高胆固醇血症兔髂外动脉内皮依赖性舒张功能的在体、离体研究

目的 :评价高胆固醇血症 (HC)兔髂外动脉内皮舒张功能 (EDD)在体、离体检测结果是否有一致性 ,证明本实验室新建参数 -充血时间的应用价值。方法 :36只雄性大耳兔随机分 3组 ,每组 1 2只 ,1组为正常兔 ,2组为 HC 2周兔 ,3组为 HC 8周兔 ,分别用高分辨超声 (HRUS)和离体动脉环舒张功能检测方法评价兔髂外动脉EDD功能。结果 :两种方法均发现 HC兔髂外动脉 EDD功能损害 ,结果有良好的相关 (r=0 .95 ,P<0 .0 0 1 ) ;EDD损害随 HC的持续而增强 ;HC兔充血时间较正常兔明显缩短〔 (7.6 1± 4.36 ) min vs (3.2 6± 1 .1 2 ) min,(3.2 0±1 .2 2 ) min,P<0 .0 5 )〕,2、 3组间无明显差异。结论 :HC兔在体 HRUS检测外周动脉 EDD功能可以反映 Ach诱发的 EDD变化 ;充血时间显示 HC兔微循环舒张功能受损。     

Comparison of Pharmacodynamics of Azithromycin and Erythromycin In Vitro and In Vivo

In this study, we determined the efficacy of various dosing regimens for erythromycin and azithromycin against four pneumococci with different susceptibilities to penicillin in an in vitro pharmacokinetic model and in a mouse peritonitis model. The MIC was 0.03 μg/ml, and the 50% effective doses (determined after one dose) of both drugs were comparable for the four pneumococcal strains and were in the range of 1.83 to 6.22 mg/kg. Dosing experiments with mice, using regimens for azithromycin of one to eight doses/6 h, showed the one-dose regimen to give the best result; of the pharmacodynamic parameters tested (the maximum drug concentration in serum [C_max], the times that the drug concentration in serum remained above the MIC and above the concentration required for maximum killing, and the area under the concentration time curve), C_max was the best predictor of outcome. The bacterial counts in mouse blood or peritoneal fluid during the first 24 h after challenge were not correlated to survival of the mice. The serum concentration profiles obtained with mice for the different dosing regimens were simulated in the in vitro pharmacokinetic model. Here as well, the one-dose regimen of azithromycin showed the best result. However, the killing curves in vivo in mouse blood and peritoneal fluid and in the vitro pharmacokinetic model were not similar. The in vitro killing curves showed a decrease of 2 log₁₀ within 2 and 3 h for azithromycin and erythromycin, respectively, whereas the in vivo killing curves showed a bacteriostatic effect for both drugs. It is concluded that the results in terms of predictive pharmacodynamic parameters are comparable for the in vitro and in vivo models and that high initial concentrations of azithromycin favor a good outcome.     

Ceftobiprole Efficacy In Vitro against Panton-Valentine Leukocidin Production and In Vivo against Community-Associated Methicillin-Resistant Staphylococcus aureus Osteomyelitis in Rabbits

