KBP-7072 is a semi-synthetic aminomethylcycline with broad-spectrum activity against Gram-positive and Gram-negative pathogens including multidrug resistant bacterial strains. The pharmacokinetics (PK) of KBP-7072 after oral and intravenous (IV) administration of single and multiple doses were investigated in animal models including during fed and fasted states and also evaluated the protein binding and excretion characteristics. In Sprague-Dawley (SD) rats, Beagle dogs, and CD-1 mice, KBP-7072 demonstrated a linear PK profile after administration of single oral and IV and multiple oral doses. Oral bioavailability ranged from 12% to 32%. Mean T_max ranged from 0.5 to 4 hours, and mean half-life ranged from approximately 6 to 11 hours. Administration of oral doses in the fed state resulted in a marked reduction in C_max and AUC compared with dosing in fasted animals. The mean bound fractions of KBP-7072 were 77.5%, 69.8%, 64.5%, 69.3%, and 69.2% in mouse, rat, dog, monkey, and human plasma, respectively. Following a single 22.5 mg/kg oral dose of KBP-7072 in SD rats, cumulative excretion in feces was 64% and in urine was 2.5% of the administered dose. The PK results in animal models are consistent with single and multiple ascending dose studies in healthy volunteers and confirm the suitability of KBP-7072 for once daily oral and IV administration in clinical studies.

In vitro and in vivo interactions of minocycline and azoles including itraconazole, voriconazole, and posaconazole against filamentous pathogenic fungi were investigated. A total of 56 clinical isolates were studied in vitro via broth microdilution checkerboard technique, including 20 strains of Aspergillus fumigatus, 7 strains of A. flavus, 16 strains of Exophiala dermatitidis, 10 strains of Fusarium solani and 3 strain s of F. oxysporum. The results revealed that minocycline individually did not exhibit any significant antifungal activity against all tested strains. However, favorable synergy of minocycline with itraconazole, voriconazole, or posaconazole were observed against 34 (61%), 28 (50%), and 38 (69%) isolates, respectively, including azole resistant A. fumigatus and Fusarium spp. with inherently high MICs of azoles. Synergistic combinations resulted in 4 fold to 16-fold reduction of effective MICs of minocycline and azoles. No antagonism was observed. In vivo effect of minocycline-azole combinations were evaluated by survival assay in Galleria mellonella model infected with E. dermatitidis strain BMU00034, F. solani strain FS9, A. fumigatus strain AF293, AFR1 and AFR2 . Minocycline acted synergistically with azoles and significantly increased larvae survival in all isolates (P<0.001), including azole resistant A. fumigatus and azole-inactive Fusarium spp.. In conclusion, the results suggested that minocycline combined with azoles may help to enhance the antifungal susceptibilities of azoles against pathogenic fungi and had the potential to overcome azole resistance issues.

Omadacycline is a novel aminomethylcycline with activity against Gram-positive and -negative organisms, including Haemophilus influenzae, which is one of the leading causes of community-acquired bacterial pneumonia (CABP). The evaluation of antimicrobial agents against H. influenzae using standard murine infection models is challenging due to the low pathogenicity of this species in mice. Therefore, 24-hour dose-ranging studies using a one-compartment in vitro infection model were undertaken with the goal of characterizing the magnitude of the ratio of the area under the concentration-time curve (AUC) to the MIC (AUC/MIC ratio) associated with efficacy for a panel of five clinical H. influenzae isolates. These five isolates, which had MIC values of 1 or 2 mg/L, were exposed to omadacycline total-drug epithelial lining fluid (ELF) concentration-time profiles based on those observed in healthy volunteers following intravenous omadacycline administration. Relationships between change in log₁₀ colony forming units (CFU) from baseline at 24 hours and total-drug ELF AUC/MIC ratio for each isolate and the isolates pooled together were evaluated using Hill-type models and non-linear least squares regression. As evidenced by the high coefficient of determination (r²) of 0.88 to 0.98, total-drug ELF AUC/MIC ratio described the data well for each isolate and the isolates pooled together. The median total-drug ELF AUC/MIC ratio associated with net bacterial stasis and 1- and 2-log₁₀ CFU/mL reductions from baseline at 24 hours was 6.91, 8.91, and 11.1, respectively. These data were useful to support the omadacycline dosing regimens selected for the treatment of patients with CABP, as well as susceptibility breakpoints for H. influenzae.

