotic and gonadal hormone exist certain side effect.
Virus (virus) belongs to noncellular microorganism.It is the virulence factor of a class minimum, obviously is different from other microorganisms.Have following feature: individual minimum, do not have cellularity, strictness to colonize on the host cell alive, infectivity arranged.Have 75% to cause among the human infectious disease approximately by virus.
The control viral infection has two kinds of methods at present: the one, put prevention first, be extensive use of vaccine (attenuated live vaccine or inactivated vaccine), existing many years of experience, but because viral species is a lot, and easily morph, therefore still can not produce various effective vaccines prevents and treats each viroid.The 2nd, viral ideal medicament is not also controlled in the applied chemical treatment agent unfortunately so far, and the relation of its reason host cell and virus is too close, and the medicine that antivirus action is strong must have very high toxicity to host cell.
Antibacterial (bacteria) is a big monoid of microorganism, belongs to prokaryote.Kind is many, distribution is wide, breeding is fast, metabolism is strong, individuality is little, effect is big, easily variation.Most of people and animals' disease nearly all is by bacterial, so it brings serious harm to human beings'health.Allly can cause that the antibacterial of human body or Animal diseases claims pathogenic bacterium or pathogen (pathogenic bacteria).By Gram staining method, often antibacterial is divided into Gram-positive and gram negative bacteria.This staining has important meaning at division bacteria, the clinical aspects such as medicine of selecting.
The control antibacterial mainly contains physical method and chemical method at present.The method for disinfection and sterilization of physics comprises mechanical sterilization's method, thermal sterilization, roentgenization method etc.Some physical agents can reach the requirement of sterilization (sterilization) and promptly kill or remove all life entities, but it only is applicable to prophylactic disinfections such as some apparatuses, vessel, air, and are inapplicable substantially for the human body of infection pathogen.Chemical method can be divided into chemosterilant and chemotherapeutant.The kind of chemosterilant is a lot, comprising: halogen, phenol derivmives blend biology, alcohols, alkylating agent, oxidant, heavy metal, surfactant, bronsted lowry acids and bases bronsted lowry, dyestuff etc., the antibacterial action of having nothing in common with each other.The chemosterilant scope of application is substantially with the physics sterilization, but it seldom can reach the sterilization requirement, and they can only remove pathogenic microorganism from object, just sterilization (disinfection).It is not suitable for the people's of pathogen infection treatment equally.The maximum characteristics of chemotherapeutant (chemotherapeutic agents) are optionally to kill or suppress antibacterial, and body is not had toxicity or less toxicity.Chemotherapeutant mainly comprises sulfonamides, antibiotics and other class at present, characteristics such as bacteriostatic activity is strong, selectivity is high though it has, has a broad antifungal spectrum use chemotherapeutant to still have four big clinical problems to need to be resolved hurrily: toxicity, allergy (allergy), superinfection and drug resistance.Wherein chemical sproof problem has greatly influenced clinical efficacy.
Therefore, need urgently to develop new therapeutic agent and Therapeutic Method, so that effectively treat all kinds of diseases that atherosclerosis, acne, antibacterial or viral infection cause in above-mentioned field.
Summary of the invention
The purpose of this invention is to provide a kind of new therapeutic agent and Therapeutic Method, they can effectively treat the relevant Kaposi sarcoma of atherosclerosis, acne, condyloma acuminatum, laryngeal papillomatosis, verruca vulgaris, wart of toe, verruca plana, bowenoid papulosis, people's acquired immune deficiency syndrome (AIDS), periodontitis, mouthful gingivitis.
In a first aspect of the present invention, the new purposes of hematoporphyrin monomethyl ether is provided, it is used to treat the medicine of atherosclerosis, acne or antibacterial and viral infection disease.
In another preference, described atherosclerosis is the constitutional atheromatous plaque; Described acne is a kind of chronic inflammatory disease dermatoses; Described bacterial infection disease is the disease that causes because of gram positive bacteria, gram positive bacterial infection; Described disease of viral infection is to infect the disease that causes because of papillomavirus, human immunodeficiency virus I, herpes simplex virus, human cytomegalic inclusion disease virus, monkey disease poison.
In another preference, described chronic inflammatory disease dermatoses can show as skin lesion such as acne, pimple, pustule, tuberosity, cyst and cicatrix; Described gram positive bacteria, gram positive bacterial infection occur in the human body periodontal.