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) can cause osteomyelitis with severe sepsis and/or local complications in which a Panton-Valentine leukocidin (PVL) role is suspected. In vitro sub-MIC antibiotic effects on growth and PVL production by 11 PVL⁺ MRSA strains, including the major CA-MRSA clones (USA300, including the LAC strain; USA400; and USA1000), and 11 PVL⁺ methicillin-susceptible S. aureus (MSSA) strains were tested in microplate culture. Time-kill analyses with ceftobiprole at its MIC were also run with LAC. Efficacies of ceftobiprole (40 mg/kg of body weight subcutaneously [s.c.] four times a day [q.i.d.]) or vancomycin (60 mg/kg intramuscularly [i.m.] twice a day [b.i.d.]) alone or combined with rifampin (10 mg/kg b.i.d.) against rabbit CA-MRSA osteomyelitis, induced by tibial injection of 3.4 × 10⁷ CFU of LAC, were compared. Treatment, started 14 days postinoculation, lasted 14 days. In vitro, 6/11 strains cultured with sub-MICs of ceftobiprole produced 1.6- to 4.8-fold more PVL than did the controls, with no link to specific clones. Rifampin decreased PVL production by all tested strains. In time-kill analyses at the LAC MIC (0.75 mg/liter), PVL production rose transiently at 6 and 8 h and then declined 2-fold at 16 h, concomitant with a 2-log₁₀-CFU-count decrease. In vivo, the mean log₁₀ CFU/g of bone for ceftobiprole (1.44 ± 0.40) was significantly lower than that for vancomycin (2.37 ± 1.22) (P = 0.034), with 7/10 versus 5/11 bones sterilized, respectively. Combination with rifampin enhanced ceftobiprole (1.16 ± 0.04 CFU/g of bone [P = 0.056], 11/11 sterile bones) and vancomycin (1.23 ± 0.06 CFU/g [P = 0.011], 11/11 sterile bones) efficacies. Ceftobiprole bactericidal activity and the rifampin anti-PVL effect could play a role in these findings, which should be of interest for treating CA-MRSA osteomyelitis.     

急性早幼粒细胞白血病患者中TCR Vβ T细胞体内外克隆性增殖的比较

为了解急性早幼粒细胞白血病(APL)患者T细胞在体内或体外经诱导后TCR Vβ亚家族的分布和克隆性增殖特点。利用T淋巴细胞液体培养法。在rhIL—2和抗CD3单抗条件下诱导扩增APL患者单个核细胞，并应用RT-PCR分别扩增培养前后患者T细胞的TCR Vβ24个亚家族基因的互补决定区3(CDR3)片段。了解各Vβ亚家族的表达情况；对阳性的PCR产物进一步经荧光素标记和基因扫描分析产物的CDR3长度。了解T细胞克隆性。结果发现，APL患者T细胞仅表达部分Vβ亚家族。但经体外培养后可检测到部分新增TCR Vβ亚家族T细胞。全部患者存在某些。TCR Vβ亚家族的克隆性增殖T细胞。2例患者均出现相似的Vβ1，Vβ3，Vβ7，Vβ16和Vβ20 T细胞的克隆性增殖情况。结论：T细胞的体外培养可诱导某些Vβ亚家族的表达。在T细胞培养不同时间中，呈持续克隆性增殖的TCR Vβ亚家族T细胞可能是患者T细胞对APL白血病细胞相关抗原的特异性免疲应答。     

新西兰白兔两性离子修饰超微超顺磁氧化铁(USPIO)体外弛豫率及动物体内血管成像的研究

目的:评价两性离子修饰超微超顺磁氧化铁(USPIO)在1.5T、3.0T的体外弛豫率及动物体内的血管成像中的效果.方法:USPIO的合成反应在单模微波化学合成仪中进行,并经两性离子进行表面修饰.将各对比剂在纯水溶液中稀释后分别于1.5T及3.0T进行扫描.测量图像信号后计算备对比剂的弛豫率.18只新西兰白兔分为3组,分别在1.5T及3.0T进行血管成像,ZM、SH U 555 C剂量均为40 μmol Fe/kg,Gd-DTPA为0.2 mmol/kg.测算腹主动脉的信噪比及对比噪声比.各个时间点对比剂组间SNR、CNR差异的比较使用方差分析,若差异有统计学意义则进一步使用最小显著差法进行两两比较.结果:1.5T、R1和R2从低到高的顺序为Gd-DTPA、ZM和SHU 555 C;3.0T,其顺序为Gd-DTPA和SHU 555 C、ZM,而两磁场中R2/R1比值由高到低均为SH U 555 C、ZM和Gd-DTPA.1.5T3组对比剂首过成像时信噪比及对比噪声比无显著差异(P=0.258及P=0.314).从15 min开始,ZM组显著优于其余2组.而3.0T前3时相,Gd-DTPA效果较优,ZM成像效果与SHU 555 C相似.从5 min开始,ZM成像效果显著优于其余2组.结论:ZM血浆半衰期长,在1.5T及3.0T弛豫率高,平衡期磁共振血管成像效果显著优于其余2种对比剂.     

