母牛分支杆菌菌苗在初治肺结核治疗中的作用

目的 观察和评价母牛分支杆菌菌苗（微卡菌苗）在初治肺结核免疫治疗中的疗效及安全性。方法 采用随机配对分组法将342例初治菌阳肺结核患者分入微卡菌苗治疗组（M组,171例）和对照组（C组,171例）。M组化疗方案为2HRZE／2HR,C组为2HRZE／4HR。M组加用微卡菌苗治疗6个月,C组不用微卡菌苗。结果 M组第1个月涂片阴转率36．8％,培养转率19．3％;第2个月涂片阴转率80．1％,培养阴转率85．9％。C组第1个月涂片阴转率19．9％,培养阴转率19．3％;第2个月涂片阴转率54．4％,培养阴转率67．8％。头2个月痰菌阴转率M组显著高于C组（P＜0．01）。疗程满6个月后M组涂片阴转率98．2％,培养阴转率99．4％;C组涂片阴转率98．8％,培养阴转率98．8％。M组与C组治疗6个月痰菌阴转率无显著性差异（P＞0．05）。病灶吸收好转及空洞缩小关闭速度,M组优于C组。M组的细胞免疫功能显著改善。1年后随访M组和C组的的细菌学复发率分别是3．0％和5．6％（P＞0．05）。结论 微卡菌苗能改善初治肺结核患者的细胞免疫功能,加快痰菌阴转、病灶吸收及空洞缩小关闭的速度,缩短短程化疗疗程。不良反应少且较轻微。复发率底。微卡菌苗可用作初治肺结核的免疫治疗和短化的辅助治疗。     

母牛分枝杆菌菌苗辅助治疗初治菌阳肺结核的临床分析

目的　观察和评价母牛分枝杆菌菌苗 (微卡菌苗)在初治菌阳肺结核治疗中的作用。方法 采用随机配对分组法,分微卡菌苗治疗组 (A组,84例 )和对照组 (B组,84例 )。 2组化疗方案均为2HRZE 4HR,A组加用微卡菌苗治疗 2月,B组不用微卡菌苗。结果 A组第 1月涂片阴转率36.9%,培养阴转率 47.6%;第 2月涂片阴转率 79.8%,培养阴转率 85.7%。B组第 1月涂片阴转率19.0%,培养阴转率 17.9%;第 2月涂片阴转率 53.8%,培养阴转率 67.9%。前 2月痰菌阴转率A组显著高于B组 (P＜0.01 )。疗程满 6个月后A组涂片阴转率 98.8%,培养阴转率 97.6%;B组涂片阴转率 96.4%,培养阴转率 97.6%。A组和B组治疗 6个月痰菌阴转率无显著性差异 (P＞0.05)。病灶吸收好转及空洞缩小关闭速度,A组优于B组。A组的细胞免疫功能显著改善。随访A组和B组的细菌学复发率分别为 1.3%和 2.6% (P＞0.05)。结论 微卡菌苗能改善初治菌阳肺结核患者的细胞免疫功能,加快痰菌阴转、病灶吸收及空洞缩小关闭的速度,不良反应少且轻微。微卡菌苗可用作初治菌阳肺结核的免疫治疗。     

Randomized trial of adjunctive interleukin-2 in adults with pulmonary tuberculosis

Interleukin (IL)-2 has a central role in regulating T cell responses to Mycobacterium tuberculosis. Adjunctive immunotherapy with recombinant human IL-2 was studied in a randomized, placebo-controlled, double-blinded trial in 110 human immunodeficiency virus-seronegative adults in whom smear-positive, drug-susceptible pulmonary tuberculosis was newly diagnosed. Patients were randomly assigned to receive twice-daily injections of 225, 000 IU of IL-2 or placebo for the first 30 days of treatment in addition to standard chemotherapy. Subjects were followed for 1 year. The primary endpoint was the proportion of patients with sputum culture conversion after 1 and 2 months of treatment. After 1 month, the proportion of patients for whom sputum culture converted to negative was 17% for the IL-2 group compared with 30% in the control group (p = 0.14; chi2). After 2 months, 77% in the IL-2 group were culture negative compared with 85% of those receiving placebo (p = 0.29, chi2). Results were similar when patients with isoniazid monoresistance were included in the analysis. There were no differences in weight gain and no improvement in fever, cough, and chest pain between groups. One patient in each arm relapsed. IL-2 did not enhance bacillary clearance or improvement in symptoms in human immunodeficiency virus-seronegative adults with drug-susceptible tuberculosis.     