In another preference, described bacterial infectious disease is selected from down group: periodontitis, mouthful gingivitis; Described viral infection disease is selected from down group: the Kaposi sarcoma that condyloma acuminatum, laryngeal papillomatosis, verruca vulgaris, wart of toe, verruca plana, bowenoid papulosis, people's acquired immune deficiency syndrome (AIDS) are correlated with.
In another preference, described hematoporphyrin monomethyl ether is the chemical compound of following structural formula
In the formula, R
1Be hydrogen atom or methyl, R
2Be methyl or hydrogen atom; Work as R
1During for hydrogen atom, R
2Be methyl; Work as R
1During for methyl, R
2Be hydrogen atom.
In another preference, the dosage of described medicine is pressed hematoporphyrin monomethyl ether and is calculated in the 0.1-100mg/kg body weight.
In another preference, described treatment is an optical dynamic therapy.
In another preference, described optical dynamic therapy condition is that the luminous flux of irradiation is 50-200 joule/cm
2, illuminance is 50-800mW/cm
2, wavelength is 300-800nm.
In a second aspect of the present invention, the purposes of hematoporphyrin monomethyl ether is provided, and it is used as the photosensitizer of diseases such as the relevant Kaposi sarcoma of optical dynamic therapy atherosclerosis, acne, condyloma acuminatum, laryngeal papillomatosis, verruca vulgaris, wart of toe, verruca plana, bowenoid papulosis, people's acquired immune deficiency syndrome (AIDS), periodontitis, mouthful gingivitis.
Beneficial effect of the present invention:
Hematoporphyrin monomethyl ether among the present invention is a kind of novel photosensitive agent, it has stronger absorbability for the light of longer wavelength commonly used, can from tissue, remove rapidly, light toxic action to normal structure is very low, acute and long term toxicity is all lower, than other photosensitizer have composition single clear and definite, form after stable, the administration lucifuge phase obviously advantage such as short.At present atherosclerosis, suppress acne, all there are some problems to be solved in antibiotic, antiviral therapy, by finding in the experiment of the hematoporphyrin monomethyl ether among the present invention being carried out optical dynamic therapy atherosclerosis, acne, bacterial infectious disease or viral infection disease, it has significantly antibiotic, antiviral, inhibition acne and to the stable and regressive effect of constitutional atheromatous plaque, has a good application prospect.
Description of drawings
Fig. 1 is the chemical structure of general formula of hematoporphyrin monomethyl ether
The specific embodiment
The inventor is extensive studies through going deep into, a large amount of chemical compounds have been screened, find that the chemical compound hematoporphyrin monomethyl ether is particularly suitable for treating antibacterial, viral infection disease or atherosclerosis, the optimum absorb wavelength of hematoporphyrin monomethyl ether is 630nm, checkout time is short, photosensitivity can disappear in 24 hours, therefore was suitable as atherosclerosis, treatment acne, antibiotic, antiviral photosensitizer.Finished the present invention on this basis.
Photoactive compounds
Be applicable to that Photoactive compounds of the present invention is a hematoporphyrin monomethyl ether.Xu Deyu, Chen Wenhui etc. " Chinese laser medical journal " (1993,2:3-7) and application number be the physicochemical property that discloses hematoporphyrin monomethyl ether in 01131939 the Chinese patent, preparation method and in the application of treatment tumor; " The 2nd Army Medical College journal " (1990,11:118-122) delivered hematoporphyrin monomethyl ether in the intravital distribution of tumor-bearing mice; Gu Ying, Liu Guangfan etc. are at " Chinese laser medical journal " (2000, Vol9,1 phase) delivered hematoporphyrin monomethyl ether in the absorption of arterial tissue and distribution character, vascular smooth muscle absorption characteristic to hematoporphyrin monomethyl ether, at " Chinese laser medical journal " (2000, Vol9,3 phases) delivered the application of hematoporphyrin monomethyl ether treatment nevus flammeus.All open as a reference at this.
Particularly, be suitable for Photoactive compounds of the present invention and have following structural formula:
R
1Be hydrogen atom or methyl, R
2Be methyl or hydrogen atom; Preferable, work as R
1During for hydrogen atom, R
2Be methyl; Work as R
1During for methyl, R
2Be hydrogen atom.