In Vitro and In Vivo Antifungal Susceptibilities of the Mucoralean Fungus Cunninghamella

We have determined the in vitro activities of amphotericin B (AMB), voriconazole, posaconazole (PSC), itraconazole (ITC), ravuconazole, terbinafine, and caspofungin against five strains of Cunninghamella bertholletiae and four of Cunninghamella echinulata. The best activity was shown by terbinafine against both species (MIC range = 0.3 to 0.6 μg/ml) and PSC against Cunninghamella bertholletiae (MIC = 0.5 μg/ml). We have also evaluated the efficacies of PSC, ITC, and AMB in neutropenic and diabetic murine models of disseminated infection by Cunninghamella bertholletiae. PSC at 40, 60, or 80 mg/kg of body weight/day was as effective as AMB at 0.8 mg/kg/day in prolonging survival and reducing the fungal tissue burden in neutropenic mice. PSC at 80 mg/kg/day was more effective than AMB at 0.8 mg/kg/day in reducing the fungal load in brain and lung of diabetic mice. Histological studies revealed an absence of fungal elements in organs of mice treated with either AMB at 0.8 mg/kg/day or PSC at 60 or 80 mg/kg/day in both models. ITC showed limited efficacy in both models. PSC could be a therapeutic option for the treatment of systemic infections caused by Cunninghamella bertholletiae.The genus Cunninghamella in the order Mucorales encompasses filamentous fungi that are inhabitants of soil and other environments and are common laboratory contaminants. Cunninghamella bertholletiae is the only member of the genus documented to cause human infections (8), although recently the species C. echinulata was also found in clinical samples (3). Infections caused by Cunninghamella are less frequent than those produced by other genera of Mucorales, e.g., Rhizopus and Mucor, but the mortality rate is higher (76%) (5, 19). In general, infections caused by the members of Mucorales are life-threatening and devastating, requiring prompt and aggressive treatment. There are several simultaneous approaches recommended for patient management, including surgical debridement, antifungal therapy, and correction of the underlying predisposing factors, when possible (5, 20).Amphotericin B (AMB) is the drug of choice, although very few data exist on the activity of this drug against some of the less frequent genera of Mucorales, such as Cunninghamella (1, 2). In a recent study in which a large set of clinical isolates of Mucorales was tested, C. bertholletiae demonstrated the highest resistance to AMB in vitro, with only 63% of the isolates tested showing MIC values under the working interpretative breakpoints described by the CLSI (2, 6). In addition, the failure of AMB therapy has been reported in clinical cases caused by Cunninghamella (4, 15, 18, 19). Posaconazole (PSC) appears to be a promising drug for the treatment of zygomycosis, having been successfully used as salvage therapy for patients who are refractory to or intolerant of AMB (10, 23). PSC is safer than AMB and shows good in vitro activity and in vivo efficacy against some zygomycetes (1, 2, 7, 22). There are only two clinical reports on the use of PSC for the management of Cunninghamella infection (9, 16), and there are no data on the use of this drug in animal models of C. bertholletiae infections. The aim of the present study, therefore, was to evaluate the in vitro activities of seven drugs against isolates of both C. bertholletiae and C. echinulata and to assess the in vivo efficacies of AMB, itraconazole (ITC), and PSC in neutropenic and diabetic murine models of disseminated infection by five strains of C. bertholletiae.     

In Vitro and In Vivo Study of Argyreia speciosa on Chronic Gastric Ulceration and Metabolic Studies

Proceedings of the National Academy of Sciences, India Section B: Biological Sciences - Chronic gastric ulcer being the most prevalent gastrointestinal disorder is considered a major cause of...     