母牛分枝杆菌菌苗对复治性肺结核的辅助治疗作用

目的观察母牛分枝杆菌菌苗（微卡）在复治性肺结核治疗中的疗效。方法将146例痰抗酸杆菌（AFB）阳性复治肺结核患者分成微卡治疗组（n：90）和对照组（n=56）疗程各6个月,前者采用复治化疗方案加用微卡治疗,后者仪用复治方案治疗。结果疗程结束时微卡治疗组和对照组痰阴转率分别为85．56％（77／90）、67．86％（38／56）,差异有显著性（P〈0．05）。微卡治疗组和对照组有效率分别为81．11％（73／90）、44．64％（25／56）,两组比较差异有显著性（P〈0．001）。结论微卡能改善难治性肺结核患者的细胞免疫功能,有助于痰菌阴转和病灶吸收,可作为复治性肺结核化疗的辅助药物。     

母牛分支杆菌菌苗治疗肺结核的临床研究

观察、评价母牛分支杆菌菌苗对肺结核患免疫功能的影响和疗效。方法将７０例痰涂片阳性初治肺结核患随机分入Ⅰ组和Ⅱ组,分别采用２ＨＲＺＳ／４ＨＲ方案和２ＨＲＺＳ／４ＨＲ加母牛分支杆菌菌苗方案治疗;将３１例耐多药肺结核患归入Ⅲ组,采用４－６种敏感药物加母牛分支杆菌菌苗治疗。     

化疗加免疫长疗程方案治疗耐多药结核病的随机对照研究

目的评价化疗加免疫长疗程方案治疗耐多药肺结核的疗效和安全性。方法对203例耐多药肺结核患者,采用1∶1随机、平行对照的方法,分为治疗组和对照组,2组患者除采用对氨基水杨酸异烟肼、利福喷汀、左旋氧氟沙星、丙硫异烟胺（Pt）、克拉霉素和阿米卡星治疗外,治疗组患者加用免疫调节剂母牛分枝杆菌菌苗（M.vaccae,微卡）,对照组患者不加用母牛分枝杆菌菌苗,疗程共18个月。结果治疗结束时（18个月）治疗组和对照组痰抗酸菌涂片阴性同时痰结核分枝杆菌培养阴性（涂阴培阴）分别为74.5%（73/98）和72.5%（66/91）,（χ²=0.09,P=0.7599）。2组比较差异无统计学意义。X线影像结果表明,2组的病灶显效率分别为72.4%（71/98）和47.3%（43/91）,差异有统计学意义（χ²＝12.52,P=0.0004,P>0.05）;有效率分别为90.8%（89/98）和82.4%（75/91）,差异无统计学意义（χ²＝2.90,P=0.0886,P>0.05）;空洞闭合率分别为33.3%（27/81）和22.1%（17/77）,差异无统计学意义（秩和检验F=1.52,P=0.1294,P>0.05）。免疫学指标CD8阳性原细胞在治疗6个月时治疗组高于对照组,CD3阳性原细胞治疗后与治疗前免疫指标差值在3和9个月差异有统计学意义外,其余CD4, CD4/CD8,NK细胞,IL-2R等免疫学指标在各治疗阶段,治疗组与对照组近似,差异无统计学意义。临床症状咳嗽、咳痰、胸痛,呼吸困难,乏力等症状有改善;治疗组改善程度均大于对照组。结论本研究所设计的方案对耐多药肺结核病均有明确的疗效,具有有效的杀菌、抑菌作用,加用免疫调节剂在促进病灶吸收,症状改善方面有一定的作用。     

Whole blood bactericidal activity during treatment of pulmonary tuberculosis

The timely evaluation of new drugs that can be used to shorten tuberculosis (TB) treatment will require surrogate markers for relapse. This study examined bactericidal activity against intracellular Mycobacterium tuberculosis in whole blood culture (whole blood bactericidal activity; WBA) during TB treatment. In the absence of chemotherapy, immune mechanisms in patient blood resulted in bacteriostasis, whereas administration of oral chemotherapy resulted in bacillary killing. Total WBA per dose was greater during the intensive phase of treatment than during the continuation phase (mean, -2.32 vs. -1.67 log(10) cfu-days, respectively; P<.001). Cumulative WBA throughout treatment was greater in subjects whose sputum cultures converted to negative by the eighth week of treatment than in those for whom conversion was delayed (mean, -365 vs. -250 log(10) cfu-days; P=.04) and correlated with the rate of decrease of sputum colony-forming unit counts during the first 4 weeks of treatment (P=.018), both of which are indicative of prognosis. These findings indicate that measurement of WBA may have a role in assessing the sterilizing activity of new anti-TB drugs.     

