In Vitro Release from Polymeric Core/Shell Nanoparticles through the Lens of Multiscale Modeling.

The large number of studies involving nanoparticles for cancer therapy is due to their peculiar features: they protect loaded active molecules while extending circulation time and can extravasate from the blood flow to the tumor to deliver drugs directly in the target area. Mathematical modeling can provide a preliminary in silico exploration of design space to optimize an experimental activity that often relies on a trial-and-error approach. However, because of the characteristic size of these vectors (10-1000 nm), numerous phenomena of interest occur at different time and length scales, making a single modeling technique insufficient to fully characterize the system of interest. In this work we employed a multiscale modeling approach, which bridges the phenomena of interest across different scales, to study the in vitro release from polymeric core/shell nanoparticles for cancer therapy loaded with an active compound assembled as a hydrophobic ion pair. The "computational microscope" provided by molecular dynamics simulations was used to track drug molecules through the release process at an atomic scale. The outcomes suggested that the drug is mainly partitioned in the polymer and released as hydrophobic ion pair rather than a free molecule, and that the hydrophobic ion pair is preferentially partitioned in Tween 20 micelles in the release media. A model at macroscale, aimed at describing the release rate and elucidating the release mechanism, was developed according to the results from molecular simulations and validated against experimental data. The outcomes provided insights that are challenging to be obtained experimentally and which supported the development and validation of a release model at macroscale. Overall, the adopted multiscale approach corroborated the experimental findings and provided significant insights into the mechanisms of release.

SubQ-Sim: A Subcutaneous Physiologically Based Biopharmaceutics Model. Part 1: The Injection and System Parameters.

PURPOSE: To construct a detailed mechanistic and physiologically based biopharmaceutics model capable of predicting 1) device-formulation-tissue interaction during the injection process and 2) binding, degradation, local distribution, diffusion, and drug absorption, following subcutaneous injection. This paper is part of a series and focusses on the first aspect. METHODS: A mathematical model, SubQ-Sim, was developed incorporating the details of the various substructures within the subcutaneous environment together with the calculation of dynamic drug disposition towards the lymph ducts and venous capillaries. Literature was searched to derive key model parameters in healthy and diseased subjects. External factors such as body temperature, exercise, body position, food or stress provide a means to calculate the impact of "life events" on the pharmacokinetics of subcutaneously administered drugs. RESULTS: The model predicts the tissue backpressure time profile during the injection as a function of injection rate, volume injected, solution viscosity, and interstitial fluid viscosity. The shape of the depot and the concentrations of the formulation and proteins in the depot are described. The model enables prediction of formulation backflow following premature needle removal and the resulting formulation losses. Finally, the effect of disease (type 2 diabetes) or the presence of recombinant human hyaluronidase in the formulation on the injection pressure, are explored. CONCLUSIONS: This novel model can successfully predict tissue back pressure, depot dimensions, drug and protein concentration and formulation losses due to incorrect injection, which are all important starting conditions for predicting drug absorption from a subcutaneous dose. The next article will describe the absorption model and validation against clinical data.

Design and optimisation of dendrimer-conjugated Bcl-2/xL inhibitor, AZD0466, with improved therapeutic index for cancer therapy.

Dual Bcl-2/Bcl-xL inhibitors are expected to deliver therapeutic benefit in many haematological and solid malignancies, however, their use is limited by tolerability issues. AZD4320, a potent dual Bcl-2/Bcl-xL inhibitor, has shown good efficacy however had dose limiting cardiovascular toxicity in preclinical species, coupled with challenging physicochemical properties, which prevented its clinical development. Here, we describe the design and development of AZD0466, a drug-dendrimer conjugate, where AZD4320 is chemically conjugated to a PEGylated poly-lysine dendrimer. Mathematical modelling was employed to determine the optimal release rate of the drug from the dendrimer for maximal therapeutic index in terms of preclinical anti-tumour efficacy and cardiovascular tolerability. The optimised candidate is shown to be efficacious and better tolerated in preclinical models compared with AZD4320 alone. The AZD4320-dendrimer conjugate (AZD0466) identified, through mathematical modelling, has resulted in an improved therapeutic index and thus enabled progression of this promising dual Bcl-2/Bcl-xL inhibitor into clinical development.