In Vitro and In Vivo Activities of the Novel Anticytomegalovirus Compound AIC246

Human cytomegalovirus (HCMV) remains a serious threat for immunocompromised individuals, including transplant recipients and newborns. To date, all drugs licensed for the treatment of HCMV infection and disease target the viral DNA polymerase. Although these drugs are effective, several drawbacks are associated with their use, including toxicity and emergence of drug resistance. Hence, new and improved antivirals with novel molecular targets are urgently needed. Here we report on the antiviral properties of AIC246, a representative of a novel class of low-molecular-weight compounds that is currently undergoing clinical phase II studies. The anti-HCMV activity of AIC246 was evaluated in vitro and in vivo using various cell culture assays and an engineered mouse xenograft model. In addition, antiviral properties of the drug were characterized in comparison to the current gold standard ganciclovir. We demonstrate that AIC246 exhibits excellent in vitro inhibitory activity against HCMV laboratory strains and clinical isolates, retains activity against ganciclovir-resistant viruses, is well tolerated in different cell types (median selectivity index, 18,000), and exerts a potent in vivo efficacy in a mouse xenograft model. Moreover, we show that the antiviral block induced by AIC246 is reversible and the efficacy of the drug is not significantly affected by cell culture variations such as cell type or multiplicity of infection. Finally, initial mode-of-action analyses reveal that AIC246 targets a process in the viral replication cycle that occurs later than DNA synthesis. Thus, AIC246 acts via a mode of action that differs from that of polymerase inhibitors like ganciclovir.Human cytomegalovirus (HCMV) is a widespread opportunistic pathogen in immunocompromised individuals, including transplant recipients and tumor or AIDS patients, and remains the leading viral cause of birth defects (1, 9, 12, 17, 29). To date, a limited number of drugs are licensed for the systemic treatment of HCMV infection and disease: ganciclovir (GCV) (Cymevene; Roche), its oral prodrug valganciclovir (VGCV) (Valcyte; Roche), cidofovir (CDF) (Vistide; Gilead), and foscarnet (FOS) (Foscavir; Astra-Zeneca). In addition, valaciclovir (VACV) (Valtrex; GlaxoSmithKline), a drug that has been primarily developed for the treatment of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infection, has gained marketing approval in certain countries for prophylaxis of HCMV infections in transplant patients. Although GCV, VGCV, CDF, and FOS are effective, several drawbacks are associated with the use of these drugs, including toxicity, poor oral bioavailability (except VGCV), and emergence of drug resistance (3, 20). The active forms of GCV, CDF, and FOS share the same molecular target, the viral polymerase UL54. Consequently, drug-resistant strains of HCMV encoding UL54 mutations have been found for all three compounds, and the emergence of cross-resistant strains has been described in clinical settings. In addition, resistance to GCV is also associated with mutations in the viral protein kinase UL97 leading to a lack of synthesis of GCV-triphosphate, the active form of the drug (15, 18). Given this, there is an urgent need to develop new, safe, and efficacious antiviral drugs with molecular targets not shared with those currently in use. In line with this, recent attempts to identify novel anti-HCMV compounds mainly concentrated on two promising novel drug targets, the viral terminase complex and the viral protein kinase UL97 (reviewed in references 3, 20, 23, and 24 ). The HCMV terminase complex is a two-subunit enzyme that catalyzes cleavage and packaging of viral DNA (8). Different molecular entities targeting this enzyme have been discovered (e.g., BDCRB, GW275175X, and BAY 38-4766) but so far no “terminase inhibitor” has attained phase II clinical development (reviewed in reference 20). Maribavir, an agent targeting the viral UL97 kinase, an enzyme that is involved in viral DNA synthesis and egress of viral capsids from cell nuclei, was under investigation in phase III clinical trials (20). However, it has been reported that maribavir failed in a recent pivotal phase III study of bone marrow transplant patients who were treated prophylactically. Moreover, since a parallel phase III trial in liver-transplanted patients was stopped, the future of this program is uncertain (34, 35).In our attempt to discover novel anti-HCMV compounds that could potentially yield new therapeutic agents, we identified 3,4-dihydro-quinazoline-4-yl-acetic acid derivatives as a novel class of compounds with anti-HCMV activity by screening a compound library in a high-throughput manner. Hit-to-lead optimization activities, including extensive structure-activity relationship studies and pharmacological analyses (unpublished data), led to the discovery of AIC246 (C₂₉H₂₈F₄N₄O₄) (Fig. ​(Fig.1).1). Due to an excellent preclinical profile with respect to efficacy, safety, tolerability, and pharmacokinetics, AIC246 was chosen as a development candidate out of this new class of anti-HCMV drugs and is currently undergoing phase II evaluations (to be published elsewhere). Here we report on the antiviral properties of AIC246 in vitro and in vivo using different HCMV laboratory strains, different clinical isolates, GCV-resistant viruses, and a mouse xenograft model. Moreover, we monitored the effects of drug removal and of time of drug addition on compound efficacy. Taken together, the studies presented here demonstrate that the novel compound AIC246 exhibits excellent anti-HCMV activity both in vitro and in vivo and suggest that the mode of action of AIC246 differs from that of polymerase inhibitors like GCV.Open in a separate windowFIG. 1.Chemical structure of AIC246.     

