阿尼芬净市场分析
芬净类调研报告20110510
卡泊芬净一、基本信息1、通用名：醋酸卡泊芬净商品名：科赛斯英文名：Caspofungin Acetate规格：注射用 (1)50mg；(2)70mg (以卡泊芬净计)用法用量：第一天给予单次70mg负荷剂量的注射用醋酸卡泊芬净，随后每天给予50mg的剂量。
适应症：本品适用于治疗对其它治疗无效或不能耐受的侵袭性曲霉菌病；对疑似真菌感染的粒缺伴发热病人的经验治疗；口咽及食道念珠菌病（在中国正在申请此适应症）；侵袭性念珠菌病，包括中性粒细胞减少症及非中性粒细胞减少症患者的念珠菌血症（美国FDA已批准，中国尚未批准）；2、注册分类：3.1医保：乙类20093、作用机制：本品为棘白菌素类抗真菌药物，是葡聚糖合成酶抑制剂，能有效抑制1,3-Beta-葡聚糖的合成，从而干扰真菌细胞壁的合成。
4、特点：有广谱抗真菌活性，对白色念珠菌、热带念珠菌、光滑念珠菌、克柔念珠菌等有良好的抗菌活性，对烟曲霉、黄曲霉、土曲霉和黑曲霉及除曲菌以外的几种丝状真菌和二形真菌也有抗菌活性。
二、临床应用三、价格情况四、国内外生产情况1、国内：暂无企业生产2、进口：默沙东(澳大利亚)制药3、申报情况：目前无国内厂家申报，只有默沙东按照3.4类申报已获批五、知识产权及行政保护合物还包括特定的填充剂和少量pH 调节剂或不含pH 调节剂，并且可以为液体或固体形式，例如可以为冻干组合物。
所述的组合物显示出良好的稳定性和从冻干产品再溶解形成的溶液中减少量的低于可见的颗粒物质。
201010144485.3 一种合成醋酸卡泊芬净的方法 本发明涉及一种制备卡泊芬净及其酸加成盐的方法，主要包括：1)使式III 化合物与乙二胺反应，得到式II 化合物或其酸加成盐；2)可选择地，由式II 化合物制备得到式II 化合物的酸加成盐；3)使化合物II 或其酸加成盐还原，得到化合物I 所示的卡泊芬净或其酸加成盐。
六、 市场情况2005-2010年销售额：2005-2010年占抗真菌药物类别的份额：米卡芬净一、基本信息1、通用名：注射用米卡芬净钠规格：注射用50mg用法用量：曲霉病：成人一般每日单次剂量为50-150mg米卡芬净钠，每日一次静脉滴注。
10、注射用阿尼芬净
阿尼芬净注射液（Anidulafungin/Eraxis）——FDA批准阿尼芬净治疗念珠菌感染关键字：阿尼芬净注射液（Anidulafungin/Eraxis）FDA批准了Eraxis™(通用名：阿尼芬净[anidulafungin])用于治疗假丝酵母（Candida）引起的某些感染。
Candida是一种能在就医病人或免疫系统受损的病人中引起严重感染的类似酵母的真菌。
“该产品为与假丝酵母相关的几种感染提供了一种新的可选疗法”，FDA的药品评价与研究中心主任Steven Galson博士称。
“它是现有用于治疗这些潜在的严重真菌病症的抗菌药物的有益补充。
”一种从未在美国上市的新分子实体Eraxis，是一种静脉注射的抗真菌药物，并被用于治疗食道（念珠菌病）、血液（念珠菌血症）中的假丝酵母感染以及其他类型的假丝酵母感染，包括腹部脓肿和腹膜炎（腹腔内壁发炎）。
临床研究评价了Eraxis的安全性和有效性，并且显示Eraxis在食道念珠菌病、念珠菌血症（candidemia）以及其他包括腹部脓肿和腹膜炎在内的假丝酵母感染的治疗中是安全且有效的。
Eraxis在临床研究中普遍很耐受。
最常见报告的不良事件是：轻度腹泻，肝酶的实验室测试水平轻微上升，以及头痛。
一些病人经历了与输液相关的反应，其中多数为轻度。
在具有重大的潜在医学状况的且正伴服多重药物的少数病人中，有严重肝异常的报道。
Eraxis由纽约州的Pfizer公司生产。
ERAXIS - anidulafungin injection, powder, lyophilized, for solutionRoerigERAXIS™ (anidulafungin) FOR INJECTION[INTRAVENOUS INFUSION, DILUTED WITH STERILE WATER FOR INJECTION] (not for IV Bolus Injection) DESCRIPTIONERAXIS for Injection is a sterile, lyophilized product for intravenous (IV) infusion that contains anidulafungin. ERAXIS (anidulafungin) is a semi-synthetic lipopeptide synthesized from a fermentation product of Aspergillusnidulans. Anidulafungin is an echinocandin, a class of antifungal drugs that inhibits the synthesis of 1,3-β-D-glucan, an essential component of fungal cell walls.ERAXIS (anidulafungin) is1-[(4R,5R)-4,5-dihydroxy-N2-[[4"-(pentyloxy)[1,1':4',1"-terphenyl]-4-yl]carbonyl]-L-ornithine]echinocandin B. Anidulafungin is a white to off-white powder that is practically insoluble in water and slightly soluble in ethanol. In addition to the active ingredient, anidulafungin, ERAXIS for Injection contains the following inactive ingredients:50 mg/vial - fructose (50 mg), mannitol (250 mg), polysorbate 80 (125 mg), tartaric acid (5.6 mg), and sodium hydroxide and/or hydrochloric acid for pH adjustment.100 mg/vial - fructose (100 mg), mannitol (500 mg), polysorbate 80 (250 mg), tartaric acid (11.2 mg), and sodium hydroxide and/or hydrochloric acid for pH adjustment.The empirical formula of anidulafungin is C58H73N7O17 and the formula weight is 1140.3.The structural formula is:Prior to administration, ERAXIS for Injection requires reconstitution with sterile Water for Injection and subsequent dilution with either 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (normal saline).DO NOT dilute with other solutions or co-infuse with other medications or electrolytes (see DOSAGE AND ADMINISTRATION).CLINICAL PHARMACOLOGYPharmacokinetics The pharmacokinetics of anidulafungin following IV administration have been characterized in healthy subjects, special populations and patients. Systemic exposures of anidulafungin are dose-proportional and have low intersubject variability (coefficient of variation <25%) as shown in Table 1. The steady state was achieved on the first day after a loading dose (twice the daily maintenance dose) and the estimated plasma accumulation factor at steady state is approximately 2.The clearance of anidulafungin is about 1 L/h and anidulafungin has a terminal elimination half-life of 40–50 hours.Distribution The pharmacokinetics of anidulafungin following IV administration are characterized by a short distribution half-life (0.5–1 hour) and a volume of distribution of 30–50 L that is similar to total body fluid volume. Anidulafungin is extensively bound (>99%) to human plasma proteins.Metabolism Hepatic metabolism of anidulafungin has not been observed. Anidulafungin is not a clinically relevant substrate, inducer, or inhibitor of cytochrome P450 (CYP450) isoenzymes. It is unlikely that anidulafungin will have clinically relevant effects on the metabolism of drugs metabolized by CYP450 isoenzymes.Anidulafungin undergoes slow chemical degradation at physiologic temperature and pH to a ring-opened peptide that lacks antifungal activity. The in vitro degradation half-life of anidulafungin under physiologic conditions is about 24 hours. In vivo, the ring-opened product is subsequently converted to peptidicdegradants and eliminated.Excretion In a single-dose clinical study, radiolabeled (14C) anidulafungin was administered to healthy subjects. Approximately 30% of the administered radioactive dose was eliminated in the feces over 9 days, of which less than 10% was intact drug. Less than 1% of the administered radioactive dosewas excreted in the urine. Anidulafungin concentrations fell below the lower limits of quantitation 6 days post-dose. Negligible amounts of drug-derived radioactivity were recovered in blood, urine, and feces 8 weeks post-dose.Special PopulationsPopulation pharmacokinetic analyses from four Phase 2/3 clinical studies including 107 male and 118 