Tuberculosis drugs' distribution and emergence of resistance in patient's lung lesions: A mechanistic model and tool for regimen and dose optimization.

BACKGROUND: The sites of mycobacterial infection in the lungs of tuberculosis (TB) patients have complex structures and poor vascularization, which obstructs drug distribution to these hard-to-reach and hard-to-treat disease sites, further leading to suboptimal drug concentrations, resulting in compromised TB treatment response and resistance development. Quantifying lesion-specific drug uptake and pharmacokinetics (PKs) in TB patients is necessary to optimize treatment regimens at all infection sites, to identify patients at risk, to improve existing regimens, and to advance development of novel regimens. Using drug-level data in plasma and from 9 distinct pulmonary lesion types (vascular, avascular, and mixed) obtained from 15 hard-to-treat TB patients who failed TB treatments and therefore underwent lung resection surgery, we quantified the distribution and the penetration of 7 major TB drugs at these sites, and we provide novel tools for treatment optimization. METHODS AND FINDINGS: A total of 329 plasma- and 1,362 tissue-specific drug concentrations from 9 distinct lung lesion types were obtained according to optimal PK sampling schema from 15 patients (10 men, 5 women, aged 23 to 58) undergoing lung resection surgery (clinical study NCT00816426 performed in South Korea between 9 June 2010 and 24 June 2014). Seven major TB drugs (rifampin [RIF], isoniazid [INH], linezolid [LZD], moxifloxacin [MFX], clofazimine [CFZ], pyrazinamide [PZA], and kanamycin [KAN]) were quantified. We developed and evaluated a site-of-action mechanistic PK model using nonlinear mixed effects methodology. We quantified population- and patient-specific lesion/plasma ratios (RPLs), dynamics, and variability of drug uptake into each lesion for each drug. CFZ and MFX had higher drug exposures in lesions compared to plasma (median RPL 2.37, range across lesions 1.26-22.03); RIF, PZA, and LZD showed moderate yet suboptimal lesion penetration (median RPL 0.61, range 0.21-2.4), while INH and KAN showed poor tissue penetration (median RPL 0.4, range 0.03-0.73). Stochastic PK/pharmacodynamic (PD) simulations were carried out to evaluate current regimen combinations and dosing guidelines in distinct patient strata. Patients receiving standard doses of RIF and INH, who are of the lower range of exposure distribution, spent substantial periods (>12 h/d) below effective concentrations in hard-to-treat lesions, such as caseous lesions and cavities. Standard doses of INH (300 mg) and KAN (1,000 mg) did not reach therapeutic thresholds in most lesions for a majority of the population. Drugs and doses that did reach target exposure in most subjects include 400 mg MFX and 100 mg CFZ. Patients with cavitary lesions, irrespective of drug choice, have an increased likelihood of subtherapeutic concentrations, leading to a higher risk of resistance acquisition while on treatment. A limitation of this study was the small sample size of 15 patients, performed in a unique study population of TB patients who failed treatment and underwent lung resection surgery. These results still need further exploration and validation in larger and more diverse cohorts. CONCLUSIONS: Our results suggest that the ability to reach and maintain therapeutic concentrations is both lesion and drug specific, indicating that stratifying patients based on disease extent, lesion types, and individual drug-susceptibility profiles may eventually be useful for guiding the selection of patient-tailored drug regimens and may lead to improved TB treatment outcomes. We provide a web-based tool to further explore this model and results at http://saviclab.org/tb-lesion/.

Predicting the Outcomes of New Short-Course Regimens for Multidrug-Resistant Tuberculosis Using Intrahost and Pharmacokinetic-Pharmacodynamic Modeling.