Mode of Action of Penicillins In Vivo and In Vitro in Bacillus megaterium

A new system in which the in vivo and in vitro formation of cross-links in the peptidoglycan of Bacillus megaterium can be compared directly has been developed. The method for the determination of the in vivo cross-linking consists of lysozyme digestion of acetylated [¹⁴C]diaminopimelic acid-labeled cells and Bio-Gel P-6 gel filtration of the digest. The elution profile indicates the cell wall synthesized in vivo consists of highly cross-linked fractions (44%), bisdisaccharide peptide(s) (38%), and disaccharide peptide(s) (18%). The in vitro system showed a high synthetic activity of cross-linked peptidoglycan. The synthesis was inhibited completely by 83.3 μg of ristocetin or vancomycin per ml or 10⁻⁴ M p-chloromercuribenzoate and inhibited only partially by penicillins. The polymerization was stimulated by high concentrations of sucrose, glycerol, amino acids, or dimethyl sulfoxide. The formation of cross-links was inhibited 50% at 0.3 μg of dicloxacillin per ml and 90% at 0.5 μg or more. It was also stimulated by high concentrations of sucrose, glycerol, or dimethyl sulfoxide. Effective concentrations of dicloxacillin on the growth, viability, and morphology of B. megaterium were determined. Sharp inhibition of cross-linking occurred in vivo and in vitro at these effective concentrations, whereas the incorporation of [¹⁴C]-diaminopimelate into bacterial cells was not affected at all. Cell-bound dicloxacillin reduced severely the degree of cross-linking in the cell wall synthesized after transfer to a dicloxacillin-free medium. Cell wall synthesized in the presence of dicloxacillin showed a higher rate of turnover than did the normal cell wall. Moreover, disaccharide peptide(s) was degraded faster than was bisdisaccharide peptide(s) in dicloxacillin-treated cells. From these observations, the primary target of penicillin action in B. megaterium is discussed in relation to the inhibition of cross-linking, penicillin-binding components, and cell lysis.     

Clofazimine Inhibits the Growth of Babesia and Theileria Parasites In Vitro and In Vivo

The present study evaluated the growth-inhibitory effects of clofazimine, currently used for treating leprosy, against Babesia bovis, B. bigemina, B. caballi, and Theileria equi in in vitro culture and against Babesia microti in mice. The 50% inhibitory concentrations (IC₅₀s) of clofazimine against the in vitro growth of B. bovis, B. bigemina, B. caballi, and T. equi were 4.5, 3, 4.3, and 0.29 μM, respectively. In mice infected with B. microti, treatment with 20 mg/kg of body weight of clofazimine administered orally resulted in a significantly lower peak parasitemia (5.3%) than that in the control group (45.9%), which was comparable to the subcutaneous administration of 25 mg/kg diminazene aceturate, the most widely used treatment for animal piroplasmosis. Although slight anemia was observed in both clofazimine- and diminazene aceturate-treated infected mice, the level and duration of anemia were lower and shorter, respectively, than those in untreated infected mice. Using blood transfusions and PCR, we also examined whether clofazimine completely killed B. microti. On day 40 postinfection, when blood analysis was performed, parasites were not found in blood smears; however, the DNA of B. microti was detected in the blood of clofazimine-treated animals and in several tissues of clofazimine- and diminazene aceturate-treated mice by PCR. The growth of parasites was observed in mice after blood transfusions from clofazimine-treated mice. In conclusion, clofazimine showed excellent inhibitory effects against Babesia and Theileria in vitro and in vivo, and further study on clofazimine is required for the future development of a novel chemotherapy with high efficacy and safety against animal piroplasmosis and, possibly, human babesiosis.     