免疫调节剂对肺结核合并2型糖尿病T细胞亚群及痰菌阴转的影响

目的探讨免疫调节剂(母牛分枝杆菌菌苗)对肺结核合并2型糖尿病T细胞亚群及痰菌阴转率的影响。方法初治菌阳肺结核合并2型糖尿病200例,均给予抗结核及降血糖治疗,观察组108例加用母牛分枝杆菌菌苗,对照组92例未使用免疫调节剂,观察两组患者治疗前及治疗2个月末T细胞亚群变化及痰菌转阴率。结果治疗2个月末观察组和对照组的T细胞亚群及痰菌转阴率比较无统计学差异(P0.05)。结论免疫调节剂(母牛分枝杆菌菌苗)对肺结核合并2型糖尿病的T细胞亚群及痰菌阴转无影响。     

Ursodeoxycholic acid as adjunctive therapy for problematic type 1 autoimmune hepatitis: a randomized placebo-controlled treatment trial

To evaluate the efficacy of ursodeoxycholic acid as adjunctive therapy in type 1 autoimmune hepatitis, 37 patients who had experienced treatment failure, repeated relapse, or incomplete response were randomized to ursodeoxycholic acid (13-15 mg/kg daily) or placebo for 6 months in addition to their usual corticosteroid schedule. Serum aspartate transaminase (70% vs. 31%, P =.04) and alkaline phosphatase (47% vs. 7%, P =.02) levels improved more commonly in the 21 patients randomized to ursodeoxycholic acid. Mean serum levels, however, were similar before and after the treatment period. The frequency of dose reduction or corticosteroid withdrawal was comparable in both groups (29% versus 31%, P >.9), and clinical improvement (48% vs. 44%, P >.9) or its absence (52% vs. 56%, P >.9) occurred as commonly in patients receiving ursodeoxycholic acid or placebo. The modified histological activity score (3.5 +/- 0.8 vs. 3. 5 +/- 0.9) and the modified fibrosis score (2.4 +/- 0.4 vs. 2.4 +/- 0.4) were similar before and after treatment with ursodeoxycholic acid and no different than after placebo therapy. We conclude that ursodeoxycholic acid can improve certain laboratory tests in problematic patients with type 1 autoimmune hepatitis when administered adjunctively for 6 months. Short-term therapy, however, does not facilitate reduction in the dose of corticosteroids or its withdrawal, affect clinical outcome, or reduce histological activity.     

Does immunotherapy with heat-killed Mycobacterium vaccae offer hope for the treatment of multi-drug-resistant pulmonary tuberculosis?

The ability of immunotherapy with heat-killed Mycobacterium vaccae (NCTC 11659), as an addition to the available chemotherapy, to improve the outcome in patients with multi-drug-resistant tubercle bacilli (MDRTB) who had not been cured by chemotherapy alone was evaluated in tuberculosis centres in Estonia, Iran, Kuwait, New Zealand, Romania, Vietnam and the U.K. A total of 337 patients in the above countries received intradermal injections of M. vaccae in addition to chemotherapy. Patients were grouped according to the length of their histories of disease: less than or greater than 2 years duration. Initially, single doses of M. vaccae were given but subsequently up to 12 doses at 2-month intervals were given. Chemotherapy varied from isoniazid alone to drugs selected according to susceptibility tests. Most patients had failed to respond to repeated courses of chemotherapy and the majority, were expected to die from their disease. Results were assessed by sputum smear and culture and by clinical observations. Cured patients were followed for 18-24 months to exclude relapse. Eighteen of 22 (82%) patients with disease for less than 2 years were bacteriologically cured by one or two doses of M. vaccae. Among 315 chronic patients, 24 (7.6%) were cured after one dose, 37.9% after seven doses and 41.6% after 12 doses. Sixty-six chronic patients were lost to follow-up, or died, during the multi-dose regimens. Nine of 33 patients (27%) with advanced disease unaffected by several courses of chemotherapy and discharged on isoniazid alone in Vietnam were cured by 3-12 injections of M. vaccae. The data provide preliminary evidence that the addition of immunotherapy with M. vaccae to chemotherapy improves the rate of cure of MDRTB, most effectively in patients with short histories of disease, but multiple dosing can have beneficial effects in chronic patients in whom chemotherapy has failed. A randomized clinical trial of this immunotherapy in MDRTB patients is therefore required.     