Short-course regimens for multidrug-resistant tuberculosis (MDR-TB) are urgently needed. Limited data suggest that the new drug bedaquiline (BDQ) may have the potential to shorten MDR-TB treatment to less than 6 months when used in conjunction with standard anti-TB drugs. However, the feasibility of BDQ in shortening MDR-TB treatment duration remains to be established. Mathematical modeling provides a platform to investigate different treatment regimens and predict their efficacy. We developed a mathematical model to capture the immune response to TB inside a human host environment. This model was then combined with a pharmacokinetic-pharmacodynamic model to simulate various short-course BDQ-containing regimens. Our modeling suggests that BDQ could reduce MDR-TB treatment duration to just 18 weeks (4 months) while still maintaining a very high treatment success rate (100% for daily BDQ for 2 weeks, or 95% for daily BDQ for 1 week during the intensive phase). The estimated time to bacterial clearance of these regimens ranges from 27 to 33 days. Our findings provide the justification for empirical evaluation of short-course BDQ-containing regimens. If short-course BDQ-containing regimens are found to improve outcomes, then we anticipate clear cost savings and a subsequent improvement in the efficiency of national TB programs.

Effect of lidocaine on kanamycin injection-site pain in patients with multidrug-resistant tuberculosis.

SETTING: Reducing pain from intramuscular injection of kanamycin (KM) could improve the tolerability of multidrug-resistant tuberculosis (MDR-TB) treatment. Lidocaine has been shown to be an effective anaesthetic diluent for some intramuscular injections, but has not been investigated with KM in the treatment of adult patients with MDR-TB. OBJECTIVE AND DESIGN: We performed a randomised single-blinded crossover study to determine if lidocaine reduces KM injection-site pain. We recruited patients aged 18 years on MDR-TB treatment at two TB hospitals in Cape Town, South Africa. KM pharmacokinetic parameters and a validated numeric pain scale were used at intervals over 10 h following the injection of KM with and without lidocaine on two separate occasions. RESULTS: Twenty participants completed the study: 11 were males, the median age was 36 years, 11 were HIV-infected, and the median body mass index was 17.5 kg/m2. The highest pain scores occurred early, and the median pain score was 0 by 30 min. The use of lidocaine with KM significantly reduced pain at the time of injection and 15 min post-dose. On multiple regression analysis, lidocaine halved pain scores (adjusted OR 0.5, 95%CI 0.3-0.9). The area under the curve at 0-10 h of KM with and without lidocaine was respectively 147.7 and 143.6 µg·h/ml. CONCLUSION: Lidocaine significantly reduces early injection-site pain and has no effect on KM pharmacokinetics.

How kanamycin A interacts with bacterial and mammalian mimetic membranes.

Biological membranes are natural barriers to the transport of molecules and drugs within human bodies. Many antibacterial agents need to cross these membranes to reach their target and elicit specific effects. Kanamycin A belongs to the family of aminoglycoside antibiotics that target cellular RNA to inhibit bacterial and viral replication. Previous studies have shown that aminoglycosides bind to mammalian but disrupt bacterial membranes. In this study, molecular dynamics (MD) simulations and infrared (IR) spectroscopy were applied to investigate the initial, first key interactions of kanamycin A, as a representative aminoglycoside, with both bacterial and mammalian lipid bilayers at the molecular level. Computational studies revealed strong hydrogen bonding interactions between the hydroxyl and amino groups of the aminoglycoside with the ester carbonyl and phosphate groups of the lipids. IR spectroscopy provided experimental verification of the important role of the lipid's ester carbonyl, phosphate and hydroxyl groups for aminoglycoside binding. The bacterial membrane became disordered upon aminoglycoside addition, whereas the mammalian membrane became stiffer and more ordered. This indicates the bacterial membrane disruption observed by previous studies.

Reduced Chance of Hearing Loss Associated with Therapeutic Drug Monitoring of Aminoglycosides in the Treatment of Multidrug-Resistant Tuberculosis.