female patients with fungal infections showed that the pharmacokinetic parameters of anidulafungin are not affected by age, race, or the presence of concomitant medications which are known metabolic substrates, inhibitors or inducers.The pharmacokinetics of anidulafungin in patients with fungal infections are similar to those observed in healthy subjects. The pharmacokinetic parameters of anidulafungin estimated using population pharmacokinetic modeling following IV administration of a maintenance dose of 50 mg/day or 100 mg/day (following a loading dose) are presented in Table 2.Dosage adjustments are not required based on gender. Plasma concentrations of anidulafungin in healthy men and women were similar. In multiple-dose patient studies, drug clearance was slightly faster (approximately 22%) in men.Dosage adjustments are not required for geriatric patients. The population pharmacokinetic analysis showed th at median clearance differed slightly between the elderly group (patients ≥ 65, median CL = 1.07 L/h) and the non-elderly group (patients < 65, median CL = 1.22 L/h) and the range of clearance was similar.Dosage adjustments are not required based on race. Anidulafungin pharmacokinetics were similar among Whites, Blacks, Asians, and Hispanics.Dosage adjustments are not required based on HIV status, irrespective of concomitantanti-retroviral therapy.Dosage adjustments are not required on the basis of mild, moderate or severe hepatic insufficiency. Anidulafungin is not hepatically metabolized. Anidulafungin pharmacokinetics were examined in subjects with Child-Pugh class A, B or C hepatic insufficiency. Anidulafungin concentrations were not increased in subjects with any degree of hepatic insufficiency. Though a slight decrease in AUC was observed in patients with Child-Pugh C hepatic insufficiency, it was within the range of population estimates noted for healthy subjects.Dosage adjustments are not required for patients with any degree of renal insufficiency including those on hemodialysis. Anidulafungin has negligible renal clearance. In a clinical study of subjects with mild, moderate, severe or end stage (dialysis-dependent) renal insufficiency, anidulafungin pharmacokinetics were similar to those observed in subjects with normal renal function. Anidulafungin is not dialyzable and may be administered without regard to the timing of hemodialysis.The pharmacokinetics of anidulafungin after daily doses were investigated in immunocompromised pediatric (2 through 11 years) and adolescent (12 through 17 years) patients with neutropenia. The steady state was achieved on the first day after administration of the loading dose (twice the maintenance dose), and the Cmax and AUCss increased in a dose-proportional manner. Concentrations and exposures following administration of maintenance doses of 0.75 and 1.5 mg/kg/day in this population were similar to those observed in adults following maintenance doses of 50 and 100 mg/day, respectively (as shown in Table 3) (see PRECAUTIONS, Pediatric Use).Table 3. Mean (%CV) Steady State Pharmacokinetic Parameters of AnidulafunginFollowing IV Administration of Anidulafungin Once Daily in Pediatric SubjectsPK Parameter Anidulafungin IV Dosing Regimen (LD/MD, mg/kg)1.5/0.75 3.0/1.5 Data were collected on Day 5LD/MD: loading dose/daily maintenance doseAge Group2–11 yrs(N = 6)12–17 yrs(N = 6)2–11 yrs(N = 6)12–17 yrs(N = 6)Cmax, ss [mg/L]3.32(50.0)4.35(22.5)7.57(34.2)6.88 (24.3)AUCss [mg∙h/L]41.1(38.4)56.2(27.8)96.1(39.5)102.9(28.2)Drug Interaction StudiesIn vitro studies showed that anidulafungin is not metabolized by human cytochrome P450 or by isolated human hepatocytes, and does not significantly inhibit the activities of human CYP isoforms (1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A) at clinically relevant concentrations. No clinically relevant drug-drug interactions were observed with drugs likely to be co-administered with anidulafungin.Cyclosporine (CYP3A4 substrate) In a study in which 12 healthy adult subjects received 100 mg/day maintenance dose of anidulafungin following a 200 mg loading dose (on Days 1 to 8) and in combination with 1.25 mg/kg oral cyclosporine twice daily (on Days 5 to 8), the steady state Cmax of anidulafungin was not significantly altered by cyclosporine; the steady state AUC of anidulafungin was increased by 22%. A separate in vitro study showed that anidulafungin has no effect on the metabolism of cyclosporine. No dosage adjustment of either drug is warranted when co-administered.Voriconazole (CYP2C19, CYP2C9, CYP3A4 inhibitor and substrate) In a study in which 17 healthy subjects received 100 mg/day maintenance dose of anidulafungin following a 200 mg loading dose, 200 mg twice daily oral voriconazole (following two 400 mg loading doses) and both in combination, the steady state Cmax and AUC of anidulafungin and voriconazole were not significantly altered by co-administration. No dosage adjustment of either drug is warranted when co-administered.Tacrolimus (CYP3A4 substrate) In a study in which 35 healthy subjects received a single oral dose of 5 mg tacrolimus (on Day 1), 100 mg/day maintenance dose of anidulafungin following a 200 mg loading dose (on Days 4 to 12) and both in combination (on Day 13), the steady state Cmax and AUC of anidulafungin and tacrolimus were not significantly altered by co-administration. No dosage adjustment of either drug is warranted when co-administered.AmBisome® (liposomal amphotericin B) The pharmacokinetics of anidulafunginwere