Omadacycline, a novel aminomethylcycline antibiotic with activity against Gram-positive and -negative organisms, including tetracycline-resistant pathogens, received FDA approval in October, 2018 for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). A previously-developed population pharmacokinetic (PK) model based on Phase 1 intravenous and oral PK data was refined using data from infected patients. Data from 10 Phase 1 studies used to develop the previous model were pooled with data from three additional Phase 1 studies, a Phase 1b uncomplicated urinary tract infection study, one Phase 3 CABP study, and two Phase 3 ABSSSI studies. The final population PK model was a three-compartment model with first-order absorption using transit compartments to account for absorption delay following oral dosing and first-order elimination. Epithelial lining fluid (ELF) concentrations were modeled as a sub-compartment of the first peripheral compartment. A food effect on oral bioavailability was included in the model. Sex was the only significant covariate identified, with 15.6% lower clearance for females relative to males. Goodness-of-fit diagnostics indicated a precise and unbiased fit to the data. The final model, which was robust in its ability to predict plasma and ELF exposures following omadacycline administration, was also able to predict the central tendency and variability in concentration-time profiles using an external Phase 3 ABSSSI dataset. A population PK model, which described omadacycline PK in healthy subjects and infected patients, was developed and subsequently used to support pharmacokinetic-pharmacodynamic (PK-PD) and PK-PD target attainment assessments.

Cyclophilins play a key role in the lifecycle of coronaviruses. Alisporivir (Debio 025) is a non-immunosuppressive analogue of cyclosporin A with potent cyclophilin inhibition properties. Alisporivir reduced SARS-CoV-2 RNA production in a dose-dependent manner in VeroE6 cell line, with an EC₅₀ of 0.46±0.04 μM. Alisporivir inhibited a post-entry step of the SARS-CoV-2 lifecycle. These results justify that a proof-of-concept Phase 2 trial be rapidly conducted with alisporivir in patients with SARS-CoV-2 infection.

Winners to qualify automatically for UEFA Champions League while commercial rights are fully centralised from group stage

One girl’s dream comes true, as she is now able to go to a village primary school, started by OM.

Massive distribution efforts by OM teams in Bangladesh over more than 10 years sowed gospel seeds and made the Bengali New Testament a #1 best seller.

Today, OM Germany Field Leader Tobias Schultz sets off on a 14-day bicycle tour through Germany, visiting OM teams in Hamburg, Halle/Saale and Heilbronn.

Governor Jack Markell, DNREC Secretary Collin O’Mara and Delaware Department of Agriculture Secretary Ed Kee joined Delmarva Wellnet Foundation-EDEN Delmarva members to celebrate the success of the foundation’s food recycling project REPLENISH.

Revolt RV 400 has finally been launched in India. With features like smartphone connectivity and multiple exhaust sounds, the RV 400 is definitely in a segment of its own. But what is an electric motorcycle to ride like? How does it compare with conventional motorcycles? Abhilasha Singh test rode the RV 400 to answer these […]

Denmark has come up with a route which is only dedicated to the cycle riders. The government is keen on promoting cycling as a major mode of transportation. It will ensure that the level of pollution is bought down and also a livelier and healthier environment…

'New type of analysis' deployed to determine plastics' toxicity

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EICMA 2019 is running in full swing and the past few hours have seen the unveiling of some of the most exciting and awaited motorcycles on the planet. Here we have picked the top five that will be launched in India in the coming months.

Hello,

Would anyone know how to setup a PSS or QPSS simulation with 25% dutycycle clock sources or if such a thing is possible with QPSS.