Hearing loss and nephrotoxicity are associated with prolonged treatment duration and higher dosage of amikacin and kanamycin. In our tuberculosis center, we used therapeutic drug monitoring (TDM) targeting preset pharmacokinetic/pharmacodynamic (PK/PD) surrogate endpoints in an attempt to maintain efficacy while preventing (oto)toxicity. To evaluate this strategy, we retrospectively evaluated medical charts of tuberculosis (TB) patients treated with amikacin or kanamycin in the period from 2000 to 2012. Patients with culture-confirmed multiresistant or extensively drug-resistant tuberculosis (MDR/XDR-TB) receiving amikacin or kanamycin as part of their TB treatment for at least 3 days were eligible for inclusion in this retrospective study. Clinical data, including maximum concentration (Cmax), Cmin, and audiometry data, were extracted from the patients' medical charts. A total of 80 patients met the inclusion criteria. The mean weighted Cmax/MIC ratios obtained from 57 patients were 31.2 for amikacin and 12.3 for kanamycin. The extent of hearing loss was limited and correlated with the cumulative drug dose per kg of body weight during daily administration. At follow-up, 35 (67.3%) of all patients had successful outcome; there were no relapses. At a median dose of 6.5 mg/kg, a correlation was found between the dose per kg of body weight during daily dosing and the extent of hearing loss in dB at 8,000 Hz. These findings suggest that the efficacy at this lower dosage is maintained with limited toxicity. A randomized controlled trial should provide final proof of the safety and efficacy of TDM-guided use of aminoglycosides in MDR-TB treatment.

Comparative study of kanamycin sulphate microparticles and nanoparticles for intramuscular administration: preparation in vitro release and preliminary in vivo evaluation.

Kanamycin sulphate (KS) is a Mycobacterium tuberculosis protein synthesis inhibitor. KS is polycationic, a property responsible for KS poor oral absorption half-life (2.5 h) and rapid renal clearance, which results in serious nephrotoxicity/ototoxicity. The current study aimed to develop KS-loaded PLGA vitamin-E-TPGS microparticles (MPs) and nanoparticles (NPs) to reduce the dosing frequency and dose-related adverse effect. In vitro release was sustained up to 10 days for KS PLGA-TPGS MPs and 13 days for KS PLGA-TPGS NPs in phosphate-buffered saline (PBS) pH 7.4. The in vivo pharmacokinetic test in Wistar rats showed that the AUC0-∞ of KS PLGA-TPGS NPs (280.58 µg/mL*min) was about 1.62-fold higher than that of KS PLGA-TPGS MPs (172.30 µg/mL*min). Further, in vivo protein-binding assay ascribed 1.20-fold increase in the uptake of KS PLGA-TPGS NPs through the alveolar macrophage (AM). The studies, therefore, could provide another useful tool for successful development of KS MPs and NPs.

Hydraphiles enhance antimicrobial potency against Escherichia coli, Pseudomonas aeruginosa, and Bacillus subtilis.

Hydraphiles are synthetic amphiphiles that form ion-conducting pores in liposomal membranes. These pores exhibit open-close behavior when studied by planar bilayer conductance techniques. In previous work, we showed that when co-administered with various antibiotics to the DH5α strain of Escherichia coli, they enhanced the drug's potency. We report here potency enhancements at low concentrations of hydraphiles for the structurally and mechanistically unrelated antibiotics erythromycin, kanamycin, rifampicin, and tetracycline against Gram negative E. coli (DH5α and K-12) and Pseudomonas aeruginosa, as well as Gram positive Bacillus subtilis. Earlier work suggested that potency increases correlated to ion transport function. The data presented here comport with the function of hydraphiles to enhance membrane permeability in addition to, or instead of, their known function as ion conductors.

Synthesis, characterization and in vitro evaluation of amphiphilic ion pairs of erythromycin and kanamycin antibiotics with liposaccharides.

The hydrophilic ion paring strategy (HIP) is a method explored to improve the cell/tissue uptake of poorly adsorbed drugs and to optimize their physico-chemical characteristics. In this context, we here describe the synthesis of some ion pairs of two model cationic antibiotics, erythromycin (ERY) and kanamycin A (KAN), with liposaccharides having different levels of lipophilicity and charge. The formation of drug-liposaccharide complexes was confirmed by Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) analysis. The effect of the amphiphilic liposaccharide moieties on the antimicrobial activity of ERY and KAN was assessed by measuring the minimal inhibitory concentration (MIC) of the compounds against a panel of bacterial strains that were susceptible or resistant to the parent antibiotics. The ion pairing did not depress the in vitro antibiotic activity, although no lowering of MIC values was registered. The experimental findings would motivate the future investigation of this ion pairing strategy in drug design, for instance allowing improvement of the encapsulation efficiency of hydrophilic antibiotics in lipid-based nanocarriers, or changing their in vivo biodistribution and pharmacokinetic profile.