examined in 27 patients that were co-administered liposomal amphotericin B. The population pharmacokinetic analysis showed that when compared to data from patients that did not receive amphotericin B, the pharmacokinetics of anidulafunginwerenot significantly altered by co-administration with amphotericin B. No dosage adjustment of anidulafungin is warranted.Rifampin (potent CYP450 inducer) The pharmacokinetics of anidulafunginwere examined in 27 patients that were co-administered anidulafungin and rifampin. The population pharmacokinetic analysis showed that when compared to data from patients that did not receive rifampin, the pharmacokinetics of anidulafungin were not significantly altered by co-administration with rifampin. No dosage adjustment of anidulafungin is warranted.MICROBIOLOGYMechanism of action Anidulafungin is a semi-synthetic echinocandin with antifungal activity. Anidulafungin inhibits glucan synthase, an enzyme present in fungal, but not mammalian cells. This results in inhibition of the formation of 1,3-β-D-glucan, an essential component of the fungal cell wall.Activity in vitro Anidulafungin is active in vitro against Candida albicans, C. glabrata, C.parapsilosis, and C. tropicalis (see INDICATIONS AND USAGE, CLINICAL STUDIES).MICs were determined according to the Clinical and Laboratory Standards Institute (CLSI) approved standard reference method M27 for susceptibility testing of yeasts. However, no correlation between in vitro activity (MIC) as determined by this method and clinical outcome has been established. There have been reports of Candida isolates with reduced susceptibility to echinocandins including anidulafungin, but the clinical significance of this observation is unknown.Activity in vivo Parenterally administered anidulafungin was effective against Candida albicans in immunocompetent and immunosuppressed mice and rabbits with disseminated infection as measured by prolonged survival and reduction in mycological burden. Anidulafungin also reduced the mycological burden of fluconazole-resistant C. albicans in an oropharyngeal/esophageal infection model in immunosuppressed rabbits.Drug Resistance Emergence of resistance to anidulafungin has not been studied.Anidulafungin was active against Candida albicans resistant to fluconazole. Cross resistance with other echinocandins has not been studied.CLINICAL STUDIESCandidemia and other Candida infections (intra-abdominal abscess, and peritonitis) The safety and efficacy of ERAXIS were evaluated in a Phase 3, randomized, double-blind study of patients with candidemia and/or other forms of invasive candidiasis. Patients were randomized to receive once daily IV ERAXIS (200 mg loading dose followed by 100 mg maintenance dose) or IV fluconazole (800 mg loading dose followed by 400 mg maintenance dose). Patients were stratified by APACHE II score (≤ 20 and > 20) and the presence or absence of neutropenia. Patientswith Candida endocarditis, osteomyelitis or meningitis, or those with infection due to C. krusei, were excluded from the study. Treatment was administered for at least 14 and not more than 42 days. Patients in both study arms were permitted to switch to oral fluconazole after at least 10 days of intravenous therapy, provided that they were able to tolerate oral medication, were afebrile for at least 24 hours, and the last blood cultures were negative for Candida species.Patients who received at least one dose of study medication and who had a positive culture for Candida species from a normally sterile site before entry into the study (modifiedintent-to-treat [MITT] population) were included in the primary analysis of global response at the end of IV therapy. A successful global response required clinical cure or improvement (significant, but incomplete resolution of signs and symptoms of the Candida infection and no additional antifungal treatment), and documented or presumed microbiological eradication. Patients with an indeterminate outcome were analyzed as failures in this population.Two hundred and fifty-six patients were randomized and received at least one dose of study medication. The median duration of IV therapy was 14 and 11 days in the ERAXIS and fluconazole arms, respectively. For those who received oral fluconazole, the median duration of oral therapy was 7 days for the ERAXIS arm and 5 days for the fluconazole arm.Patient disposition is presented in Table 4.Table 4. Patient Disposition and Reasons for Discontinuation inCandidemia and other Candida Infections StudyERA XISFluconaz olen(%)n (%) Treated patients131125Patients completing study through 6 week follow-up94(71.8)80 (64.0)Discontinuations from Study MedicationTotal discontinued from study medication34(26.0)48 (38.4)Discontinued due to adverse events12(9.2)21 (16.8)Discontinued due to lack of efficacy11(8.4)16 (12.8)Two hundred and forty-five patients (127 ERAXIS, 118 fluconazole) met the criteria for inclusion in the MITT population. Of these, 219 patients (116 ERAXIS, 103 fluconazole) had candidemia only. Risk factors for candidemia among patients in both treatment arms in this study were: presence of a central venous catheter (78%), receipt of broad-spectrum antibiotics (69%),recent surgery (42%), recent hyperalimentation (25%), and underlying malignancy (22%). The most frequent species isolated at baseline was C. albicans (61.6%), followed by C. glabrata (20.4%), C. parapsilosis (11.8%) and C. tropicalis (10.6%). The majority (97%) of patients werenon-neutropenic (ANC > 500) and 