Evaluation of a multi-agent chemotherapy protocol combining dexamethasone, melphalan, actinomycin D, and cytarabine for the treatment of resistant canine non-Hodgkin high-grade lymphomas: a single centre's experience.

The DMAC protocol (dexamethasone, melphalan, actinomycin-D, cytarabine) has been evaluated in American studies for the treatment of relapsed canine lymphoma, comparing similarly to other rescue protocols. The aim of this study was to evaluate efficacy and toxicity of DMAC, in a larger UK cohort of resistant canine lymphomas. Medical records of dogs with resistant non-Hodgkin high-grade lymphomas that received DMAC as a rescue protocol were reviewed from 2007 to 2017. Response, time from initiation to discontinuation (TTD) and toxicity (Veterinary Cooperative Oncology Group criteria) were assessed. One hundred dogs were included; 86 received CEOP (modified CHOP including epirubicin) as first-line treatment. Thirty-five dogs (35%) responded: 21 complete responders (CRs) and 14 partial responders (PRs). Responders had significantly longer TTD (P < 0.001) compared with non-responders: 62 days (range 28-952) for CR vs 32 days (range 20-70) for PR. Six CR received more than six cycles of DMAC (range 7-36 cycles) and experienced a longer TTD (median 508, range 126-952 days). Thrombocytopenia occurred in 45% (24 grade 1-2, 21 grade 3-4) and neutropenia in 36% of cases (29 grade 1-2, 7 grade 3-4). Gastrointestinal toxicity occurred in 42% of dogs (40 grade 1-2, 2 grade 3-4). Owing to chemotherapy toxicity, treatment was discontinued in five, and hospitalization required in six cases. In this study, response to DMAC was lower and of generally shorter duration than previously reported. Toxicity was high, but infrequently led to hospitalization or discontinuation of treatment.

Nanocrystal formulations of a poorly soluble drug. 1. In vitro characterization of stability, stabilizer adsorption and uptake in liver cells.

In the present work, milled nanocrystals of a poorly soluble compound using different stabilizers were prepared and characterized. The aim of the study was to evaluate a fundamental set of properties of the formulations prior to i.v. injection of the particles. Two polyethylene oxide containing stabilizers; (distearoyl phosphatidylethanol amine (DSPE)) -PEG2000 and the triblock copolymer Pluronic F127, were investigated, with and without polyvinylpyrrolidone K30/Aerosol OT (PVP/AOT) present. The solubility in water was around 10nM for the compound, measured from nanocrystals, but 1000 times higher in 4% human serum albumin. The particles were physically stable during the time investigated. The zeta potential was around -30 and -10mV for DSPE-PEG2000 and Pluronic F127 stabilized particles, respectively, at the conditions selected. The dissolution rate was similar for all four formulations and similar to the theoretically predicted rate. Critical micelle concentrations were determined as 56nM and 1.4µM for DSPE-PEG2000 and Pluronic F127, respectively. The adsorption isotherms for the PEG lipid showed a maximum adsorbed amount of about 1.3mg/m2, with and without PVP/AOT. Pluronic F127 showed a higher maximum amount adsorbed, at around 3.1mg/m2, and marginally lower with PVP/AOT present. Calculated data showed that the layer of Pluronic F127 was thicker than the corresponding DSPE-PEG2000 layer. The total amount of particles distributed mainly to the liver, and the hepatocellular distribution in vitro (Liver sinusoidal endothelial cells and Kupffer cells), differed depending on the stabilizing mixture on the particles. Overall, DSPE-PEG2000 stabilized nanocrystals (with PVP/AOT) accumulated to a larger degree in the liver compared to particles with Pluronic F127 on the surface. A theoretical model was developed to interpret in vivo pharmacokinetic profiles, explaining the balance between dissolution and liver uptake. With the present, fundamental data of the nanocrystal formulations, the platform for forthcoming in vivo studies was settled.

Why is it hard to terminate failing projects in pharmaceutical R&D?

'Quick-kill' strategies in pharmaceutical research and development aim to reduce late-stage attrition by bringing project termination decisions forward, to an earlier point in the process. How can the barriers to implementing such strategies be overcome?

In silico predictions of gastrointestinal drug absorption in pharmaceutical product development: application of the mechanistic absorption model GI-Sim.