Hematoporphyrin monomethyl ether also can be united use with other Photoactive compounds.But the effectiveness of treatment depends on light and is absorbed by Photoactive compounds, therefore, if use mixture, then uses to good with the compound with similar maximum absorption band.
The optical dynamic therapy method
Some term of light treatment relating to parameters is different in different authors and publication.Such as luminous flux, also claim light dosage, optical energy density; Illuminance, also success rate intensity, power density.These terms are that those skilled in the art uses and understands, and are illustrated at this.
After the Photoactive compounds administration, target organ, target tissue are shone under selecteed drug absorption wavelength.For hematoporphyrin monomethyl ether, selected wave-length coverage about 300-700nm, more preferably is that the penetration power of this range of wavelength in body tissue is relatively good about 600-700nm generally.
The result of irradiation causes Photoactive compounds to be in excited state, and interacts with other chemical compounds, forms singlet oxygen (Singlet Oxygen) and other free radicals, causes that cellularity destroys.Singlet oxygen and other free radical main damage membrane structures comprise cell membrane, mitochondrial membrane, lysosome membrane and nuclear membrane, cause the necrosis and the apoptosis of pathological tissues cell; Photosensitizer and histiocytic binding site are mainly at the fat film, and therefore, PDT can cause the release of lysosomal hydrolase, further increases the weight of primary cellular defect; In addition, find that also PDT pair cell hereditary material is also influential, can cause the damage of DNA.This shows that PDT is a too many levels to the effect of target tissue.
According to the degree of depth of type, the target tissue of tissue and the amount of fluid or blood on it, the luminous flux of irradiation can have very big change.That preferable is 50-200 joule/cm
2
Illuminance generally changes in 50-800mW/cm
2, with about 100-600800mW/cm
2For good.Yet.Select to use higher illuminance, can shorten treatment time and reach same effect.
After the Photoactive compounds administration to the most in good time interbody spacer between the light treatment also according to administering mode, form of medication and preparation type and different.Interval after the photosensitizer administration was from 1 minute to 2 hours, and preferable is 5-30 minute, and better is 10-25 minute.
Administration and dosage
Photoactive compounds can be with various administrations, as oral, parenterai administration or rectally.Be advisable with parenterai administration, as intravenous, intramuscular or subcutaneous injection.With intravenous injection is best.
The dosage of Photoactive compounds can be according to administering mode, preparation type, whether coupling targeting part has very big variation.It is generally acknowledged, relevant between photoactive preparation, administering mode and dosage level.Usually, the typical doses scope of hematoporphyrin monomethyl ether is 0.1-100mg/kg, and preferable dosage range is 0.5-50mg/kg, and better dosage range is 1-10mg/kg.Those skilled in the art also can be determined by experiment proper dosage.
Being used for various parameters effective, the selective light photodynamic therapy in the present invention is to be mutually related.Therefore, can adjust dosage with respect to other parameters (for example in the photodynamic therapy interval between employed luminous flux, illuminance, persistent period and dosage, administration and the rayed etc.).The obvious damage of using these parameters all should adjust to significantly improve therapeutic effect and not producing normal structure is advisable.Those skilled in the art can determine suitable parameters by test.
In other words, when the dosage of Photoactive compounds reduced, the luminous flux that produces therapeutic effect had the trend of increase; Otherwise, need to reduce luminous flux, then need to increase the dosage of Photoactive compounds or increase the enrichment degree that the targeting promotion increases the diseased region Photoactive compounds.
Treatment mechanism
The present invention relates to diseases such as optical dynamic therapy atherosclerosis, acne, condyloma acuminatum, laryngeal papillomatosis, verruca vulgaris, wart of toe, verruca plana, bowenoid papulosis, Kaposi sarcoma that people's acquired immune deficiency syndrome (AIDS) is relevant, periodontitis, mouthful gingivitis.
In to the constitutional atherosclerosis therapy; the special absorption hemoporphyrin of constitutional atheromatous plaque methyl ether; use the photodynamic therapy among the present invention; propagation, migration and secretory function that can be by suppressing smooth muscle cell, the adaptability reconstruct of promotion blood vessel wall and protect endotheliocyte, keep the endothelium structural integrity are played effectively stable and regressive effect to the former pulse atherosclerosis speckle that starts.