Limited sampling strategies for therapeutic drug monitoring of amikacin and kanamycin in patients with multidrug-resistant tuberculosis.

Amikacin and kanamycin are considered important and effective drugs in the treatment of multidrug-resistant tuberculosis (MDR-TB). Unfortunately, the incidence of toxicity is high and is related to elevated drug exposure. In order to achieve a balance between efficacy and toxicity, a population pharmacokinetic (PPK) model may help to optimise drug exposure. Patients with MDR-TB who had received amikacin or kanamycin as part of their treatment and who had routinely received therapeutic drug monitoring were evaluated. A PPK model was developed and subsequently validated. Using this model, a limited sampling model was developed. Eleven patients receiving amikacin and nine patients receiving kanamycin were included in this study. The median observed 24-h area under the concentration-time curve (AUC0-24h) was 77.2 mg h/L [interquartile range (IQR) 64.7-96.2 mg h/L] for amikacin and 64.1 mg h/L (IQR 55.6-92.1 mg h/L) for kanamycin. The PPK model was developed and validated using n-1 cross-validation. A robust population model was developed that is suitable for predicting the AUC0-24h of amikacin and kanamycin. This model, in combination with the limited sampling strategy developed, can be used in daily routine to guide dosing but also to assess AUC0-24h in phase 3 studies.

Pharmacokinetics of Second-Line Antituberculosis Drugs after Multiple Administrations in Healthy Volunteers.

Therapeutic drug monitoring (TDM) of second-line antituberculosis drugs would allow for optimal individualized dosage adjustments and improve drug safety and therapeutic outcomes. To evaluate the pharmacokinetic (PK) characteristics of clinically relevant, multidrug treatment regimens and to improve the feasibility of TDM, we conducted an open-label, multiple-dosing study with 16 healthy subjects who were divided into two groups. Cycloserine (250 mg), p-aminosalicylic acid (PAS) (5.28 g), and prothionamide (250 mg) twice daily and pyrazinamide (1,500 mg) once daily were administered to both groups. Additionally, levofloxacin (750 mg) and streptomycin (1 g) once daily were administered to group 1 and moxifloxacin (400 mg) and kanamycin (1 g) once daily were administered to group 2. Blood samples for PK analysis were collected up to 24 h following the 5 days of drug administration. The PK parameters, including the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve during a dosing interval at steady state (AUCτ), were evaluated. The correlations between the PK parameters and the concentrations at each time point were analyzed. The mean Cmax and AUCτ, respectively, for each drug were as follows: cycloserine, 24.9 mg/liter and 242.3 mg · h/liter; PAS, 65.9 mg/liter and 326.5 mg · h/liter; prothionamide, 5.3 mg/liter and 22.1 mg · h/liter; levofloxacin, 6.6 mg/liter and 64.4 mg · h/liter; moxifloxacin, 4.7 mg/liter and 54.2 mg · h/liter; streptomycin, 42.0 mg/liter and 196.7 mg · h/liter; kanamycin, 34.5 mg/liter and 153.5 mg · h/liter. The results indicated that sampling at 1, 2.5, and 6 h postdosing is needed for TDM when all seven drugs are administered concomitantly. This study indicates that PK characteristics must be considered when prescribing optimal treatments for patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT02128308.).

Plasma drug activity in patients on treatment for multidrug-resistant tuberculosis.