Comparison of the In Vivo Pharmacokinetics and In Vitro Dissolution of Raltegravir in HIV Patients Receiving the Drug by Swallowing or by Chewing

The pharmacokinetics of raltegravir (RAL) in HIV patients is characterized by high interpatient/intrapatient variability. We investigated the potential contribution of the drug pharmaceutical formulation to RAL pharmacokinetics. We first compared in vivo the pharmacokinetics of RAL for 67 patients to whom the drug was administered by swallowing the intact tablet with those obtained from 13 HIV-infected patients who chewed the RAL tablet due to swallowing difficulties. Subsequently, we evaluated in vitro the dissolution of RAL tablets under different conditions. In the in vivo study, we found that patients given RAL by chewing the tablets presented pharmacokinetic profiles characterized by significantly higher RAL absorption than did patients receiving the drug by swallowing. The in vitro studies showed that when the whole tablets were exposed to an acidic medium, the release of RAL was very low, whereas when the tablets were crushed, the profiles presented significantly higher concentrations of RAL. Crushed tablets tested in water or in a pH 6.8 buffer exhibited prompt and complete dissolution of RAL. HIV-infected patients receiving RAL by chewing the tablet showed higher drug absorption and reduced pharmacokinetic variability compared with patients swallowing the intact tablet. This is related to problems in tablet disintegration and to erratic drug absorption. The amelioration of the RAL pharmaceutical formulation could improve drug pharmacokinetics.     

Sodium-coupled Taurocholate Transport in the Proximal Convolution of the Rat Kidney In Vivo and In Vitro

Using the standing droplet technique in the renal proximal convolution and simultaneous microperfusion of the peritubular capillaries, the zero net flux transtubular concentration difference of taurocholate (ΔC_TC⁻) at 45 s was determined as a measure of active bile acid reabsorption in vivo. Starting with 0.1 mmol/liter taurocholate in both perfusates the control ΔC_TC⁻ of 0.042 mmol/liter fell to 0.006 mmol/liter (P < 0.001) when the Na⁺ concentration in the perfusates was reduced to zero. Removal of bicarbonate from the perfusates to alter pH had no influence on ΔC_TC⁻. When glycocholate was added to the perfusates ΔC_TC⁻ was decreased, while probenecid increased ΔC_TC⁻.     

In Vitro and In Vivo Efficacy of the Triazole TAK-187 against Cryptococcus neoformans

Multiple isolates of Cryptococcus neoformans, including those with fluconazole resistance, were tested to assess the in vitro activity of the new triazole TAK-187. MICs of TAK-187 were at least eightfold lower than those of fluconazole, and fungicidal concentrations for most isolates were 4 μg/ml or less. TAK-187 also was evaluated as intermittent therapy using two dosages in a rabbit model of experimental cryptococcal meningitis. Compared to daily treatment with fluconazole, as little as two doses of TAK-187 given 7 days apart were found to be effective. Plasma and cerebrospinal fluid TAK-187 concentrations were many times higher than MICs and fungicidal concentrations. Based upon its therapeutic efficacy and long half-life in the rabbit model, TAK-187 should be investigated for intermittent dosing in treatment or suppression of cryptococcal infections in humans.     

In Vitro and In Vivo Activities of the Nitroimidazole TBA-354 against Mycobacterium tuberculosis