微卡辅助治疗耐多药肺结核的临床研究

目的　探讨评价微卡(母牛分枝杆菌菌苗)治疗耐多药肺结核的疗效。方法 60例耐多药肺结核患者按入院先后顺序分为微卡加化疗组即治疗组,与单纯化疗组即对照组。化疗方案均为3PaL₂AKZThV/15PaL₂ZThV。治疗组为病人头3个月每15d肌注微卡(22.5μg),随后的3个月每月肌注1次微卡。观察2组治疗后肺部病灶吸收情况、痰菌阴转情况、症状改善情况、免疫功能变化情况。结果 治疗组与对照组3个月时痰菌阴转率分别为56.6%和26.6%,18个月时为93.3%和73.3%有显著差异(P<0.05);X线吸收率及空洞缩小、闭合率均有明显差异P<0.05;CD4⁺、CD4⁺/CD₈⁺9个月时治疗组与同组治疗前及对照组均有显著差异P<0.05。结论 微卡能调节免疫功能,提高痰菌阴转率,有助于病灶吸收空洞闭合,可作为耐多药肺结核化疗的辅助治疗。     

Nicotine inhaler and nicotine patch as a combination therapy for smoking cessation: a randomized, double-blind, placebo-controlled trial

BACKGROUND: Nicotine replacement therapy is an effective treatment for nicotine-dependent smokers. However, cessation rates are modest, and preliminary studies suggest that combination therapy may be superior. We compared the efficacy of the nicotine inhaler plus nicotine patch vs nicotine inhaler plus placebo patch for smoking cessation. METHODS: A double-blind, randomized, placebo-controlled trial was conducted in 400 subjects who had smoked 10 or more cigarettes per day for 3 years or longer. Group 1 (n = 200) received the nicotine inhaler plus nicotine patch (delivering 15 mg of nicotine per 16 hours) for 6 weeks, then inhaler plus placebo patch for 6 weeks, then inhaler alone for 14 weeks. Group 2 (n = 200) received the nicotine inhaler plus placebo patch for 12 weeks, then inhaler for 14 weeks. Inhaler was used at a rate of 6 to 12 cartridges per day ad libitum for 3 months and then tapered off. Main outcome measures were complete abstinence (self-reported) and expired carbon dioxide concentration less than 10 ppm. RESULTS: Group 1 vs group 2 complete abstinence rates were 60.5% and 47.5% at 6 weeks (P =.009), 42.0% and 31.0% at 12 weeks (P =.02), 25.0% and 22.5% at 6 months (P =.56), and 19.5% and 14.0% at 12 months (P =. 14). One-year survival analysis showed a significant association between abstinence and treatment with nicotine inhaler plus nicotine patch (P =.04). Mean nicotine substitution at week 6 was 60.1% (group 1) and 24.6% (group 2) (P<.001). At 12 months, the frequency of respiratory symptoms in abstinent subjects fell significantly and lung function showed a trend toward improvement. The most common adverse events were throat irritation (inhaler) and itching (patch). CONCLUSIONS: Treatment with the nicotine inhaler plus nicotine patch resulted in significantly higher cessation rates than inhaler plus placebo patch.     