Fig1 (below) is a snapshot of the circuit I am trying to characterize. This has 4 clock ports each with 25%duty cycle in the ON state. Fig2 below shows two of these clocks.

Each path in the circuit consists of two switches with a low pass RC sandwiched in between. The Input is a 50Ohm port sine wave and the output is a 1K resistor. The output nets of all paths are connected together.

I am trying to determine the swept frequency response from input to output (voltage) when the input is from 500Mhz to  510MHz. The Period (T=1/Fp) of each of the pulses is such that Fp=500MHz. The first pulse source has a delay=0, second has delay=T/4, third delay=2T/4, etc...

I am currently getting it working and seeing the correct result (bandpass response) with Transient but the problem is doing a dft at 500MHz with 10KHz spacings needs at least 100us and takes up a lot of time and disk space.

Many Thanks,
Chris.

Fig1

Fig2

Several reports this week agree that cleantech investments fell in 2013, but that's not a bad thing. And the big question is what happens next: how much more is needed?

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While today's smartphones are loaded with Google Maps or Apple Maps, they are merely quick solutions for traveling short distances. Believe it or not, getting a dedicated GPS device for your car or truck is still the best way to get to your destination safely and with ease. 

Companies like Garmin and TomTom specialize in safe car travel and update their maps and traffic reports whenever changes occur on the road. GPS devices also offer the peace of mind that you'll never get lost, even when you're in a new location — including remote areas. They can also help you find the nearest restaurants, shopping mall, rest area, and other locations that might be considered off-the-beaten-path.  Read more...

Halfway through his 30-minute bike ride to work, police ordered Juan Pasamar to dismount, accusing him of breaking Spain’s coronavirus lockdown rules by exercising in public.

By Chimaobi Nwaiwu – Nnewi The Anambra State Commissioner for Transport, Dr. Christian Madubuko has warned Commercial Tricycle Owners and Riders Welfare Association of Anambra State, CTORWAAS, and their alleged paid agents to desist from peddling false allegations against his Ministry or face the wrath of the law. Dr. Madubuko also warned CTORWAAS, its Chairman,
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The post Anambra Commissioner warns tricycle operators against peddling falsehood appeared first on Vanguard News.

Narrated by Zhang Minghong I walked into the studio of the Beijing TV on October 30, 2019 and participated in the recording of a TV program to talk about my life after retirement from the Chinese military over 30 years ago. In fact, I am a very ordinary Chinese veteran. I have been retired from the Chinese People's Liberation Army (PLA) for nearly 30 years and have been earning a living by loading and unloading and riding a tricycle in Ya'an, a city in the western part of China's Sichuan Province. During this time, I haven't done anything incredible. I think the reason why the TV station invited me to participate in the show has to do with the belief that I have persisted for so many years....

U. K. transport secretary Grant Shapps has announced emergency funding to enable local authorities to pay for “pop-up” cycling and walking infrastructure to enable physical distancing during lockdown. ......

Since tea cultivation began around 800 years ago in what’s now Shizuoka Prefecture, it has been renowned as Japan’s largest tea-producing region. Benefitea repackages the ...

Ryo Saegusa started the Kotaki Rice & Future Project in 2015 to promote and sell the rice lovingly cultivated by Kotaki’s farmers. Today, it’s marketed ...

The 39 year old man was taken to hospital, where he was certified as suffering from grievous injuries 

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Trinidad and Tobago loves its "heights" -- and a skilful cyclist on a homemade bike that reaches 10-12 feet in height does not disappoint.

Grant agreements outline the terms of an agreement for a grant. This document dated 7 May 2020 is provided for the ADB project 54229-001 in Fiji.

ADB today announced a $400,000 grant to the Government of Fiji to help fund priority recovery activities following Tropical Cyclone Harold, which hit Fiji's western, central, and eastern divisions on 8 and 9 April.

ADB today approved a $200,000 (460,000 pa’anga) grant to the Government of Tonga to help restore life-sustaining services following the damage from Tropical Cyclone Harold.