Oral drug delivery is the predominant administration route for a major part of the pharmaceutical products used worldwide. Further understanding and improvement of gastrointestinal drug absorption predictions is currently a highly prioritized area of research within the pharmaceutical industry. The fraction absorbed (fabs) of an oral dose after administration of a solid dosage form is a key parameter in the estimation of the in vivo performance of an orally administrated drug formulation. This study discloses an evaluation of the predictive performance of the mechanistic physiologically based absorption model GI-Sim. GI-Sim deploys a compartmental gastrointestinal absorption and transit model as well as algorithms describing permeability, dissolution rate, salt effects, partitioning into micelles, particle and micelle drifting in the aqueous boundary layer, particle growth and amorphous or crystalline precipitation. Twelve APIs with reported or expected absorption limitations in humans, due to permeability, dissolution and/or solubility, were investigated. Predictions of the intestinal absorption for different doses and formulations were performed based on physicochemical and biopharmaceutical properties, such as solubility in buffer and simulated intestinal fluid, molecular weight, pK(a), diffusivity and molecule density, measured or estimated human effective permeability and particle size distribution. The performance of GI-Sim was evaluated by comparing predicted plasma concentration-time profiles along with oral pharmacokinetic parameters originating from clinical studies in healthy individuals. The capability of GI-Sim to correctly predict impact of dose and particle size as well as the in vivo performance of nanoformulations was also investigated. The overall predictive performance of GI-Sim was good as >95% of the predicted pharmacokinetic parameters (C(max) and AUC) were within a 2-fold deviation from the clinical observations and the predicted plasma AUC was within one standard deviation of the observed mean plasma AUC in 74% of the simulations. GI-Sim was also able to correctly capture the trends in dose- and particle size dependent absorption for the study drugs with solubility and dissolution limited absorption, respectively. In addition, GI-Sim was also shown to be able to predict the increase in absorption and plasma exposure achieved with nanoformulations. Based on the results, the performance of GI-Sim was shown to be suitable for early risk assessment as well as to guide decision making in pharmaceutical formulation development.

Diurnal rhythm in British Antarctic personnel.

INTRODUCTION: The diurnal rhythm of saliva cortisol and its association to adaptation, performance and health were examined in personnel over-wintering at two British Antarctic stations. METHODS: In total, 55 healthy individuals (49 males, 6 females) participated in the study. Cortisol in saliva was sampled on 3 consecutive days (at awakening, 15 and 45 min after waking, at 15.00 h, and 22.00 h) immediately after arrival at the station, midwinter, and the last week before departure. Subjective health complaints were also measured at arrival, midwinter, and the last week before departure, while depression (Burnam screen for depression) and positive and negative affect (PANAS) were measured at midwinter only. At the end of the winter appointment, base commanders evaluated the performance of all personnel. RESULTS: The variations in external light (darkness during winter, midnight sun during arrival and departure) did not influence the diurnal rhythms. The normal peak level in the morning, and the normal and gradual fall towards the evening were observed at arrival, midwinter, and before departure. Immediately after arrival the cortisol values were relatively high and correlated positively with base commander's evaluation of performance. During midwinter, approximately 58% scored for depression on the Burnam scale. However, when examining these data more closely, only 4 participants (7%) reported depression, the main reason for the high score on the depression scale was related to sleep problems and tiredness. CONCLUSIONS: There was no indication that over-wintering led to any disturbance in the diurnal rhythm of cortisol in British Antarctic personnel. There were no other indications of any 'over-wintering syndrome' than reports of subjective sleep problems and tiredness.

Exploiting induced variation to dissect quantitative traits in barley.

The identification of genes underlying complex quantitative traits such as grain yield by means of conventional genetic analysis (positional cloning) requires the development of several large mapping populations. However, it is possible that phenotypically related, but more extreme, allelic variants generated by mutational studies could provide a means for more efficient cloning of QTLs (quantitative trait loci). In barley (Hordeum vulgare), with the development of high-throughput genome analysis tools, efficient genome-wide identification of genetic loci harbouring mutant alleles has recently become possible. Genotypic data from NILs (near-isogenic lines) that carry induced or natural variants of genes that control aspects of plant development can be compared with the location of QTLs to potentially identify candidate genes for development--related traits such as grain yield. As yield itself can be divided into a number of allometric component traits such as tillers per plant, kernels per spike and kernel size, mutant alleles that both affect these traits and are located within the confidence intervals for major yield QTLs may represent extreme variants of the underlying genes. In addition, the development of detailed comparative genomic models based on the alignment of a high-density barley gene map with the rice and sorghum physical maps, has enabled an informed prioritization of 'known function' genes as candidates for both QTLs and induced mutant genes.