81% had APACHE II scores less than or equal to 20.Global success rates in patients with candidemia and other Candida infections are summarized in Table 5.Table 5. Efficacy Analysis: Global Success in patients with Candidemia and otherCandida Infections (MITT Population)Timepoint ERAXIS(N=127)n (%)Fluconazole(N=118)n (%)TreatmentDifference , %(95% C.I.)Calculated as ERAXIS minus fluconazole33 patients in each study arm (26% ERAXIS and 28.8 % fluconazole-treated) switched to oral fluconazole after the end of IV therapy.98.3% confidence intervals, adjusted post hoc for multiple comparisons of secondary time pointsEnd of IV Therapy96 (75.6)71 (60.2)15.42 (3.9, 27.0)End of All Therapy94 (74.0)67 (56.8)17.24 (2.9, 31.6 )2 Week Follow-up82 (64.6)58 (49.2)15.41 (0.4, 30.4 )6 Week Follow-up71 (55.9)52 (44.1)11.84 (-3.4, 27.0 )Table 6 presents outcome and mortality data for the MITT population.Table 6. Outcomes & Mortality in Candidemia and other Candida InfectionsERAXISFluconazoleBetween groupdifference (95% CI)Calculated as ERAXIS minus fluconazoleNo. of MITT patients127118Favorable Outcomes (MITT) At End Of IV Therapy All MITT patientsCandidemia88/116(75.9%)63/103(61.2%)14.7 (2.5, 26.9)Neutropenic1/22/4-Non neutropenic87/114 61/99 -Table 6. Outcomes & Mortality in Candidemia and other Candida InfectionsERAXISFluconazoleBetween groupdifference (95% CI)(76.3%)(61.6%)Multiple sitesPeritoneal fluid/intra-abdominal abscess4/65/6-Blood/ peritoneum(intra-abdominal abscess)2/20/2-Blood /bile-1/1-Blood/renal-1/1-Pancreas-0/3-Pelvic abscess-1/2-Pleural fluid1/1--Blood/ pleural fluid0/1--Blood/left thigh lesion biopsy1/1--Total8/11(72.7%)8/15(53.3%)-MortalityOverall study mortality29/127(22.8 %)37/118(31.4%)-Mortality during study therapy10/127(7.9%)17/118(14.4%)-Mortality attributed to Candida2/127(1.6%)5/118(4.2%)-Esophageal CandidiasisERAXIS was evaluated in a double-blind, double-dummy, randomized Phase 3 study. Three hundred patients received ERAXIS (100 mg loading dose IV on Day 1 followed by 50 mg/day IV) and 301 received oral fluconazole (200 mg loading dose on Day 1 followed by 100 mg/day). Treatment duration was 7 days beyond resolution of symptoms for a minimum of 14 and a maximum of 21 days.Of the 442 patients with culture confirmed esophageal candidiasis, most patients (91%) had C. albicans isolated at the baseline.Treatment groups were similar in demographic and other baseline characteristics.In this study, of 280 patients tested, 237 (84.6%) tested HIV positive. In both groups the median time to resolution of symptoms was 5 days and the median duration of therapy was 14 days.The primary endpoint was endoscopic outcome at end of therapy (EOT). Patients were considered clinically evaluable if they received at least 10 days of therapy, had an EOT assessment with a clinica l outcome other than ‘indeterminate’, had an endoscopy at EOT, and did not have any protocol violations prior to the EOT visit that would affect an assessment of efficacy.An endoscopic success, defined as cure (endoscopic grade of 0 on a 4 point severity scale) or improvement (decrease of one or more grades from baseline), was seen in 225/231 (97.4%) ERAXIS-treated patients and 233/236 (98.7%) fluconazole-treated patients (Table 7). The majority of these patients were endoscopic cures (grade=0). Two weeks after completing therapy, the ERAXIS group had significantly more endoscopically-documented relapses than the fluconazole group, 120/225 (53.3%) vs. 45/233 (19.3%), respectively (Table 7).Table 7. Endoscopy Results in Patients with Esophageal Candidiasis (ClinicallyEvaluable Population)Calculated as ERAXIS minus fluconazoleEndoscopic Response at End of TherapyResponseERAXISN= 231FluconazoleN= 236TreatmentDifference95% CIEndoscopic Success, n (%)225 (97.4)233 (98.7)-1.3%-3.8%,1.2%Cure204 (88.3)221 (93.6) Improvement21 (9.1)12 (5.1)Failure, n (%) 6 (2.6) 3 (1.3) Endoscopic Relapse Rates at Follow-up, 2 Weeks Post-TreatmentERAXIS FluconazoleTreatmentDifference95% CIEndoscopic Relapse, n/N (%)120/225(53.3%)45/233(19.3%)34.0%25.8%,42.3%Clinical success (cure or improvement in clinical symptoms including odynophagia/dysphagia and retrosternal pain) occurred in 229/231 (99.1%) of the ERAXIS-treated patients and 235/236 (99.6%) of the fluconazole-treated patients at the end of therapy. For patients with C. albicans, microbiological success occurred in 142/162 (87.7%) of the ERAXIS-treated group and 157/166 (94.6%) of the fluconazole-treated group at the end of therapy. For patients with Candida species otherthan C. albicans, success occurred in 10/12 (83.3%) of the ERAXIS-treated group and 14/16 (87.5%) of the fluconazole-treated group.INDICATIONS AND USAGEERAXIS is indicated for use in the treatment of the following fungal infections:Candidemia and other forms of Candida infections (intra-abdominal abscess, and peritonitis) (see CLINICAL STUDIESand MICROBIOLOGY).ERAXIS has not been studied in endocarditis, osteomyelitis, and meningitis due to Candida, and has not been studied in sufficient numbers of neutropenic patients to determine efficacy in this group.Esophageal candidiasis (see CLINICAL STUDIES, Table 7 for higher relapse rates off ERAXIS therapy).Specimens for fungal culture and other relevant laboratory studies (including histopathology) should be obtained prior to therapy to isolate and identify causative organism(s). Therapy may be instituted before the results of the cultures and other laboratory studies are known. However, once these results become available, antifungal