In to remedy of acne, after giving photosensitizer, the hemoporphyrin methyl ether can be absorbed by epithelial cell and pilosebaceous unit, when the light of appropriate wavelength shines, not only can activate propionibacterium acnes self and produce endogenous Photoactive compounds porphyrin, simultaneously can also activate the hemoporphyrin methyl ether, thereby can improve acne with destroying pilosebaceous unit by the selective killing propionibacterium acnes.
In the viral infection treatment of diseases such as Kaposi sarcoma that condyloma acuminatum, laryngeal papillomatosis, verruca vulgaris, wart of toe, verruca plana, bowenoid papulosis, people's acquired immune deficiency syndrome (AIDS) are correlated with, the mechanism of hematoporphyrin monomethyl ether light dynamic method inactivation of viruses is that they have affinity with the lipid and the glycolipid that constitute the peplos integral part, after photodynamic action, the destroy integrity of peplos, being considered to by the cell membrane of viral infection and peplos all is the binding site of this class photosensitizer.
In treatment to bacterial infectious diseases such as periodontitis, mouthful gingivitis, the hemoporphyrin methyl ether is injected in the periodontal pocket, alternative is incorporated into the component substances on the bacteria cell wall, as lipopolysaccharide, cytoplasmic membrane composition, after the laser irradiation of appropriate wavelength, photosensitizer activates and produces active oxygen, can stop cytotoxic activity, can also destroy bacteria cell wall in lethal ground, thereby reach the effect of targeting sterilization.
Medicable disease
The invention provides the method for diseases such as the relevant Kaposi sarcoma of a kind of optical dynamic therapy atherosclerosis, acne, condyloma acuminatum, laryngeal papillomatosis, verruca vulgaris, wart of toe, verruca plana, bowenoid papulosis, people's acquired immune deficiency syndrome (AIDS), periodontitis, mouthful gingivitis, comprise that patient to this treatment of needs takes the Photoactive compounds preparation of the patient part enrichment q.s photosensitizer that is enough to make the patients receiving treatment; Allow time enough to make the Photoactive compounds of effective dose be enriched in patient's sufferer place; With the rayed affected part that is fit to sensitiser absorption.
Because in Therapeutic Method of the present invention, utilize hematoporphyrin monomethyl ether, by photodynamic therapy stable effectively and disappeared former start the pulse atherosclerosis speckle, effectively killed and wounded propionibacterium acnes and destroyed pilosebaceous unit, effectively deactivation virus and antibacterial, so the inventive method can be used for treating atherosclerosis, acne, bacterial infectious disease and viral infection disease.Representative viral infection disease includes but is not limited to: the Kaposi sarcoma that condyloma acuminatum, laryngeal papillomatosis, verruca vulgaris, wart of toe, verruca plana, bowenoid papulosis, people's acquired immune deficiency syndrome (AIDS) are correlated with; Representative bacterial infectious disease includes but is not limited to: periodontitis, mouthful gingivitis.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after the content of having read the present invention's instruction, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
The experimental technique of unreceipted actual conditions in the following example is usually according to the normal condition or the condition of advising according to manufacturer.
Embodiment 1: the preparation of hematoporphyrin monomethyl ether and therapeutic agent
A. the preparation of hematoporphyrin monomethyl ether
Press the method described in the Chinese patent application of CN 01131939, take by weighing 20 grams 3,8-two (1-bromoethyl) deuteroporphyrin IX hydrobromate, with the mixed liquor stirring reaction of the methanol of itself and 3000 milliliters and water 2 hours, this reactant liquor is regulated pH to 13 with the sodium hydroxide of 10mol/L, stirred 4 hours, and with the pH to 4-5 of glacial acetic acid conditioned reaction liquid, separated out precipitation again.The precipitation that buchner funnel filter collection is separated out, washing, drying obtains 19.5 gram crude products.Obtain 3.9 gram hematoporphyrin monomethyl ethers (Fig. 1) through silica gel column chromatography separating purification.
Repeat above-mentioned steps, obtain about 20 gram hematoporphyrin monomethyl ethers.