母牛分支杆菌菌苗免疫治疗肺结核临床观察--2年随访结果

目的　评价母牛分支杆菌 (M.vaccae)菌苗免疫治疗缩短初治菌阳肺结核化疗疗程及对耐多药肺结核的疗效。方法 142例初治菌阳肺结核和46例耐多药肺结核，配对随机分为M.vaccae菌苗免疫治疗组和单纯化疗对照组。初治治疗组 (A组)采用M.vaccae菌苗深部肌肉注射6次及4个月化疗，初治对照组 (B组)采用6个月化疗而不行免疫治疗；耐多药肺结核 (C组、D组)均给予18个月化疗，但治疗组 (C组)给予M.vaccae菌苗免疫治疗6次，对照组 (D组)单用化疗。M.vaccae菌苗免疫治疗结束，A组痰菌阴转率为95.8% (68/71)，B组为97.2% (69/71)，P＞0.05；C组和D组痰菌阴转率分别为34.8% (823)和4.7% (123)，P＜0.05。本文对疗程结束痰菌阴转且未失访的141例病人进行了2年随访。结果 A组2年复发率为6.3% (464)，B组为4.5% (366)P＞0.05，C组、D组2年复发率分别为11.1% (1/9)和50.0% (1/2)，P＞0.05。结论 M.vaccae菌苗免疫治疗可将初治菌阳肺结核的化疗疗程缩短为4个月，痰菌阴转率、2年复发率与对照组无差异，耐多药肺结核痰菌阴转率明显提高，复发率与对照组无差异。因此，M.vaccae菌苗免疫治疗可缩短初治菌阳肺结核的疗程，提高耐多药肺结核的疗效，建议推广。     

母牛分枝杆菌菌苗治疗菌阳肺结核的疗效评价

目的　评价化疗并用母牛分枝杆菌菌苗 (微卡菌苗 )治疗菌阳肺结核的疗效。方法　将 191例初、复治菌阳肺结核患者随机分为 A、B、C、D组 ,A、C组 (各 5 0例 )分别采用 2 HRZS/ 4 HR和 2 HRZES/ 6 HRE加微卡菌苗方案治疗 ;B组 (46例 )、D组 (45例 )单纯用 2 HRZS/ 4 HR和 2 HRZES/ 6 HRE方案治疗。观察治疗后肺部病灶吸收、痰菌阴转情况。结果　第 2月末痰菌阴转率 :A、B组分别为 96 .0 %和 78.3% ;C、D组分别为 92 .0 %和 6 8.9% ;疗程结束痰菌阴转率 A、B组分别为 98.0 %和 87.0 % ;C、D组 96 .0 %和 77.8%。疗程结束胸片改善有效率 A、B组96 .0 %和 84 .8% ;C、D组 92 .0 %和 73.3%。空洞闭合 A、B、C、D组分别为 83.33%、5 2 .6 3%、78.5 7%、4 5 .0 0 %。结论　微卡菌苗能提高痰菌阴转率 ,促进病灶吸收 ,是一种较好的免疫制剂。     

高危人群抗结核方案的探讨

目的观察高危人群适当弱化结核治疗强度对药物性肝损发生率及痰菌阴转率的影响,探讨高危人群的抗结核治疗方案。方法选取2007年6月～2008年6月收治于南京胸科医院结核科94例存在高危因素的初治菌阳病人,随机分为标化组（46例）与非标化治疗组（48例）,比较药物性肝损发生率及痰菌阴转率。结果 2个月内,非标化治疗组药物性肝损害发生率显著低于标化组（14.6%VS34.8%,P〈0.05）;2个月末,标化组与非标化治疗组：痰集菌阴转率相比差异无统计学意义（65.2%VS64.6%,P〉0.05）,痰结核菌培养阴转率相比差异无统计学意义（60.9%VS60.4%,P〉0.05）。结论对于高危因素人群应制订合理的个体化抗结核治疗方案。     

A randomized, placebo-controlled trial of granulocyte-macrophage colony-stimulating factor and nucleoside analogue therapy in AIDS

Preliminary preclinical and clinical data suggest that granulocyte-macrophage colony-stimulating factor (GM-CSF) may decrease viral replication. Therefore, 105 individuals with AIDS who were receiving nucleoside analogue therapy were enrolled in a placebo-controlled, double-blind study and were randomized to receive either 125 microgram/m(2) of yeast-derived, GM-CSF (sargramostim) or placebo subcutaneously twice weekly for 6 months. Subjects were evaluated for toxicity and disease progression. A significant decrease in mean virus load (VL) was observed for the GM-CSF treatment group at 6 months (-0.07 log(10) vs. -0.60 log(10); P=.02). More subjects achieved human immunodeficiency virus (HIV)-RNA levels <500 copies/mL at >/=2 evaluations (2% on placebo vs. 11% on GM-CSF; P=.04). Genotypic analysis of 46 subjects demonstrated a lower frequency of zidovudine-resistant mutations among those receiving GM-CSF (80% vs. 50%; P=.04). No difference was observed in the incidence of opportunistic infections (OIs) through 6 months or survival, despite a higher risk for OI among GM-CSF recipients. GM-CSF reduced VL and limited the evolution of zidovudine-resistant genotypes, potentially providing adjunctive therapy in HIV disease.     