therapy should be adjusted accordingly.CONTRAINDICATIONSERAXIS is contraindicated in persons with known hypersensitivity to anidulafungin, any component of ERAXIS, or other echinocandins.PRECAUTIONSHepatic Effects Laboratory abnormalities in liver function tests have been seen in healthy volunteers and patients treated with ERAXIS. In some patients with serious underlying medical conditions who were receiving multiple concomitant medications along with ERAXIS, clinically significant hepatic abnormalities have occurred. Isolated cases of significant hepatic dysfunction, hepatitis, or hepatic failure have been reported in patients; a causal relationship to ERAXIS has not been established. Patients who develop abnormal liver function tests during ERAXIS therapy should be monitored for evidence of worsening hepatic function and evaluated for risk/benefit of continuing ERAXIS therapy.Drug Interactions Pre-clinical in vitro and in vivo and clinical studies demonstrated that anidulafungin is not a clinically relevant substrate, inducer, or inhibitor of cytochrome P450 isoenzymes. Anidulafungin has negligible renal clearance. Minimal interactions are expected from the concomitant medications (see CLINICAL PHARMACOLOGY –Drug Interaction Studies).Drug interaction studies were performed with anidulafungin and other drugs likely to be co-administered. When used in therapeutic doses, no dosage adjustment of either drug is recommended when anidulafungin is co-administered with voriconazole or tacrolimus, and no dosage adjustment for anidulafungin is recommended when co-administered with amphotericin B or rifampin(see CLINICAL PHARMACOLOGY –Drug Interaction Studies).Co-administration with cyclosporine slightly increased the steady state AUC of anidulafungin by 22%. A separate in vitro study showed that anidulafungin has no effect on the metabolism of cyclosporine. Adverse events observed in the study were consistent with adverse events observed from other studies with the administration of anidulafungin alone. No dosage adjustment of either drug is warranted for patients on concomitant cyclosporine (see CLINICAL PHARMACOLOGY –Drug Interaction Studies).Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal carcinogenicity studies of anidulafungin have not been conducted.Anidulafungin was not genotoxic in the following in vitro studies: bacterial reverse mutation assays, a chromosome aberration assay with Chinese hamster ovary cells, and a forward gene mutation assay with mouse lymphoma cells. Anidulafungin was not genotoxic in mice using the invivo micronucleus assay.Anidulafungin produced no adverse effects on fertility in male or female rats at intravenous doses of 20 mg/kg/day (equivalent to 2 times the proposed therapeutic maintenance dose of 100 mg/day on the basis of relative body surface area).PregnancyPregnancy Category C Embryo-fetal development studies were conducted with doses up to 20 mg/kg/day in rats and rabbits (equivalent to 2 and 4 times, respectively, the proposed therapeutic maintenance dose of 100 mg/day on the basis of relative body surface area). Anidulafungin administration resulted in skeletal changes in rat fetuses including incomplete ossification of various bones and wavy, misaligned or misshapen ribs. These changes were not dose-related and were within the range of the laboratory's historical control database. Developmental effects observed in rabbits (slightly reduced fetal weights) occurred in the high dose group, a dose that also produced maternal toxicity. Anidulafungin crossed the placental barrier in rats and was detected in fetal plasma.There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, ERAXIS should be used during pregnancy only if the potential benefit justifies the risk to the fetus.Nursing Mothers ERAXIS should be administered to nursing mothers only if the potential benefit justifies the risk. Anidulafungin was found in the milk of lactating rats. It is not known whether anidulafungin is excreted in human milk.Pediatric Use Safety and effectiveness of anidulafungin in pediatric patients has not been established (see CLINICAL PHARMACOLOGY-Special Populations/Pediatric).ADVERSE REACTIONSGeneral Possible histamine-mediated symptoms have been reported with ERAXIS, including rash, urticaria, flushing, pruritus, bronchospasm, dyspnea, and hypotension. These events are infrequent when the rate of ERAXIS infusion does not exceed 1.1 mg/minute.Overall ERAXIS Safety Experience The safety of ERAXIS for Injection was assessed in 929 individuals, including 672 patients in clinical studies and 257 individuals in Phase 1 studies. A total of 633 patients received ERAXIS at daily doses of either 50 or 100 mg. A total of 481 patients received ERAXIS for ≥14 days.Candidemia/other Candida Infections Three studies (one comparative vs. fluconazole, two non-comparative) assessed the efficacy and safety of ERAXIS (100 mg) in patients with candidemia and other Candida infections. Table 8 presents treatment-related adverse events that were reported in ≥2.0% of subjects r eceiving ERAXIS or fluconazole therapy in the comparative candidemia study.Table 8. Treatment-related adverse events reported in ≥2.0% of subjects receivingERAXIS or fluconazole therapy for candidemia/other Candida infectionsERAXIS 100 mg N = 131Fluconazole 400 mgN = 125N (%)N (%)Treatment-related AEs are defined as those that are possibly or probably related to study treatment, as determined by the investigator.Maintenance doseSubjects with at least 1 treatment-related AE32 (24.4)33 (26.4)Gastrointestinal SystemDiarrhea 4 (3.1) 2 (1.6) InvestigationsALT ↑ 3 (2.3) 4 (3.2) AST ↑ 1 (0.8) 3 (2.4) Alkaline phosphatase ↑ 2 (1.5) 5 (4.0) Hepatic enzyme ↑ 2 (1.5)9 (7.2) Metabolic and Nutritional SystemsHypokalemia 4 (3.1) 3 (2.4) Vascular System。