B. the preparation of hematoporphyrin monomethyl ether lyophilized formulations
Take by weighing 10 gram hemoporphyrin methyl ether crude drug, be stirred well to dissolving with the sodium hydrate aqueous solution of an amount of 0.2mol/L, the hydrochloric acid conditioning solution pH to 7-8 of reuse 0.2mol/L adds an amount of mannitol, is settled to 400 milliliters with water for injection again; Aseptic filtration is distributed into every bottle and contains 100 milligrams of medicines.Put lyophilization in the freezer dryer, jump a queue and seal, label.Redissolve to the desired concn administration with normal saline during use.
C. the preparation of hematoporphyrin monomethyl ether injection
Take by weighing 10 gram hemoporphyrin methyl ether crude drug, be stirred well to dissolving, the hydrochloric acid conditioning solution pH to 7-8 of reuse 0.2mol/L with the sodium hydrate aqueous solution of an amount of 0.2mol/L, add an amount of mannitol, be settled to 1000 milliliters with water for injection again, the aseptic filtration packing, jump a queue and seal, label.Direct administration during use.
Embodiment 2: hemoporphyrin methyl ether-photodynamic therapy is to the action effect of constitutional atheromatous plaque
Experimental technique
25 New Zealand white rabbit by the mode of aortic sac inner film injury,, induce to form two atheromatous plaque at ventral aorta in two zones at about 1.5cm place.
During the 8th week, get first group of 15 white rabbit, press the hemoporphyrin methyl ether injection of embodiment 1 preparation, carry out intravenous injection with the dosage of 5.0mg/kg, then respectively 1,12, put to death after 24,48 and 72 hours, with the ventral aorta exposure of every animal, record the content distribution of hematoporphyrin monomethyl ether in arteriosclerosis plaque and normal tremulous pulse with fluorescence spectrophotometry, count content the highest time of distribution ratio in arteriosclerosis plaque and normal tremulous pulse of hematoporphyrin monomethyl ether.
Get second group of 10 white rabbit, press the hemoporphyrin methyl ether injection of embodiment 1 preparation, dosage with 5.0mg/kg carries out intravenous injection, in the appearance hematoporphyrin monomethyl ether content distribution the highest time of ratio of first treated animal statistics, use the aseptic technique anesthetized animal and expose their ventral aorta, recognize every derivative two atheromatous plaque of animal, select bigger one to carry out optical dynamic therapy, another in contrast.Optical dynamic therapy uses the electric filament lamp of 220V, 300W as light source, shines after paraboloidal mirror is concentrated, and the illumination wavelength that produces with filter blocking-up back is 630nm, treatment area 25cm
2, dosage is 20J/cm
2Put to death animal, observe the curative effect in the 2nd, 4,6 weeks respectively at last.
The result
The experimental result of first treated animal sees Table 1, and the result shows, behind the intravenous injection hemoporphyrin methyl ether 48 hours, medicine reached peak at arteriosclerosis plaque and content distribution ratio in the normal tremulous pulse, is fit to carry out optical dynamic therapy.Second treated animal is accepted optical dynamic therapy at the intravenous injection hematoporphyrin monomethyl ether after 48 hours, and put to death in the 2nd, 4,6 weeks respectively, experimental result shows, its atheromatous plaque of accepting hematoporphyrin monomethyl ether-optical dynamic therapy is compared with the contrast speckle all dwindling in various degree, and the degree maximum that the animal arteriosclerosis plaque that the 6th week put to death dwindles.
Distribution after the intravenous injection of table 1 hematoporphyrin monomethyl ether in rabbit ventral aorta plaque and normal tremulous pulse
Embodiment 3: hemoporphyrin methyl ether-photodynamic therapy is to the effect of acne treatment
Therapeutic Method
Press the hemoporphyrin methyl ether lyophilized formulations of embodiment 1 preparation, be prepared into the therapeutic agent that concentration is 10mg/ml, every 100mg, the skin test negative patient is with the 3.5-5mg/kg intravenous injection.Behind the administration 15min, carry out the acne local irradiation with IECU210 type copper vapor laser therapy apparatus, wavelength 510nm and 570nm, pulse recurrence frequency is 6kHz, pulse width 20-40ns, the treatment power density is 70-100mW/cm
2, energy density is 150-360J/cm
2, spot diameter 4-10cm, treatment area 2-70cm
2Normal skin and eye around suitably hiding during irradiation adopt single-spot or many hot spots irradiation treatment according to acne affected part area size, and irradiation treatment is all finished in the 20min-3.5h after administration.Treat weekly 2 times, finish after 6 times.1,4,8 weeks of before the treatment and treatment back are observed skin, make therapeutic evaluation, and write down untoward reaction simultaneously.