Bupropion for smoking cessation: a randomized trial

BACKGROUND: Bupropion hydrochloride is recommended for smoking cessation; however, there have been relatively few clinical trials examining its efficacy. METHODS: A total of 244 current smokers were enrolled in an outpatient randomized blinded smoking cessation trial conducted at the San Francisco Veterans Affairs Medical Center, San Francisco, Calif. Of the 244 participants, 121 received a 7-week course of bupropion and 123 received placebo. All participants received 2 months of transdermal nicotine replacement therapy and 3 months of cognitive-behavioral counseling. We determined on-medication treatment, end-of-medication treatment, 3-month, 6-month, and 1-year quit rates. RESULTS: During treatment with bupropion vs placebo, there was a trend toward increased quit rates among participants randomized to bupropion; the self-reported end-of-medication treatment quit rates were 64% for the bupropion group vs 57% for the placebo group (P =.23). The trend favoring bupropion persisted at 3 months of follow-up (P =.12) but was not apparent at 6 months and 1 year of follow-up (both P>.78). The 12-month quit rates, validated by either saliva cotinine or spousal proxy, were 22% in the bupropion group and 28% in the placebo group (P =.31). Based on biochemical validation, 19% of the bupropion group vs 24% of the placebo group had quit smoking by 1 year (P =.36). CONCLUSIONS: In this randomized blinded trial of mostly veteran participants, the addition of a brief 7-week bupropion trial to treatment with nicotine replacement therapy and counseling did not significantly increase smoking cessation rates.     

耐多药肺结核对异烟肼和利福平复敏的治疗疗效分析

目的探讨复敏后的耐多药肺结核INH、RFP联合治疗的疗效。方法 50例经痰结核菌培养确定的耐多药肺结核对INH、RFP均复敏的患者随机分为两组,治疗组采用3HRZAKPT/18HRPT化疗方案治疗;对照组采用3VZPTAKCTM/18VPTCTM化疗方案治疗。比较治疗3个月、6个月、12个月、18个月、21个月的痰菌阴转率（涂片与培养）,X线胸片变化及药物不良反应。结果治疗组疗程满3个月痰菌涂片与培养阴转率（32%,28%）分别与对照组（16%,12%）无明显差异（P〉0.05）;两组满疗程痰菌涂片阴转率（48%,40%）、培养阴转率（44%,40%）,X线病灶吸收率（68%,64%）和空洞闭合率（24%,28%）均无明显差异（P〉0.05）;两组均无严重不良反应。结论 INH、RFP对复敏后的耐多药肺结核,近期临床疗效不比对照组第三线化疗方案[1]的疗效差,而且治疗费用低,值得临床推广。     

A double-blind, randomized, placebo-controlled trial of itraconazole capsules as antifungal prophylaxis for neutropenic patients.

To evaluate the efficacy of itraconazole capsules in prophylaxis for fungal infections in neutropenic patients, we conducted a prospective, double-blind, placebo-controlled, randomized trial. Patients with hematologic malignancies or those who received autologous bone marrow transplants were assigned either a regimen of itraconazole (100 mg orally twice daily; n=104) or of placebo (n=106). Overall, fungal infections (superficial or systemic) occurred more frequently in the placebo group (15% vs. 6%; P=.03). There were no differences in the empirical use of amphotericin B or systemic fungal infections. Among patients with neutropenia that was profound (<100 neutrophils/mm3) and prolonged (for at least 7 days), those receiving itraconazole used less empirical amphotericin B (22% vs. 61%; P=.0001) and developed fewer systemic fungal infections (6% vs. 19%; P=.04). For patients with profound and prolonged neutropenia, itraconazole capsules at the dosage of 100 mg every 12 h reduce the frequency of systemic fungal infections and the use of empirical amphotericin B.