棘白菌素类药物的药动学和药效学指导临床用药优化
棘白菌素类药物的药动学和药效学指导临床用药优化夏迪;施毅【期刊名称】《中国感染与化疗杂志》【年(卷),期】2015(015)004【总页数】4页(P383-386)【关键词】棘白菌素;卡泊芬净;米卡芬净;阿尼芬净;药动学;药效学【作者】夏迪;施毅【作者单位】南京大学医学院临床学院,南京军区南京总医院呼吸与危重症医学科,南京210002;南京大学医学院临床学院,南京军区南京总医院呼吸与危重症医学科,南京210002【正文语种】中文【中图分类】R978.5免疫抑制人群的增加、抗菌药物的广泛应用、重症监护病房患者生存率的提高、诊断方法的改进等因素使诊断为真菌感染患者的数量显著增加。
在抗真菌治疗过程中，多种宿主和医源性因素均会影响疾病的转归，其中药物选择、给药剂量和给药时间是众多因素的重要部分。
因此，充分了解抗真菌药物的药动学和药效学特点，实现用药优化具有重要的临床意义。
抗真菌药物研究在过去的10年中发展迅速，使得侵袭性真菌感染的治疗有了多种选择。
棘白菌素类是新近问世的一类抗真菌药物，美国感染病协会(IDSA)将其推荐用于既往使用过唑类药物或危重患者念珠菌感染的一线治疗和预防[1]，也可用于两性霉素B及唑类药物耐药或不能耐受的侵袭性曲霉感染的二线治疗[2]。
棘白菌素类药物对绝大部分念珠菌有良好的抗菌活性，尤其是光滑念珠菌，后者已成为念珠菌感染的常见致病菌。
有学者认为在送检标本菌种及药敏结果出来之前，棘白菌素类可作为念珠菌感染的一线用药[3]。
本文就该类新型抗真菌药物的药动学、药效学特点进行综述，为该类药物的合理应用提供一定的理论依据。
棘白菌素类抗真菌药物通过抑制真菌细胞壁β-1,3-葡聚糖合成，破坏细胞壁的完整结构，使细胞内外渗透压失衡，对念珠菌具有杀菌作用，对曲霉及肺孢子菌具有抑菌作用[4]。
已应用于临床的棘白菌素类药物有卡泊芬净、米卡芬净和阿尼芬净，目前进入我国市场的只有卡泊芬净和米卡芬净2种。
3种棘白菌素类药物均为半合成脂肽类化合物，分子量大，口服生物利用度低，只能通过静脉给药。
阿尼芬净中间体生物转化工艺研究
DOI:10.19392/ki.1671-7341.201827004阿尼芬净中间体生物转化工艺研究吴㊀娟杭州华东医药集团新药研究院有限公司㊀浙江杭州㊀310011摘㊀要:对放线菌来源的棘白霉素脱酰基酶产生菌ECBN 的转化工艺进行研究,通过单菌筛选和转化时间两个方面的优化,确定最佳的转化条件,从而提高转化效率㊂关键词:棘白霉素;阿尼芬净;转化效率;优化㊀㊀棘白霉素类抗生素是21世纪初开发的新型药物,具有全新的作用机理,抗真菌谱较广,对念珠菌属以及曲霉菌属均有效,无交叉耐药性,无因其本身作用机制而引发的明显不良反应,是迄今为止安全性最高的一种抗真菌药物,也是目前用于治疗全身性真菌感染的新型药物㊂近年来,棘白霉素类抗真菌药发展迅猛,已有卡泊芬净㊁米卡芬净㊁阿尼芬净等多个广谱㊁低毒㊁高效的新化合物进入了临床研究,[1-3]作为棘白霉素类抗真菌药物阿尼芬净和米卡芬净,它们的合成过程是将其对应的棘白菌素类母核链接不同的侧链形成,其母核的形成是有对应的前体物质棘白霉素B 和脱去侧链产生,因此脱酰基过程对于合成该类药物至关重要,化学方法反应条件剧烈,选择性又差,几乎没办法实现,文献报道可以通过微生物转化完成,所使用的转化菌株有游动放线菌属的菌株,尤其以犹他游动放线菌居多,和链霉菌属的菌株,包括环圈链霉菌与一些未确定种的链霉菌属菌株㊂以阿尼芬净中间体ECB 为底物,对筛选放线菌来源的棘白霉素脱酰基酶产生菌ECBN 的转化工艺进行研究,通过单菌筛选和转化时间两个方面优化,确定最佳的转化条件,从而提高转化效率㊂1实验与方法1.1供试菌来源供试菌来源于本实验室菌种库㊂1.2培养基种子培养基:蔗糖2%,玉米淀粉2%(糊化),棉籽饼粉1%,酵母粉1%,碳酸钙0.2%,pH6.5㊂发酵培养基:蔗糖3%,棉籽饼粉2%,酵母粉2%,磷酸氢二钾0.05%,氯化钾0.1%,硫酸镁0.1%,碳酸钙0.2%,pH6.5㊂1.3方法通过单菌分筛,转涂斜面,挑选优势单菌进行摇瓶试验㊂分别将单菌接种瓶,种瓶装量60mL /500mL 瓶,30ħ,250rpm 摇床培养48h㊂按10%接种量接入发酵培养基,30ħ,250rpm,摇床培养4天㊂按2000u 添加重含40.8%的ECB 底物进行转化试验,定时取样,采用HPLC 法测定发酵液效价来判断转化效率的高低㊂1.4HPLC 检测高效色谱仪:Agilent Technologies 1260Infinity,色谱柱:xBridgeAmide3.5um,流动相:乙腈-水(含7.8g L -1NaH 2PO 4,pH3.0),波长:210nm,进样量:10μL,流速:1mL min -1,柱温:40ħ2结果与讨论将保藏的棘白霉素脱酰基酶产生菌ECBN,涂平板,自然分筛,挑选出30株单菌进行斜面培养,再通过斜面外观,菌液,镜检,选出斜面外观比较饱满,菌液挂壁良好,镜检形态比较舒展的单菌共8株进行转化试验,结果可见表1㊂由表1可见通过菌种分筛试验,在转化时间相同的情况下,1号单菌与8号单菌转化效率较高㊂表1不同单菌在转化时间相同下的转化效率单菌编号平行试验1(μg mL -1)平行试验2(μg mL -1)111151077295493638708144990950582884569059237922881810391030㊀㊀选取1号单菌进行不同转化时间试验,控制转化18h㊁21h㊁24h 检测效价,结果可见表2㊂由表2可见转化时间在21h 时,转化效率最高㊂表21#单菌在不同转化时间下的转化效率转化时间(h)平行试验1(μg mL -1)平行试验2(μg mL -1)18121310382112281048241192960㊀㊀通过单菌筛选获得优势单菌1号和8号,通过对1号单菌转化时间的考察,确定最佳转化时间为21小时,从而提高了转化效率㊂参考文献:[1]陈由页,曹国颖,傅得兴,等.棘白霉素类抗真菌药的研究进展[J ].中国新药杂志,2007,16(14):1082-1087.[2]叶丽娟,朱辉,田敏.微生物来源的真菌细胞壁抑制剂的研究进展[J ].国外医药抗生素分册,2005,26(1):34-41.[3]蒋正立,林建群,陈文红.棘白霉素类抗真菌药的研究新进展[J ].天津药学,2005,17(5):62-64.4科技创新科技风2018年9月. All Rights Reserved.。
转载抗生素行业背景资料
转载抗生素行业背景资料[转载]抗生素行业背景资料看看业内人士对抗生素的观点，兼听则明。
我在博客里明确不看好科伦，是因为它把抗生素作为一个主要方向，大输液占有率也比较高了。
而中恒的红霉素只是主业的有益补充，做好了锦上添花，做不好也只是拉低净资产收益率，也不至于亏损、拖后腿。
抗生素——一个时代的远去转自盗亦有道2008年，我扛着希舒美、舒普深、大扶康、威凡，苦苦奋斗了一年。
当时跟我一起鏖战沙场的兄弟单位的战友们，大多跟我一样，转战其他领域了。
外资企业的抗生素市场，风头已大不如前。
其实又何止是外企，国产大包十几年来只要在珠江口的一个河岸架起几个独家抗生素就可以霸占一个医院的时代，同样是一去不复返了。
一、β-内酰胺类类到了2009年，罗氏芬（头孢曲松、罗氏）、复达欣（头孢他啶、葛兰素）、马斯平（头孢吡肟、施贵宝）的推广力度渐成强弩之末，特治星（哌拉西林/他唑巴坦、惠氏）已经被辉瑞收购。
如今外资公司的头孢类抗生素产品线，只有辉瑞的舒普深（头孢哌酮/舒巴坦）和特治星在并肩作战了。
让我们再次聆听这几个药物发出过的声音吧：罗氏芬：一天一次，抗菌活性维持24小时。
复达欣：绿脓王。
舒普深：非发酵菌感染或中重度院内感染的理想选择。
忆往昔，抗生素的市场，一度烽烟四起，“浪花淘尽英雄”。
尤其是复达欣、舒普深这两个著名的品牌，不知成就了多少药代。
俱往矣，“几度夕阳红”。
二、大环内酯类大环内酯类，迄今还有辉瑞的阿齐霉素（希舒美）和雅培的克拉霉素（克拉仙）两支部队顽强地坚守在在国产抗生素的密林中厮杀。
相对而言，雅培最近几年人员队伍变动太大，加上克拉仙推广乏力，其品牌影响力和市场份额显然都不是能够与希舒美相提并论的。
克拉仙主要是在消化科推广幽门螺旋杆菌的疗效，在耳鼻喉科宣传免疫抗炎的作用。
希舒美最大的问题在于它对肺炎链球菌的高耐药率。
尽管希舒美的代表时常会辩驳：肺炎链球菌所致的CAP比例很小，希望以此来转移视线，继续坚守典型阳性菌的阵地。
世界在研100种新药详解
世界在研100种新药详解1. AGI-1067 8AGI-1067是选择性阻断动脉粥样硬化炎症过程的新型口服药物。
AGI-1067阻断了血管内膜内皮细胞的信号传导，继而抑制了VCAM-1和其他炎症因子的生成。
VCAM-1能使炎症细胞募集到内皮细胞表面，触发慢性炎症反应过程，最终导致动脉粥样硬化形成。
AGI-1067 是具有抗氧化作用的降血脂药物普罗布考的单丁二酸酯。
普罗布考Probucol能降低冠状血管成形术后的再狭窄，后因能引起心电图Q-T 间期延长等一系列不良反应，以及口服生物利用度的有限性和多变性而撤出美国市场。
研究人员对普罗布考的结构进行修饰，开发出具有抗氧化作用和降低LDL 胆固醇水平双重作用机制的化合物AGI-1067。
该化合物与普罗布考Probucol相比，水溶性和细胞穿透性更好，降脂作用和抗氧活性显著。
此外，它还能抑制单细胞化学引诱剂蛋白-1（monocyte chemoattractant protein-1，MCP-1）和血管细胞粘附分子-1（vascular cell adhesion molecule-1，VCAM-1）的表达，美国AntheroGenics 公司目前正在进行Ⅲ期临床研究，考察其对患有冠状动脉疾病（CAD）的病人动脉粥样硬化的治疗情况。
AGI-1067 是新血管保护剂家族中旨在降低血管壁炎症的首个药物。
本品CAS：216167-82-7分子式：C35H52O5S2结构式：[开发背景]：动脉粥样硬化是一种慢性炎症性疾病，而氧自由基的产生对动脉粥样硬化的发展有重要作用。
普罗布考Probucol是一种已经上市的抗氧化剂，并具有降脂作用，当降脂作用的机制并不明了。
Probucol可以降低血管成形术后血管再狭窄的发生率，但该产品已经被撤出美国市场，原因是该药物可以诱导QT间期延长、明显地降低HDL水平，以及有限的及不稳定的口服生物利用度，此外，该药物对内皮细胞VCAM-1的表达也缺乏影响。
阿尼芬净合成前体棘白菌素B发酵条件优化