Curative effect determinate standard
Estimate curative effect according to the percentage rate that facial skin lesion total mark reduces: skin lesion reduces 〉=90% than original skin lesion integration and is recovery from illness, and 60%～89% is produce effects, and 20%～59% for taking a turn for the better, and＜20% is invalid, effective percentage=cure rate+obvious effective rate.After finishing, 4 weeks of treatment respectively acne, pimple, pustule, 4 kinds of skin lesion of tuberosity are carried out the evaluation of skin lesion quantity slip, skin lesion number * 100% before skin lesion quantity slip=(skin lesion number before the treatment-treatment back skin lesion number)/treatment.
The result
After treating 6 times, efficacy result sees Table 2.46 routine patients behind 6 hemoporphyrin methyl ether-optical dynamic therapies, 38 examples of fully recovering, produce effects 4 examples, 3 examples that take a turn for the better, invalid 1 example, cure rate is 82.6%, effective percentage is g1.3%.Only there are slight erythema, edema, burn feeling, decortication, no obvious pain in the part behind hemoporphyrin methyl ether-optical dynamic therapy, does not influence treatment.
The dissimilar patients with acne of table 2 behind hemoporphyrin methyl ether-optical dynamic therapy curative effect statistics (example, %)
Embodiment 4: hemoporphyrin methyl ether-photodynamic therapy is to the effect of condyloma acuminatum treatment
Condyloma acuminatum is to infect the proliferative disease that causes by HPV, occupies second of sexually transmitted disease (STD) incidence rate, and human body is that (this virus can cause the squamous epithelial cancer propagation of human body skin and mucosa to the human papillomavirus for human papillomavirus, only host HPV).Hemoporphyrin methyl ether-photodynamic therapy be a kind of simple, safety, effectively, the method for treatment condyloma acuminatum that low, the better tolerance of relapse rate, side effect are little.
Therapeutic Method
Press the hemoporphyrin methyl ether lyophilized formulations of embodiment 1 preparation, be prepared into the therapeutic agent that concentration is 10mg/ml, every 100mg, the skin test negative patient is with the 3.5-5mg/kg intravenous injection.Behind the injection 15min, to the skin lesion local irradiation of condyloma acuminatum affected part, wavelength is 635nm, laser radiation 20min, and about the about 15cm of irradiation distance, dosage 100J/cm
2Treatment weekly 1 time is finished treatment 1-3 time.All the patient all finishes the back observe the curative effect in treatment.
Curative effect determinate standard
Effect (CR) is the skin lesion complete obiteration fully, continues 1 month; Obviously effect (SR) is dwindled more than 50% for skin lesion maximum gauge product vertical with it or the skin lesion height, and continues more than 1 month; Slightly effectively (MR) dwindles less than 50% for above-mentioned product, and continues more than 1 month; Invalid (NR) do not dwindle for skin lesion has or increases.
The result
8 routine condyloma acuminatum patients all finish treatment smoothly, and 6 routine condyloma in prepuce patients reach complete effect after 3 treatments, reach complete effect after 2 treatments of 2 an example left side gang pudendum condyloma acuminatum patients.Effective percentage 100% is observed in this research.Have 2 routine condyloma in prepuce patient's postoperative parts that slight edema has taken place, remission is disappeared behind short-term hormone, anti-inflammatory treatment.Slight sensation of pricking all appears in 8 routine patient's laser radiations, without special handling, and the symptom Lock-out of treatment back.
Embodiment 5: hemoporphyrin methyl ether-photodynamic therapy is to the lethal effect of periodontitis pathogenic bacterium
Experimental technique
Difference picking periodontitis pathogenic bacterium (comprising gram positive bacteria and gram negative bacteria) strain list bacterium colony, be inoculated in 3ml LB liquid, 37 ℃ of following shaken cultivation are spent the night, to the logarithmic growth later stage, bacteria suspension is inoculated in the 100ml LB liquid centrifugal (4000r/min behind 37 ℃ of shaken cultivation 3h with 1: 100 ratio, 10min), abandon supernatant, the suspension thalline is in PBS, makes OD
650=0.7 (being equivalent to about 107CFU/ml), put 4 ℃ standby.