Wideband energy reflectance measurements of ossicular chain discontinuity and repair in human temporal bone.

OBJECTIVE: Recent studies have suggested the potential of wideband energy reflectance (ER) for the assessment of middle ear disorders. The purpose of this study was to examine the use of wideband ER in the evaluation of an ossicular discontinuity and its repair in human cadaver temporal bones. DESIGN: ER measurements at ambient pressure were made on five human cadaver ears in three conditions: (1) baseline with intact ossicular chain, (2) with the ossicular chain cut using an argon laser, and (3) with the ossicular chain repaired. Laser Doppler vibrometry measurements of stapes footplate velocity were also made in the three conditions to monitor the effect of the experimental manipulations on sound transfer through the middle ear. RESULTS: Disarticulating the ossicular chain resulted in the appearance of a deep notch in ER in each specimen ranging in center frequency from 561 to 841 Hz. The average reduction in ER was 31% at a frequency of 630 Hz. Laser Doppler vibrometry measurements confirmed the effect of the disarticulation and then repair using ionomeric cement. The low-frequency notch in ER was eliminated following repair of the ossicular chain. There was a small decrease in average high-frequency ER for both the cut and repaired conditions. A simple series impedance model of the middle ear was used to model the change in ER based on changes in middle ear impedance. The primary finding of the modeling was that the low-frequency notch in ER in the disarticulated ear occurs at the resonance frequency at which the reactance goes through zero consistent with the data. CONCLUSIONS: A disarticulation of the ossicular chain in human cadaver ears produces a low-frequency notch in ER that recovers with repair of the disarticulation. These results suggest that ER has the potential for use in the diagnosis of ossicular discontinuity and to monitor the status of the repaired ossicular chain. More data are needed to compare ER results from patients undergoing surgery for ossicular discontinuity with those of patients with other ossicular disorders such as otosclerosis.

Psychological selection of Antarctic personnel: the "SOAP" instrument.

INTRODUCTION: The potential advantage of including a psychological test battery in the selection process for service in the Antarctic was examined in 348 applicants for employment in Antarctica with the British Antarctic Survey (BAS). METHODS: Applicants were screened with the Selection of Antarctic Personnel battery (SOAP) consisting of nine well-known psychological instruments. The SOAP scores were not revealed to the BAS selection panel members, who based the selection on operational criteria, interview, and a general medical examination. The SOAP scores of those selected (n = 177) were further compared with station commanders' reports of winter adaptation (n = 140), and subjective health complaints (SHC) (n = 86). RESULTS: There were no significant agreements between SOAP scores (n = 348) and those actually selected by the BAS panel (121 accepted, 227 not accepted) (Cohen's Kappas for inter-rater agreement < 0.20). Participants characterized as exceptionally well adapted by the station commanders had higher scores on Openness on the NEO-FFI (the "Big Five" personality inventory) [Odds Ratio (OR) = 5.2], and higher levels of Emotion-Focused Coping (OR = 2.7) and fewer SHC (OR = 0.3). Participants rated by station commanders as "poor" had higher levels of Defensive Hostility (OR = 4.2), and lower levels of Emotion-Focused Coping (OR = 0.3). Women had higher rates of success in service than men, but were less likely to be selected. DISCUSSION AND CONCLUSION: Adding a psychological test battery would improve the odds of selecting good performers, and reduce the odds of selecting poor performers.

Telemedicine in the British Antarctic survey.

Medicine in the Antarctic is probably the most isolated situation in which a doctor can practise, differing in degree of severity even from that of the Arctic region. The increasing use of Telemedicine has helped to reduce this isolation and to improve access to secondary healthcare for those who live in the most remote bases in the world. The article describes the way in which Antarctic Telemedicine has evolved in the British Antarctic survey, outlining the use of low cost and low technology systems to improve the availability of emergency advice, both to the doctor and to isolated field parties, specialist consultation, medical education, and healthcare records. The Antarctic is a useful proving ground for technologies which may have applications in space and other extreme and isolated environments.