Nitroimidazoles are a promising new class of antitubercular agents. The nitroimidazo-oxazole delamanid (OPC-67683, Deltyba) is in phase III trials for the treatment of multidrug-resistant tuberculosis, while the nitroimidazo-oxazine PA-824 is entering phase III for drug-sensitive and drug-resistant tuberculosis. TBA-354 (SN31354[(S)-2-nitro-6-((6-(4-trifluoromethoxy)phenyl)pyridine-3-yl)methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine]) is a pyridine-containing biaryl compound with exceptional efficacy against chronic murine tuberculosis and favorable bioavailability in preliminary rodent studies. It was selected as a potential next-generation antituberculosis nitroimidazole following an extensive medicinal chemistry effort. Here, we further evaluate the pharmacokinetic properties and activity of TBA-354 against Mycobacterium tuberculosis. TBA-354 is narrow spectrum and bactericidal in vitro against replicating and nonreplicating Mycobacterium tuberculosis, with potency similar to that of delamanid and greater than that of PA-824. The addition of serum protein or albumin does not significantly alter this activity. TBA-354 maintains activity against Mycobacterium tuberculosis H37Rv isogenic monoresistant strains and clinical drug-sensitive and drug-resistant isolates. Spontaneous resistant mutants appear at a frequency of 3 × 10⁻⁷. In vitro studies and in vivo studies in mice confirm that TBA-354 has high bioavailability and a long elimination half-life. In vitro studies suggest a low risk of drug-drug interactions. Low-dose aerosol infection models of acute and chronic murine tuberculosis reveal time- and dose-dependent in vivo bactericidal activity that is at least as potent as that of delamanid and more potent than that of PA-824. Its superior potency and pharmacokinetic profile that predicts suitability for once-daily oral dosing suggest that TBA-354 be studied further for its potential as a next-generation nitroimidazole.     

Penetration of Cefazolin, Cephaloridine, and Cefamandole into Interstitial Fluid in Rabbits

We compared the penetration of three cephalosporins into interstitial fluid. Interstitial fluid was obtained in rabbits from Silastic tissue cages. Cefazolin, cephaloridine, and cefamandole were administered by the intramuscular route (30 mg/kg per injection). Peak blood levels and interstitial concentrations were studied after a single injection. Interstitial levels were also compared in a three-injection study (one injection every 12 h) and in a cumulative effect study (six injections), in which the interval between injections was established for each drug on the basis of its common therapeutic use. After a single injection, cephaloridine activity was detected more rapidly and attained higher levels than the other two drugs within the first 4 h. However, 2 h after the third injection, cefazolin levels in tissue fluid were higher than with cephaloridine. Cefamandole consistently gave the lowest interstitial levels. With all three drugs, detectable concentrations were present in interstitial fluid at a time when no detectable antibiotic was found in serum. In the six-injection study, the interstitial levels obtained with cefazolin were significantly higher than those observed with the other drugs. Our data suggest that cefazolin is a drug of choice due to its high extravascular levels.     

In Vitro and In Vivo Efficacy of Amphotericin B Combined with Posaconazole against Experimental Disseminated Sporotrichosis

We evaluated the combination of posaconazole with amphotericin B in vitro and in a murine model of systemic infections caused by Sporothrix brasiliensis and Sporothrix schenckii sensu stricto. In vitro data demonstrated a synergistic effect, and although posaconazole alone was effective against sporotrichosis, efficacy in terms of survival and burden reduction was increased with the combination. This combination might be an option against disseminated sporotrichosis, especially when itraconazole or amphotericin B at optimal doses are contraindicated.     

Studying the Origin of Reverberation Clutter in Echocardiography: In Vitro Experiments and In Vivo Demonstrations

Clutter in echocardiography hinders the visualization of the heart and reduces the diagnostic value of the images. The detailed mechanisms that generate clutter are, however, not well understood. We present five different hypotheses for generation of clutter based on reverberation artifact with a focus on apical four-chamber view echocardiograms. We demonstrate the plausibility of our hypotheses by in vitro experiments and by comparing the results with in vivo recordings from four volunteers. The results show that clutter in echocardiography can be originated both at structures that lie in the ultrasound beam path and at those that are outside the imaging plane. We show that reverberations from echogenic structures outside the imaging plane can make clutter over the image if the ultrasound beam gets deflected out of its intended path by specular reflection at the ribs. Different clutter types in the in vivo examples show that the appearance of clutter varies, depending on the tissue from which it originates. The results of this work can be applied to improve clutter reduction techniques or to design ultrasound transducers that give higher quality cardiac images. The results can also help cardiologists have a better understanding of clutter in echocardiograms and acquire better images based on the type and the source of the clutter.