Press the hematoporphyrin monomethyl ether crude drug of embodiment 1 preparation, be configured as the PBS buffer of 0.1mol/L, regulate pH to 7-8.The bacteria suspension of variable concentrations hematoporphyrin monomethyl ether carries out illumination after 37 ℃ of lucifuges are hatched 30min, promptly each test tube is got 1ml in quartz colorimetric utensil, is placed on apart from 75W bromine tungsten filament lamp light source 1cm place to carry out visible light illumination, and the light merit density of light source is 200mW/cm
2, light application time 30min.Hatch 30min and not only directly tap into row experiment for other one group.
Bacteria suspension with two groups of variable concentrations hematoporphyrin monomethyl ethers of 1: 10 gradient dilution, get 100u L respectively in count of bacteria culture medium plate, evenly coating rapidly, gram positive bacteria is constant temperature culture in 37 ℃ of biochemical incubators, gram negative bacteria takes out behind the 24h and carries out colony counting and draw the inactivation rate bar diagram in 34 ℃ of constant temperature culture.Experiment repeats 3 times, averages.Inactivation rate (%)=(N-n)/N * 100, in the formula: N is a matched group number meansigma methods; N is an experimental group number meansigma methods.
The result
The result shows, hematoporphyrin monomethyl ether all has photodynamic killing effect to two kinds of antibacterials, along with the rising of hematoporphyrin monomethyl ether concentration, the inactivation of bacteria rate is also high more, and under the illumination to the fragmentation effect of gram positive bacteria and gram negative bacteria than more obvious under the condition that does not have illumination.As shown in Table 2, hematoporphyrin monomethyl ether is very strong to the photodynamic killing effect of gram positive bacteria, and hematoporphyrin monomethyl ether concentration just can be killed the antibacterial more than 90% under the illumination when 5mg/L is above; As shown in Table 3, hematoporphyrin monomethyl ether concentration is that 75mg/L and 150mg/L can kill 59.3% and 99.9% gram negative bacteria by photodynamics respectively, and not illumination does not then have lethal effect basically to it.
Hematoporphyrin monomethyl ether concentration that table 3 is different and the relation between the gram positive bacteria inactivation rate
Hematoporphyrin monomethyl ether concentration that table 4 is different and the relation between the gram negative bacteria inactivation rate
The result of embodiment 2,3,4,5 shows, with the hematoporphyrin monomethyl ether is the photodynamic therapy of photosensitizer, can effectively treat diseases such as the relevant Kaposi sarcoma of atherosclerosis, acne, condyloma acuminatum, laryngeal papillomatosis, verruca vulgaris, wart of toe, verruca plana, bowenoid papulosis, people's acquired immune deficiency syndrome (AIDS), periodontitis, mouthful gingivitis.
All quote in this application as a reference at all documents that the present invention mentions, just quoted as a reference separately as each piece document.Should be understood that in addition after having read above-mentioned teachings of the present invention, those skilled in the art can make various changes and modification to the present invention, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Claims (9)
1. the purposes of hematoporphyrin monomethyl ether is characterized in that, is used to prepare the medicine of treatment atherosclerosis, acne, bacterial infectious disease or viral infection disease.
2. purposes as claimed in claim 1 is characterized in that, described atherosclerosis is the constitutional atheromatous plaque; Described acne is a kind of chronic inflammatory disease dermatoses; Described bacterial infection disease is the disease that causes because of gram positive bacteria, gram positive bacterial infection; Described disease of viral infection is to infect the disease that causes because of papillomavirus, human immunodeficiency virus I, herpes simplex virus, human cytomegalic inclusion disease virus, monkey disease poison.
3. purposes as claimed in claim 2 is characterized in that, described chronic inflammatory disease dermatoses can show as skin lesion such as acne, pimple, pustule, tuberosity, cyst and cicatrix; Described gram positive bacteria, gram positive bacterial infection occur in the human body periodontal.