Little is known about plasma drug concentrations relative to quantitative susceptibility in patients with multidrug-resistant tuberculosis (MDR-TB). We previously described a TB drug activity (TDA) assay that determines the ratio of the time to detection of plasma-cocultured Mycobacterium tuberculosis versus control growth in a Bactec MGIT system. Here, we assess the activity of individual drugs in a typical MDR-TB regimen using the TDA assay. We also examined the relationship of the TDA to the drug concentration at 2 h (C2) and the MICs among adults on a MDR-TB regimen in Tanzania. These parameters were also compared to the treatment outcome of sputum culture conversion. Individually, moxifloxacin yielded superior TDA results versus ofloxacin, and only moxifloxacin and amikacin yielded TDAs equivalent to a -2-log killing. In the 25 patients enrolled on a regimen of kanamycin, levofloxacin, ethionamide, pyrazinamide, and cycloserine, the C2 values were found to be below the expected range for levofloxacin in 13 (52%) and kanamycin in 10 (40%). Three subjects with the lowest TDA result (<1.5, a finding indicative of poor killing) had significantly lower kanamycin C2/MIC ratios than subjects with a TDA of ≥1.5 (9.8 ± 8.7 versus 27.0 ± 19.1; P = 0.04). The mean TDAs were 2.52 ± 0.76 in subjects converting to negative in ≤2 months and 1.88 ± 0.57 in subjects converting to negative in >2 months (P = 0.08). In Tanzania, MDR-TB drug concentrations were frequently low, and a wide concentration/MIC range was observed that affected plasma drug activity ex vivo. An opportunity exists for pharmacokinetic optimization in current MDR-TB regimens, which may improve treatment response.

Real-time, aptamer-based tracking of circulating therapeutic agents in living animals.

A sensor capable of continuously measuring specific molecules in the bloodstream in vivo would give clinicians a valuable window into patients' health and their response to therapeutics. Such technology would enable truly personalized medicine, wherein therapeutic agents could be tailored with optimal doses for each patient to maximize efficacy and minimize side effects. Unfortunately, continuous, real-time measurement is currently only possible for a handful of targets, such as glucose, lactose, and oxygen, and the few existing platforms for continuous measurement are not generalizable for the monitoring of other analytes, such as small-molecule therapeutics. In response, we have developed a real-time biosensor capable of continuously tracking a wide range of circulating drugs in living subjects. Our microfluidic electrochemical detector for in vivo continuous monitoring (MEDIC) requires no exogenous reagents, operates at room temperature, and can be reconfigured to measure different target molecules by exchanging probes in a modular manner. To demonstrate the system's versatility, we measured therapeutic in vivo concentrations of doxorubicin (a chemotherapeutic) and kanamycin (an antibiotic) in live rats and in human whole blood for several hours with high sensitivity and specificity at subminute temporal resolution. We show that MEDIC can also obtain pharmacokinetic parameters for individual animals in real time. Accordingly, just as continuous glucose monitoring technology is currently revolutionizing diabetes care, we believe that MEDIC could be a powerful enabler for personalized medicine by ensuring delivery of optimal drug doses for individual patients based on direct detection of physiological parameters.

Influencing uptake and localization of aminoglycoside-functionalized peptoids.

The development of small-molecule therapeutics that target RNA remains a promising field but one hampered with considerable challenges that include programming high affinity, specificity, cell permeability, and favorable pharmacokinetic profiles. Previously, we employed the use of peptoids to modularly display RNA-binding modules to enhance binding affinity and specificity by altering valency and the distance between ligand modules. Herein, factors that affect uptake, localization, and toxicity of peptoids that display a kanamycin derivative into a variety of mammalian cells lines are reported. A series of peptoids that display various spacing modules was synthesized to determine if the spacing module affects permeability and localization. The spacing module does affect cellular permeability into C2C12, A549, HeLa, and MCF7 cell lines but not into Jurkat cells. Moreover, the modularly assembled peptoids carrying the kanamycin cargo localize in the cytoplasm and perinuclear region of C2C12 and A549 cells and throughout HeLa cells, including the nucleus. These studies could contribute to the development of general strategies to afford cell permeable, modularly assembled small molecules that specifically target RNAs present in a variety of cell types.

Development and characterization of a transdermal patch and an emulgel containing kanamycin intended to be used in the treatment of mycetoma caused by Actinomadura madurae.