阿尼芬净合成前体棘白菌素B发酵条件优化牛坤;吴豪;毛健;邹树平【摘要】阿尼芬净为新一代棘白菌素类抗生素,其前体物质棘白菌素B(ECB)发酵单位的高低将直接影响阿尼芬净的市场前景.利用构巢曲霉发酵合成ECB,采用单因素实验考察不同参数对ECB产量的影响.结果显示:低温培养有利于ECB的合成,选择前3天37℃培养,后9天25℃培养,ECB产量可达1 237 mg/L,比25℃恒温培养提高了69.9％;最佳的初始pH为6.5;添加0.6 g/LZnCl2可使ECB产量达到1 100 mg/L,比初始发酵培养基提高了69.2％;前体物质脯氨酸及鸟氨酸的添加可以显著提高ECB产量,在第6天添加2 g/L脯氨酸或在第3天添加2 g/L鸟氨酸可使ECB 产量分别提高57.4％和55.2％.【期刊名称】《发酵科技通讯》【年(卷),期】2017(046)001【总页数】5页(P11-15)【关键词】棘白菌素B;构巢曲霉;发酵;条件优化【作者】牛坤;吴豪;毛健;邹树平【作者单位】浙江工业大学生物工程研究所,浙江杭州310014;浙江工业大学生物工程研究所,浙江杭州310014;浙江工业大学生物工程研究所,浙江杭州310014;浙江工业大学生物工程研究所,浙江杭州310014【正文语种】中文【中图分类】Q92棘白菌素类抗生素是20世纪70年代发现的一组天然产物,具有类似的环状多肽核心和不同的脂肪酸侧链,能够非竞争性地抑制真菌细胞壁β-1,3-葡聚糖合成酶的活性,从而达到抗真菌的目的[1].FDA已批准上市的这类药物包括卡泊芬净(Caspofungin)、米卡芬净(Micafungin)和阿尼芬净(Anidulafungin),其中前两者已在国内上市,阿尼芬净已在国内临床中[2-3].阿尼芬净是由前体化合物棘白菌素B(ECB)经犹他游动放线菌产生的酰化酶作用脱去侧链亚油酰基,然后在DMF中与活性中间体4″-戊氧基-[1,1′,4′,1″]三苯基-4-甲酸-2,4,5-三氯-苯基酯反应制得.ECB 与阿尼芬净的化学结构式[4]分别为ECB是合成阿尼芬净的主要前体化合物,其发酵单位的高低将直接影响阿尼芬净的市场前景.根据文献和专利报道,目前国内外ECB 均是利用微生物发酵制备,其中主要是以构巢曲霉(Aspergillus nidulans)进行发酵[5-6].Papagianni等[7]综述了发酵过程中接种量、碳氮源种类及浓度、pH、温度和搅拌速率等因素对构巢曲霉生长的影响,当温度从23 ℃提高至37 ℃后,构巢曲霉的比生长速率从1.54 h-1增加至3.24 h-1,菌体生长加快,可见提高温度有利于构巢曲霉的生长.Benz等[8]通过红外、核磁共振等方法确定了ECB的分子结构,且发现其水解成分中包括了亚油酸、4-羟基-L-脯氨酸、4-羰基-L-脯氨酸、L-苏氨酸、(2S,3S,4S)-4-甲基-3-羟脯氨酸等,并且发酵培养基中添加碳酸盐、磷酸盐、硫酸盐及硝酸盐等组分对ECB产量的提高均有促进作用.目前,关于ECB发酵的文献报道较少,国内尚无企业生产阿尼芬净,导致其市场垄断、价格高.因此,现阶段对阿尼芬净的高效生产技术进行研发,实现其国产化,将有助于打破国际制药企业的垄断,为患者提供价廉质优的抗真菌药物,具有重要的经济和社会效益.笔者采用单因素实验,初步考察了发酵温度、初始pH、金属离子和前体等对ECB发酵过程的影响,以确定最优发酵条件,为阿尼芬净的工业化生产奠定坚实的数据基础.1.1 菌种构巢曲霉Aspergillus nidulans ZJB09223,由本实验保藏.1.2 培养基斜面培养基:PDA培养基.种子培养基(g/L):葡萄糖10,甘油10,棉籽粉25,pH 6.8～7.0,121 ℃灭菌20 min. 初始发酵培养基(g/L):花生油20,甘油10,蛋白胨10,L-脯氨酸1,甘露醇90,豆粉40,K2HPO4·3H2O 8,MgSO4·7H2O 0.5,MnSO4·H2O 0.1,FeSO4·7H2O0.05,CaCl2 0.3,pH 7.0,121 ℃灭菌20 min.1.3 主要仪器与设备恒温调速摇床(上海杜科自动化设备有限公司DKY-1);高效液相色谱(日本SHIMADZU);高压蒸汽灭菌锅(日本SANYO,MLS-3780);电子分析天平(上海精密仪器仪表有限公司FA2004);高速冷冻离心机(美国Bechman Coulter,X-22).1.4 培养方法1.4.1 斜面培养将传好种的斜面置于25 ℃培养箱中培养8～16 d,菌落表面呈现墨绿色后取出置于15～20 ℃室温,继续培养,一般5～20 d都可接种用于种子培养.1.4.2 种子液培养接种后的种子培养基在220 r/min,25 ℃条件下培养2 d.1.4.3 摇瓶发酵培养发酵温度、初始pH、金属离子及前体物质添加等实验均在摇瓶中进行.按照10%接种量进行接种,接种后在220 r/min,25 ℃条件下培养12 d,第6天起定时取样测定ECB产量.每个条件做3个平行样,最终结果取平均值.1.5 分析方法发酵液预处理:取1 mL发酵液12 000 r/min离心8 min,弃上清.所得菌体加入1 mL甲醇,25 ℃振荡萃取30 min,12 000 r/min离心8 min,留上清液备用.残留菌体中再加入1 mL甲醇重复萃取,25 ℃振荡摇匀30 min,12 000 r/min离心8 min,所得上清液与前一步上清液合并,12 000 r/min离心2 min,上清液用0.45 μm水膜过滤,进行检测.高效液相色谱(HPLC)检测:产物ECB采用HPLC进行检测,色谱柱为ODS-C18柱(大连依利特,4.6 mm×250 mm,5 μm),流动相为V(乙腈)∶V(甲醇)∶V(水)=2∶7∶1,流速为1.0 mL/min,紫外检测波长为222 nm,进样量20 μm,柱温40 ℃.2.1 发酵温度对ECB产量的影响发酵温度是影响菌体生长和代谢的关键因素,本实验着重考察了温度对产物ECB的影响.图1结果表明:发酵温度由25 ℃提高至37 ℃的过程中,ECB的质量浓度随温度的升高呈现降低的趋势;最佳发酵温度为25 ℃,此时ECB最高质量浓度为728 mg/L;而当温度提高至37 ℃后,基本无ECB产生,由此可知低温有利于ECB的合成. 实验过程中发现温度过低不利于菌体生长,因此本实验考虑在培养过程中进行温度的调节,以得到最佳的温度控制方式.实验开始(第0天)在25,28，37 ℃条件下进行发酵培养,然后分别在第3天、第6天和第9天进行温度调节,具体调节方式为:由28 ℃和37 ℃调节至25 ℃,培养至发酵结束;由25 ℃调节至28 ℃,培养至发酵结束.分别测定ECB质量浓度,结果如表1所示.从表1可以看出:前3天采用较高温度(28～37 ℃)培养,后续采用低温(25 ℃)培养,ECB质量浓度有较大的提高;前3天采用37 ℃培养,之后降低温度至25 ℃培养,ECB发酵质量浓度由728 mg/L提高至1 237 mg/L,比25 ℃恒温培养提高了69.9%.这可能是由于ECB的发酵过程为生长非偶联型,在发酵前3天采用37 ℃培养可以使菌体大量快速生长,而3天后ECB开始合成,此时降低温度则有利于ECB的产生.研究也表明构巢曲霉比生长速率会随温度的升高而升高,但是温度升高后菌体出现失水加剧的现象,最终会导致目标化合物的合成量降低,这与本实验的结果一致,而实验结果表明通过这种温度调节方式可以使ECB的质量浓度显著增加[7].2.2 初始pH值对ECB产量的影响pH值也是影响微生物生长和代谢的重要因素.由文献可知:中性pH值有利于构巢曲霉菌体生长和孢子生成,而当pH小于3时则不利于菌体生长,不同初始pH值对产物的合成也具有重要影响[7].本实验着重考察了初始pH值对ECB产量的影响.由图2可知:在初始pH值4.5～9.5范围内,ECB的质量浓度呈现先上升后下降的趋势,最佳的初始pH值为6.5,此时,ECB的发酵产量为1 116 mg/L;而当pH小于6或者大于7时,ECB质量浓度会降低至500 mg/L以下.因此过酸或过碱性的环境均不适合ECB的合成.2.3 金属离子对ECB产量的影响文献报道,金属离子对卡泊芬净合成前体Pneumocandin B0的发酵具有重要影响,因此本实验考察了金属离子对ECB产量的影响[9].图3为最佳金属离子浓度下ECB的发酵情况,从结果可以看出:金属离子对ECB发酵产量也有重要影响,在初始发酵培养基中,ECB质量浓度约为640 mg/L,Cu2+和Zn2+的添加可以使ECB的质量浓度提高,当添加0.6 g/L ZnCl2时,ECB质量浓度可以达到1 100 mg/L,比初始培养基的结果提高了69.2%,而Co2+对ECB质量浓度的影响不大.2.4 前体浓度及添加时间对ECB产量的影响2.4.1 脯氨酸对ECB产量的影响相关文献中报道脯氨酸对真菌类微生物的生长与代谢有着重要的作用[10-11].实验考查了不同脯氨酸质量浓度及添加时间对ECB发酵结果的影响.以初始发酵培养基为对照,在不同时间向发酵液中添加脯氨酸,使其最终质量浓度分别为2,5，8 g/L,结果如表2所示.由表2可知:第0天添加1 g/L脯氨酸的对照组,ECB质量浓度为540 mg/L左右,而在不同添加时间下,2 g/L的脯氨酸添加量均表现出较好的效果;在第0天添加2 g/L脯氨酸,ECB质量浓度最终达到780 mg/L左右,并且随着脯氨酸质量浓度的上升而下降;在第3天添加2 g/L脯氨酸,ECB质量浓度最终达到700 mg/L左右;第6天添加2 g/L脯氨酸,ECB质量浓度达到886 mg/L左右;第9天添加2 g/L脯氨酸,ECB质量浓度则为840 mg/L左右.由上述结果可知：在第6天添加2 g/L的脯氨酸效果最佳,ECB质量浓度比初始培养基提高57.4%.2.4.2 苏氨酸对ECB产量的影响除脯氨酸之外,本实验还考查了不同苏氨酸质量浓度及添加时间对ECB发酵结果的影响.以初始发酵培养基为对照,在不同时间向发酵液中添加苏氨酸,使其最终质量浓度分别为2,5,8 g/L,结果如表3所示.由表3可知:苏氨酸对ECB产量的影响较小,而且苏氨酸质量浓度过高(8 g/L)会抑制ECB的合成,不同时间添加苏氨酸均使ECB 的质量浓度降低,因此选择苏氨酸的最终添加质量浓度2 g/L;由添加时间看出,选择在第0天(发酵初始)添加苏氨酸,可使ECB质量浓度由524 mg/L提高至639 mg/L左右,产量提高了21.9%.2.4.3 鸟氨酸对ECB产量的影响本实验还考查了不同鸟氨酸质量浓度及添加时间对ECB发酵结果的影响.以初始添加2 g/L脯氨酸的发酵培养基为对照,在不同时间向发酵液中添加鸟氨酸,使其最终质量浓度分别为2,5，8 g/L,结果如表4所示.表4表明:在第3天添加2 g/L鸟氨酸时,ECB质量浓度会有大幅度提高,最终质量浓度达到1 204 mg/L左右,比对照组提高了55.2%;在发酵第6天添加鸟氨酸时,ECB质量浓度会随鸟氨酸质量浓度的增加而增加,添加8 g/L鸟氨酸可以使ECB质量浓度提高至1 173 mg/L左右,而在第9天添加鸟氨酸则对ECB的质量浓度影响不大.因此,分析实验结果本实验选择在发酵第3天添加2 g/L鸟氨酸.采用单因素实验对抗真菌药物阿尼芬净的前体物质ECB的发酵条件进行了优化,得到结果如下:高温有利于菌体生长,低温培养有利于ECB的合成,选择在前3天37 ℃培养,后9天25 ℃培养,可以使ECB的最终质量浓度达到1 237 mg/L,比25 ℃恒温培养提高了69.9%;最佳初始pH为6.5,pH小于6或大于7均不利于ECB的合成;金属离子Cu2+和Zn2+有利于ECB的合成,而Co2+对ECB合成的促进作用不大,添加0.6 g/L ZnCl2可以使ECB的质量浓度提高69.2%;最佳前体物质为脯氨酸与鸟氨酸,选择在发酵第6天和第3天添加2 g/L脯氨酸和鸟氨酸,ECB发酵产量分别达到850，1 204 mg/L.在上述最优发酵条件,ECB发酵单位可以达到1 200 mg/L以上.通过对ECB发酵过程中基本培养条件的优化,提高了ECB的发酵产量,为阿尼芬净的工业化提供了一定的实验基础,当然笔者所涉及的只是初步工作,今后还有许多工作需要进行,例如发酵罐实验的优化与放大,而本实验也为今后工作的展开提供参考.【相关文献】[1] 曹国颖,傅得兴.新型棘白菌素类抗真菌药阿尼芬净[J].中国新药杂志,2005,14(11):1358-1361.[2] 李岷,沈永年,吕桂霞,等.棘白菌素类抗真菌药[J].中国真菌学杂志,2009,4(4):249-256.[3] BERGOGNE-BÉRÉZI N E. Anidulafungin, a new antifungaldrug[J].Antibiotiques,2007,9(3):212-215.[4] 王海燕,李晓露,蒋沁,等.Echinocandin B的分离纯化工艺研究[J].中国抗生素杂志,2012,37(3):216-219.[5] COCKSHOTT A R, SULLIVAN G R. Improving the fermentation medium for Echinocandin B production. Part I: sequential statistical experimental design[J].Process biochemistry,2001,36(7):647-660.[6] COCKSHOTT A R, HARTMAN B E. Improving the fermentation medium for Echinocandin B production. Part II: Particle swarm optimization[J].Process biochemistry,2001,36(7):661-669.[7] PAPAGIANNI M. Fungal morphology and metabolite production in submerged mycelial processes[J].Biotechnology advances,2012,22(3):189-259.[8] BENZ F, KNÜSEL F, NÜESCH J, et al. Metabolic products of microorganism 143. Echinocandin B, a new polypeptide antibiotic from Aspergillus nidulans var echinulatus: isolation and building units[J].Helvetica chimica acta,1974,57(8):2459-2477.[9] TKACZ J S, GIACOBBE R A, MONAGHAN R L. Improvement in the titer of echinocandin-type antibiotics: a magnesium-limited medium supporting the biphasic production ofpneumocandins A0 and B0[J].Journal of industrial microbiology,1993,11(2):95-103. [10] PETERSEN L A, HUGHES D L, HUGHES R, et al. Effects of amino acid and trace element supplementation on pneumocandin production by Glarea lozoyensis: impact on titer, analogue levels, and the identification of new analogues of pneumocandin B0[J].Journal of industrial microbiology and biotechnology,2001,26(4):216-221.[11] 刘靓,娄忻,张莉,等.卡泊芬净合成前体Pneumocandin B0的发酵工艺研究[J].化学与生物工程,2011,28(9):80-82.。