In vivo characterization of piezoelectric transducers for implantable hearing AIDS.

BACKGROUND: Piezoelectric bimorph transducers may be used at the input stage of implantable hearing aids to convert ossicle vibrations into electrical waveforms, and at the output stage to convert electrical signals into mechanical motion that drives the ossicles. This study assessed transducer performance in anesthetized, acutely implanted cats using computer-averaged, laser-Doppler vibrometer measures and cochlear potentials. METHODS: Measures of output linearity and distortion for a transducer placed on the umbo were obtained from averaged laser-Doppler vibrometer outputs. Frequency response and equivalent sound pressure level for transducers placed against the stapes were estimated by comparing compound action potentials and cochlear microphonics elicited preoperatively by acoustic signals with responses elicited postoperatively by signals presented through transducers. RESULTS: The transducer placed on the umbo exhibited an effective bandwidth that exceeded 8 kHz, linear response behavior for driving voltages up to 2 Vrms, and harmonic distortion of -40 dB or better at all frequencies greater than 250 Hz. Except for a shorter latency, transducer-elicited cochlear potentials were indistinguishable from acoustically elicited responses. Frequency response varied widely across transducers, ranging from reasonably flat to possessing a bandpass characteristic with a peak at 2 to 4 kHz; 1-Vrms signals applied to transducers with various geometries yielded equivalent intensities of 62 to 108 dB sound pressure level at 4 kHz, 51 to 98 dB sound pressure level at 2 kHz, and 55 to 80 dB sound pressure level at 1 kHz. Differences in frequency response and equivalent sound pressure level stemmed from different resonance frequencies in transducers with dissimilar lengths and, more importantly, from variation in transducer-stapes contact force. CONCLUSIONS: Appropriately designed piezoelectric transducers can provide the cochlea with high-fidelity, wide-bandwidth signals. However, using them in implantable hearing aids requires that geometry and contact force be optimized to reduce variability in output level. Recording cochlear potentials is a cost-effective means of assessing transducer performance intraoperatively, but care must be exercised to take into account any temporary, drill-induced sensitivity loss.

Wideband energy reflectance measurements in adults with middle-ear disorders.

The purpose of this study was to examine wideband energy reflectance (ER) at ambient pressure in adults with a variety of middle-ear disorders. The ER results from 9 participants with middle-ear disorders and 1 participant with bilateral sensorineural hearing loss were compared with data provided by a group of 40 young adults with normal hearing sensitivity. Wideband ER results for the participant with sensorineural hearing loss followed the typical pattern of the data for young adults with normal hearing. For the 9 participants with middle-ear disorders (13 ears), the wideband ER responses fell outside the 5th to 95th percentile of the normative data for some portion of the frequency range in patterns that were distinct for otitis media with effusion, otosclerosis, ossicular discontinuity, and perforation of the tympanic membrane. Two ears with hypermobile 226-Hz tympanograms and normal hearing sensitivity had low-frequency ER patterns similar to that of a patient with ossicular discontinuity. One participant with negative middle-ear pressure had high ER in the low frequencies. This distinct ER pattern was similar to the patterns produced by participants with otosclerosis, demonstrating that a correction for middle ear pressure will be important for the clinical application of ER. Overall, the results suggest that wideband ER may be useful as a diagnostic tool in the assessment of middle-ear disorders.

The envoy® totally implantable hearing system, st. Croix medical.

The Totally Implantable Envoy® System is currently undergoing clinical trials in both the United States and Europe. The fully implantable hearing device is intended for use in patients with sensorineural hearing loss. The device employs piezoelectric transducers to sense ossicle motion and drive the stapes. Programmable signal processing parameters include amplification, compression, and variable frequency response. The fully implantable attribute allows users to take advantage of normal external ear resonances and head-related transfer functions, while avoiding undesirable earmold effects. The high sensitivity, low power consumption, and high fidelity attributes of piezoelectric transducers minimize acoustic feedback and maximize battery life (Gyo, 1996; Yanagihara, (1987) and 2001). The surgical procedure to install the device has been accurately defined and implantation is reversible.