BACKGROUND: Mycetoma is a chronic, degenerative, and incapacitating infection of the skin and subcutaneous tissue. AIM: This study focuses on developing a kanamycin-based auxiliary system intended to be used in the treatment of mycetoma caused by Actinomadura madurae. METHODS: Transdermal patches (with two different formulations: one with free kanamycin [K] and the other one with kanamycin adsorbed in silica [K-SG]) and an emulgel were developed. Both patches were prepared by the casting-evaporation technique. To characterize them, differential scanning calorimetry, bioadhesion, post-moisture detachment, strength and rupture distance, gas exchange, water uptake, and dissolution studies were carried out. The emulgel (containing 0.57% of kanamycin) was prepared from an oil-in-water emulsion, which was then incorporated to a gel. RESULTS: the patches with the best characteristics contained 22.9% of silica and 14.6% of kanamycin. Dissolution studies indicated that 8.8% of kanamycin released from K and 3.2% from K-SG at 24h. The emulgel containing 0.57% of kanamycin showed good technological characteristics for its application to the skin (viscosity, 44.9 +/- 1.4 poises; pH, 6.9 +/- 0.4; and penetrability, 52.7 +/- 5.1). CONCLUSIONS: The optimal patches were those containing 15.9% of freely dispersed kanamycin (K) and 14.6% of kanamycin adsorbed in silica (K-SG), which corresponds to the batch 2-0.8. The assessments performed to both pharmaceutical forms (patches and emulgel) show that they have the adequate technological characteristics for being used as an auxiliary in the treatment of actinomycetoma caused by A. madurae.

LC method for the analysis of kanamycin residue in swine tissues using derivatization with 9-fluorenylmethyl chloroformate.

A sensitive and robust HPLC method was developed for the determination of kanamycin (Kan) in swine tissues. Kan was extracted from tissue with 10% TCA (w/v) solution and cleaned up with MCX SPE column. The purified extract was derivatized with 9-fluorenylmethyl chloroformate, and then separated on a C18 column and detected by a fluorescence detector. The linear range of the calibration curve was 0.025-1 microg/mL with R(2) of 0.9998. The limits of quantification were determined to be 0.1 mg/kg in muscle, 0.2 mg/kg in liver, and 0.6 mg/kg in kidney, and the average recoveries of Kan from swine tissues at different fortification levels (0.1-0.4 mg/kg for muscle, 0.2-1.2 mg/kg for liver, and 0.6-5.0 mg/kg for kidney) ranged from 80.7 to 91.3% with intraday and interday coefficient of variations less than 12.1%. The validated method was successfully applied to determine Kan in incurred samples, indicating that it can be used as a routine tool for the surveillance of Kan residue in swine tissues.

Study of drug transport between the blood and lymph in the predominant direction.

Our method for evaluating the time course and intensity of antibiotics and other drugs transport in the predominant direction between the blood and lymph in humans promotes a more objective evaluation of drug circulation mechanisms, which is essential for determining the time of their repeated administration and route of administration. Calculation of the lymph/blood difference coefficient, based on parallel repeated measurements of the drug concentration in the lymph and blood, and of the lymph/blood coefficient provides complete data on the direction and time course of drug transport between the lymph and blood in the predominant direction.

Efficient Agrobacterium tumefaciens-mediated transformation of Malus zumi (Matsumura) Rehd using leaf explant regeneration system

Malus zumi is known as an excellent dwarfing apple rootstock occurring in natural or arid/semiarid soil or salina. Gene manipulation of M. zumi through transgenic technology can modify plant feature for further improvement fruit tree production by grafting the scion on a transgenic rootstock. Here, we report the establishment of an efficient, in vitro, shoot regeneration system and Agrobacterium tumefaciens- mediated transformation from the leaf explants for Malus zumi (Matsumura) Rehd. Leaf explants were infected with Agrobacterium strains containing nptII and gus gene. The highest frequency of shoot regeneration was obtained on MS medium containing 500 mg l-1 Lactalbumin hydrolysate, 30 g l-1 fructose, supplemented with 3.0 mg l-1 BA, 0.2 mg l-1 NAA.Using fructose instead of sucrose significantly increases the shoot regeneration and decreases vitrification. This regeneration procedure was incorporated into an Agrobacterium-mediated transformation procedure in M. zumi. Kanamycin was an efficient selective agent for selection. Pre-selection (5 days after co-cultivation) improved the transformation efficiency. The emergence of expected bands by PCR analysis and Southern blot in transgenic plantlets confirmed the transformation of foreign DNA into plant genome.