新型抗真菌药阿尼芬净的研究进展
新型抗真菌药阿尼芬净的研究进展
谢新宇
【期刊名称】《河北化工》
【年(卷),期】2011(34)5
【摘要】阿尼芬净是一种新型的棘白菌素类抗真菌药,能够抑制真菌细胞壁中1,3-β-D-葡聚糖的合成,对真菌有较高的特异性;对于念珠菌属以及曲霉菌属均有良好的抗菌作用,且安全性较高.介绍了阿尼芬净的作用机制、抗菌活性、药动学和临床评价.
【总页数】3页(P33-34,57)
【作者】谢新宇
【作者单位】华北制药集团新药研究开发有限责任公司,微生物药物国家工程研究中心,河北省工业微生物代谢工程技术研究中心,河北,石家庄,050015
【正文语种】中文
【中图分类】TQ465
【相关文献】
1.烯丙胺类抗真菌药萘替芬和特比萘芬的研究进展 [J], 温守明;黄家章
2.新型棘白菌素类抗真菌药阿尼芬净 [J], 曹国颖;傅得兴
3.阿尼芬净中间体生物转化工艺研究 [J], 吴娟
4.基于脱酰基酶转化阿尼芬净前体echinocandin B条件的研究 [J], 朱进伟;滕云;张敏;高祥;郑玲辉
5.阿尼芬净侧链的制备 [J], 孟国彬;张为革
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抗真菌药 阿尼芬净——anidulafungin
割 豪评 徐
Ｉ Ｉ ０ 本品适用于下列真菌感染： 念珠菌血症及 － ｊ 一项随机双盲Ｉ期临床研 ＿
或） 其他 类型的念珠菌感染（ 腹腔脓肿 、腹膜炎） 食管念 血 症 和（ 其他 类 型侵 袭性 念珠 菌， ；② 品的安全性和疗效 。患者随机一 日１ 珠 菌病 。
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阴道白色念珠菌对抗真菌药物的敏感性分析
妇幼健康阴道白色念珠菌对抗真菌药物的敏感性分析商娇 （瓦房店轴承医院检验科，辽宁瓦房店 116300）摘要：目的 分析阴道白色念珠菌对抗真菌药物的敏感性。
方法 选取2021年2月~2022年2月我院收治的阴道白色念珠菌病患者105例作为研究对象，按照疾病有无复发情况分为复发阴道白色念珠菌病组（n=50）和未复发阴道白色念珠菌病组（n=55）。
两组患者均进行阴道分泌物采集并培养念珠菌，应用Rosco纸片扩散法进行抗真菌药物的药敏试验，分析药敏结果。
结果 完全敏感的药物包括卡泊芬净、阿尼芬净、米卡芬净等。
复发阴道白色念珠菌病组患者的氟康唑、伊曲康唑、伏立康唑、氟胞嘧啶等耐药性高于未复发阴道白色念珠菌病组（P＜0.05）。
结论 复发阴道白色念珠菌病患者各类菌株耐药性明显提升，需要加强临床管控，科学用药，保障治疗效果。
关键词：阴道白色念珠菌病；抗真菌药物；阴道分泌物；药敏试验阴道炎是女性常见妇科疾病，主要与各种病原体感染、外部刺激、激素水平等有关[1]。
白色念珠菌属于常见致病菌，其感染引发的阴道内霉菌性感染称为阴道白色念珠菌病[2~3]，临床表现为阴道分泌物增多、外阴瘙痒、坐立不安等症状。
若未进行有效治疗，炎症进一步蔓延，可出现膀胱炎、尿道炎、子宫内膜炎等并发症，危及患者生命健康[4~6]。
临床治疗此疾病以缓解外阴瘙痒等症状，控制炎症进展，预防并发症为原则。
主要方法有抗生素治疗、雌激素治疗、日常生活管控等，以抗生素治疗较为多见。
不同的抗真菌药物因其成分和作用机制不同，产生的抗菌效果也有所差异[7~8]。
本研究旨在探讨阴道白色念珠菌对抗真菌药物的敏感性，详细报道如下：1 资料与方法1.1 一般资料选取2021年2月~2022年2月我院收治的阴道白色念珠菌病患者105例作为研究对象，按照疾病有无复发情况分为复发阴道白色念珠菌病组（n=50）和未复发阴道白色念珠菌病组（n=55）。
复发阴道白色念珠菌病组患者均为女性，年龄23~63岁，均值为（43.07±3.25）岁；体重47~77kg，均值为（61.95±1.41）kg；病程1~5年，均值为（3.02±1.08）年。
阿尼芬净前体物的研发
阿尼芬净前体物的Echinocandin B的研发
侵袭性真菌感染是越来越多的免疫低下患者死亡的一个重要原因。
常见致病菌为白色念珠菌、烟曲菌、热带念珠菌和新型隐球菌。
近年来深部真菌感染呈持续增多趋势，这与人类平均寿命延长，肿瘤化疗、器官移植等免疫缺陷患者增多，以及广谱抗生素、肾上腺皮质激素、免疫抑制剂等药物的广泛应用有关。
目前仅有3类药物可用于系统性真菌感染的治疗，包括多烯类（两性霉素B），康唑类(伊曲康唑、伏立康唑、泊沙康唑、氟康唑等)，以及棘球白素类（卡泊芬净、阿尼芬净、米卡芬净等）。
Echinocandin B是生产阿尼芬净的主要原料。
阿尼芬净（anidulafungin）于2006年获FDA批准，是第三个上市的棘球白素类药物。
我公司于2005年在国内率先开始对Echinocandin B进行开发研究，目前已经取得的较佳的发酵和后提取工艺，欢迎同业者合作开发。
目前研发状态：
发酵水平：0.4-0.8g/L
发酵时间：6-7天
产品收率：45%
生产规模：实验室。
棘白霉素类抗真菌药的临床应用
棘白霉素类抗真菌药的临床应用（作者:___________单位: ___________邮编: ___________）论文关键词：抗真菌药卡泊芬净米卡芬净阿尼芬净论文摘要:一类全新的抗真菌药，通过非竞争性抑制β(1,3)D糖苷合成酶，破坏真菌细胞壁糖苷的合成，在临床上显示了广谱、低毒、高效的特性。
本文综述了棘白霉素类抗真菌研究新进展,介绍了三个新药物卡泊芬净（Caspofungin）、米卡芬净（Micafungin）和阿尼芬净（Anidulafunngin），与目前医院使用的抗真菌药相比，均显示了独特的优点。
在自然界，真菌是一种无处不在的微生物（国外也有学者将真菌归入“低等植物类”）。
真菌的种类与形态繁多，迄今已被科学家鉴定出的真菌仅有数千种，而实际存在于自然界的真菌至少有数万种。
在形形色色的真菌中，只有大约20来种是真正的致病菌，人类99％的真菌病系由这20来种真菌所引起。
从广义上分析，真菌病大体上可以分为以下四类：侵袭性真菌病与全身性真菌病（如曲霉病和念珠菌病等）、粘膜型真菌病（如“鹅口疮”等）、浅表型皮肤真菌病（如“香港脚”或“头皮癣”、“灰指甲”等）和过敏型真菌病（如哮喘与慢性炎症等）。
在以上四类真菌病中，以第一类对人类危害最大，而后三类真菌病相应较轻一些。
据来自国外的临床统计资料，在死于感染性疾病的人群中，有4％是死于全身性曲霉菌类真菌感染，大约2％的人死于全身性念珠菌感染。
临床统计表明，病人一旦患上全身性曲霉病，其死亡率将高达85％，如患血液性念珠菌病则死亡率可达40％。
利用现有抗真菌药物治疗全身性真菌病或血液感染型真菌病的效果至今仍无法令人满意。
因此，药学界正全力寻找可抑制全身性真菌感染的新型药物。
目前，国内外已开发上市的抗真菌药物大体上有四大类：即多烯类（如两性霉素B）、三唑类（如氟康唑、咪康唑、益康唑、依曲康唑和酮康唑等）、烷基胺类（如特比萘芬）和新开发上市的棘白菌素（echinocandins）类（如卡帕芬净）。
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阿尼芬净市场分析
阿尼芬净市场浅析
一、简介
1、阿尼芬净是一种抗真菌药物，属于抗感染药物类全身用抗真菌药物。
主要治疗念珠菌血症和其他形式的念珠菌感染(腹腔脓肿、腹膜炎)和食管念珠菌病等。
2、根据目前公开资料显示，国内尚无阿尼芬净的批文。
二、全身用抗真菌类药物市场及医保情况。
全身用抗真菌类药物在SFDA南方所药物分类中仅8个品种，品种较少。
全身用抗真菌类药物8个品种中只有硝酸咪康唑不在国家医保;氟康唑口服剂型属国家甲类医保;氟康唑注射剂、伏立康唑、伊曲康唑、两性霉素B、氟胞嘧啶等均在国家乙类医保。
全身用抗真菌类药物2009年样本医院销售额为7亿。
氟康唑、伊曲康唑等排名靠前销售过亿的药品是以口服剂型为主。
硝酸咪康唑销售排名靠后，去年在样本医院销售仅20万。
三、同类品种市场情况简介
阿尼芬净属于全身抗真菌类棘白菌素药物，其同类品种有卡泊芬净和米卡芬净。
1、卡泊芬净
卡泊芬净全名为注射用醋酸卡泊芬净，于2001年上市，有50mg和70mg两个规格。
其主要生产企业为中美杭州默沙东制药有限公司。
该品种在国家医保乙类目录中，有4个进口批文。
以中美杭州默沙东制药有限公司生产的卡泊芬净品种为例，综合2009年青海、北京、济南军区、陕西等地区中标价，卡泊芬净(50mg)平均中标价为1912元;
综合2009年青海、北京、陕西等地区中标价，卡泊芬净(70mg)平均中标价为2449元。
其中(50mg)2009年在海南、山东最高零售价为1997元，卡泊芬净(70mg)2009年在海南、山东最高零售价为2578元。
卡泊芬净05年在国内样本医院销售约1043支，销售金额约为200万元;2009年国内样本医院共销售约51671支，销售金额约为1亿。
2、米卡芬净
米卡芬净全名为注射用米卡芬净钠，规格为50mg，于2007年上市，有3个进口批文，在国家医保乙类目录。
其中日本藤泽药品工业株式会社占据大部分的市场份额。
米卡芬净在国内零售价为660元，综合四川、海南、济南军区、陕西等地区2009年中标价，其平均中标价为577.7元。
2007年米卡芬净在国内样本医院销售约3522支，销售金额为200万元;2008
年国内样本医院销售约19376支，销售金额约为1100万;2009年国内样本医院销售约33127支，销售金额约为1850万。
四、阿尼芬净市场浅析
通过对卡泊芬净和米卡芬净市场销售情况的了解，对阿尼芬净的市场销售情况进行预测。
阿尼芬净是继卡泊芬净、米卡芬净之后的新一代全身抗真菌类棘白霉素衍生物药物，属于3.1类新药，国内无生产与进口。
卡泊芬净和米卡芬净等分别占据全身抗真菌药物排名的第4位和第6位。
卡泊芬净和米卡芬净等棘白霉素衍生物类药品09年的样本医院销售为约为1.18亿，占全身抗真菌类药物的16.8%。
同时我们也要看到卡泊芬净和米卡芬净单价高，单从数量上看不及抗生素类和抗病毒类药物的月均销量。
按照目前的市场销售数量，假设阿尼芬净的销售数量与现有的卡泊芬净和米卡芬净同等数量，则销售金额如下:
卡泊芬净2009年在样本医院销量为51671支左右，销售金额为为人民币1亿元。
阿尼芬净若同期销售51671支，则按765元/支计算(注:参照人民币:美元
=6.8:1)，合计人民币3952万元。
米卡芬净2009年在样本医院销量为33127支，销售金额为人民币1800万。
阿尼芬净若同期销售33127支，则按765元/支计算(注:参照人民币:美元=6.8:1计)，则金额为2534万元。
五、总结。
1、抗感染类药物分抗生素、抗病毒、抗真菌，抗真菌药物品种相对不多，在临床研究上不及抗生素和抗病毒类药物成熟。
但抗生素品种及厂家非常之多，竞争较为激烈，目前该类品种国内无生产厂家，如能首家上市，具有一定竞争优势。
2、阿尼芬净在单价上与卡泊芬净较差距较大，和米卡芬净价格相差不大。
如需达到同类产品的销售额，则需要增加其销售量。
参
考全身抗真菌类销售靠前的药品，如需阿尼芬净在短期内快速上量，建议先申请进入国家医保。
3、在SFDA南方所的药品分类中，全身抗真菌类药物仅有8个药品，同比全身抗感染类药物中的抗生素和抗病毒等较为成熟的药品，临床使用量和临床使用范围低于抗生素和抗病毒等药物。
因对医生的前期推广需大量的临床资料，故在前期研发的过程中应注意其学术的研究，积累学术资料，使之在推广时有据可依。
4、结合销售情况和相关国家药品销售政策，我企业在拿到阿尼芬净的正式批文投入生产后，至少需2年的市场启动期，在全国区域通过招标形成一定的市场规模最少需要3年以上的时间。
注:以上数据来源于SFDA南方研究所、国家食品药品监督管理局和新药部资料，仅供参考～。