4. purposes as claimed in claim 1 is characterized in that, described bacterial infectious disease is selected from down group: periodontitis, mouthful gingivitis; Described viral infection disease is selected from down group: the Kaposi sarcoma that condyloma acuminatum, laryngeal papillomatosis, verruca vulgaris, wart of toe, verruca plana, bowenoid papulosis, people's acquired immune deficiency syndrome (AIDS) are correlated with.
5. purposes as claimed in claim 1 is characterized in that, described hematoporphyrin monomethyl ether is the chemical compound of following structural formula
In the formula, R
1Be hydrogen atom or methyl, R
2Be methyl or hydrogen atom; Work as R
1During for hydrogen atom, R
2Be methyl; Work as R
1During for methyl, R
2Be hydrogen atom.
6. purposes as claimed in claim 1 is characterized in that, the dosage of described medicine is pressed hematoporphyrin monomethyl ether and calculated in the 0.1-100mg/kg body weight.
7. purposes as claimed in claim 1 is characterized in that described treatment is an optical dynamic therapy.
8. purposes as claimed in claim 7 is characterized in that, described optical dynamic therapy condition is that the luminous flux of irradiation is 50-200 joule/cm
2, illuminance is 50-800mW/cm
2, wavelength is 300-800nm.
9. the purposes of hematoporphyrin monomethyl ether, it is characterized in that, as the photosensitizer of diseases such as photodynamic therapy treatment atherosclerosis, acne, condyloma acuminatum, laryngeal papillomatosis, verruca vulgaris, wart of toe, verruca plana, bowenoid papulosis, Kaposi sarcoma that people's acquired immune deficiency syndrome (AIDS) is relevant, periodontitis, mouthful gingivitis.
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| CN200910055460A CN101612149A (en) | 2009-07-28 | 2009-07-28 | Hematoporphyrin monomethyl ether is in the new purposes of field of medicaments |
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| CN200910055460A CN101612149A (en) | 2009-07-28 | 2009-07-28 | Hematoporphyrin monomethyl ether is in the new purposes of field of medicaments |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2445027C1 (en) * | 2010-07-19 | 2012-03-20 | ФГУ "НКЦ Оториноларингологии" Федерального медико-биологического агентства России | Method of treating larynx papillomatosis |
| CN103601727A (en) * | 2013-10-23 | 2014-02-26 | 中国医学科学院生物医学工程研究所 | Use of novel amine compound modified protoporphyrin |
| RU2561890C2 (en) * | 2013-12-19 | 2015-09-10 | государственное бюджетное образовательное учреждение высшего профессионального образования "Северо-Западный государственный медицинский университет им. И.И. Мечникова" Министерства здравоохранения Российской Федерации | Method of treating patients with periodontitis |
| CN105435225A (en) * | 2015-12-27 | 2016-03-30 | 海宁市绿升医药科技有限公司 | Chlorin e6 monoester freeze-dried preparation for injection and preparation method of chlorin e6 monoester freeze-dried preparation |
| CN105579063A (en) * | 2013-06-05 | 2016-05-11 | 法尔哈德·哈菲泽 | Method of applying a composition and pharmaceutical composition with a regimen of administering it, including photo-activating the active component. |
-
2009
- 2009-07-28 CN CN200910055460A patent/CN101612149A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2445027C1 (en) * | 2010-07-19 | 2012-03-20 | ФГУ "НКЦ Оториноларингологии" Федерального медико-биологического агентства России | Method of treating larynx papillomatosis |
| CN105579063A (en) * | 2013-06-05 | 2016-05-11 | 法尔哈德·哈菲泽 | Method of applying a composition and pharmaceutical composition with a regimen of administering it, including photo-activating the active component. |
| CN103601727A (en) * | 2013-10-23 | 2014-02-26 | 中国医学科学院生物医学工程研究所 | Use of novel amine compound modified protoporphyrin |
| RU2561890C2 (en) * | 2013-12-19 | 2015-09-10 | государственное бюджетное образовательное учреждение высшего профессионального образования "Северо-Западный государственный медицинский университет им. И.И. Мечникова" Министерства здравоохранения Российской Федерации | Method of treating patients with periodontitis |
| CN105435225A (en) * | 2015-12-27 | 2016-03-30 | 海宁市绿升医药科技有限公司 | Chlorin e6 monoester freeze-dried preparation for injection and preparation method of chlorin e6 monoester freeze-dried preparation |
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