Estudio comparativo de la actividad antibacteriana in vitro de los neumatóforos de Heritiera fomes y Xylocarpus moluccensis / A comparative study on the in vitro antibacterial activity of the pneumatophores of Heritiera fomes and Xylocarpus moluccensis

Se evaluó la actividad antibacteriana in vitro de los extractos de etanol de los neumatóforos de Xylocarpus moluccensis (Familia: Meliaceae) y Heritiera fomes (Familia: Sterculiaceae) frente a diversas cepas bacterianas utilizando el ensayo de difusión en disco. Ambos extractos presentaron perfiles antibacterianos similares, y las zonas de inhibición fueron >10 mm en la mayoría de los casos. Estos extractos presentaron la máxima actividad frente a aerógenos Enterobacter, siendo las zonas de inhibición de 19 y 21 mm, respectivamente. La concentración inhibitoria mínima(CIM) se determinó mediante el método de dilución en caldo de cultivo. El extracto de X. moluccensis fue el más potente frente a Shigella boydii y Shigella sonnie (CIM = 200 y 300 mg/mL, respectivamente). Se puede asumirque X. moluccensis y H. fomes podrían ser fuentes potenciales de nuevos descubrimientos para el desarrollo de fármacos (AU)

The ethanol extracts of the pneumatophores of Xylocarpus moluccensis (Family: Meliaceae) and Heritiera fomes (Family: Sterculiaceae) were assessed for in vitro antibacterial activities against a number of bacterial strains using the disc diffusion assay. Both extracts showed similar antibacterial profiles, and the zones of inhibitions were >10 mm in the most cases. These extracts exhibited the most prominent activity against Enterobacter aerogenes, with the zones of inhibition of 19 and 21 mm, respectively. The minimum inhibitory concentration (MIC) was determined by the broth dilution method. The extract of X. moluccensis was the most potent against Shigella boydii and Shigella sonnie (MIC = 200 and 300 mg/mL, respectively). It can be assumed that that X. moluccensis and H. fomes could be potential sources for novel ‘lead’ discovery for antibacterial drug development (AU)

[Changes in morphofunctional condition of the cochlear vascular stripe in response to the ototoxic antibiotic]. / Izmeneniia morfofunktsional'nogo sostoianiia sosudistoi poloski ulitki pod vliianiem ototoksicheskogo antibiotika.

The experiments were made on guinea pigs injected i.m. kanamycin for 7 and 14 days in a dose 400 mg/kg. The cochleas of the guinea pigs were studied electron microscopically after 7- and 14-day courses of the antibiotic and 30 days after the end of aminoglycoside administration. To assess the vascular stripe (VS) function, the number of secretory vacuoles in apical cytoplasm of the marginal cells on the ultrathin sections was calculated. The animals which had got kanamycin for 7 days exhibited insignificant VS ultrastructural alterations, the number of vacuoles in the marginal cells (38.9 +/- 2.4) was higher than normal (33.9 +/- 1.5) but the difference was insignificant. After 14-day administration of the antibiotic VS of the animals had noticeable ultrastructural disorders of the interstitial and marginal cells and statistically significant (p < 0.01) suppression of secretory activity of the marginal cells (18.6 +/- 1.1). Natural reparative processes normalized ultrastructure of all types of VS cells 30 days after kanamycin discontinuation though secretion in the marginal cells remained significantly subnormal (the number of the vacuoles reduced to 23.4 +/- 1.7). Thus, aminoglycoside antibiotic kanamycin induces morphofunctional disorders in VS cells which do not return to normal after 30 days of follow-up.