In Vivo rapid delivery of vasopressin from an implantable drug delivery micro-electro-mechanical device

A miniaturized implantable rapid drug delivery device based on micro-electro-mechanical-systems technology was recently developed and characterized. This device is intended to address acute conditions in high-risk subjects. This work provides an in vivo proof-of-concept for the device in a rabbit model, by releasing a physiologically active dose of vasopressin, a vasoconstrictor. The devices were implanted subcutaneously and activated to rapidly release vasopressin, with monitoring of mean arterial pressure and plasma levels.Device releases showed a rapid and measurable effect on mean arterial pressure as well as a continuous diffusion of vasopressin into the bloodstream, consistent with a depot effect. Plasma levels in rabbits receiving vasopressin with the device rose monotonically to 24.4 ± 2.9 ng/mL after one hour. Bioavailability after one hour was calculated to be 6.2 ± 2.8 % (mean ± s.d.).A new modality for rapid and controlled drug delivery has been developed. The device can be used as a new implantable device controlled by medical algorithms (based on heart rate or mean arterial pressure, for example) for autonomous operation in high-risk populations that require immediate ambulatory intervention.Keywords: Subcutaneous drug delivery; vasopressin; MEMS; rabbit; bioavailability

In Vivo rapid delivery of vasopressin from an implantable drug delivery micro-electro-mechanical device

A miniaturized implantable rapid drug delivery device based on micro-electro-mechanical-systems technology was recently developed and characterized. This device is intended to address acute conditions in high-risk subjects. This work provides an in vivo proof-of-concept for the device in a rabbit model, by releasing a physiologically active dose of vasopressin, a vasoconstrictor. The devices were implanted subcutaneously and activated to rapidly release vasopressin, with monitoring of mean arterial pressure and plasma levels.Device releases showed a rapid and measurable effect on mean arterial pressure as well as a continuous diffusion of vasopressin into the bloodstream, consistent with a depot effect. Plasma levels in rabbits receiving vasopressin with the device rose monotonically to 24.4 ± 2.9 ng/mL after one hour. Bioavailability after one hour was calculated to be 6.2 ± 2.8 % (mean ± s.d.).A new modality for rapid and controlled drug delivery has been developed. The device can be used as a new implantable device controlled by medical algorithms (based on heart rate or mean arterial pressure, for example) for autonomous operation in high-risk populations that require immediate ambulatory intervention.Keywords: Subcutaneous drug delivery; vasopressin; MEMS; rabbit; bioavailability

Spatial repellents transfluthrin and metofluthrin affect the behavior of \u3cem\u3eDermacentor variabilis\u3c/em\u3e, \u3cem\u3eAmblyomma americanum\u3c/em\u3e, and \u3cem\u3eIxodes scapularis\u3c/em\u3e in an \u3cem\u3ein vitro\u3c/em\u3e vertical climb assay

Repellents serve an important role in bite protection. Tick repellents largely rely on biomechanisms that induce responses with direct contact, but synthetic pyrethroids used as spatial repellents against insects have received recent attention for potential use in tick protection systems. An in vitro vertical climb assay was designed to assess spatial repellency against Dermacentor variabilis, Amblyomma americanum, and Ixodes scapularis adult, female ticks. Climbing behavior was assessed with and without the presence of two spatial repellents, transfluthrin and metofluthrin. Repellency parameters were defined to simulate the natural questing behavior of ambushing ticks, including measures of detachment, pseudo-questing duration, climbing deterrence, and activity. Significant effects were observed within each parameter. D. variabilis showed the greatest general susceptibility to each repellent, followed by A. americanum, and I. scapularis. The most important and integrative measure of repellency was climbing deterrence–a measure of the spatial repellent’s ability to disrupt a tick’s natural propensity to climb. Transfluthrin deterred 75% of D. variabilis, 67% of A. americanum, and 50% of I. scapularis. Metofluthrin was slightly more effective, deterring 81% of D. variabilis, 73% of A. americanum, and 72% of I. scapularis. The present study poses a novel paradigm for repellency and reports a preliminary assessment of spatial repellent effect on tick behavior. Further research will assess spatial repellency in a more natural setting, scale exposure conditions, and incorporate host cues

On the importance of sluggish state memory for learning long term dependency

The vanishing gradients problem inherent in Simple Recurrent Networks (SRN) trained with back-propagation, has led to a significant shift towards the use of Long Short-term Memory (LSTM) and Echo State Networks (ESN), which overcome this problem through either second order error-carousel schemes or different learning algorithms respectively. This paper re-opens the case for SRN-based approaches, by considering a variant, the Multi-recurrent Network (MRN). We show that memory units embedded within its architecture can ameliorate against the vanishing gradient problem, by providing variable sensitivity to recent and more historic information through layer- and self-recurrent links with varied weights, to form a so-called sluggish state-based memory. We demonstrate that an MRN, optimised with noise injection, is able to learn the long term dependency within a complex grammar induction task, significantly outperforming the SRN, NARX and ESN. Analysis of the internal representations of the networks, reveals that sluggish state-based representations of the MRN are best able to latch on to critical temporal dependencies spanning variable time delays, to maintain distinct and stable representations of all underlying grammar states. Surprisingly, the ESN was unable to fully learn the dependency problem, suggesting the major shift towards this class of models may be premature

An Implantable MEMS Drug Delivery Device for Rapid Delivery in Ambulatory Emergency Care

We introduce the first implantable drug delivery system based on MEMS (Micro-Electro-Mechanical-Systems) technology specifically designed as a platform for treatment in ambulatory emergency care. The device is named IRD[superscript 3] (implantable rapid drug delivery device) and allows rapid delivery of drugs. Vasopressin was used as a model drug for in vitro tests as it is a commonly used drug for cardiac resuscitation. Experimental results reveal that the IRD3 provides an effective method for rapid delivery without significant drug degradation. Several medical uses and delivery modalities for IRD3 are proposed

A combined experimental-computational approach for spatial protection efficacy assessment of controlled release devices against mosquitoes (Anopheles).

This work describes the use of entomological studies combined with in silico models (computer simulations derived from numerical models) to assess the efficacy of a novel device for controlled release of spatial repellents. Controlled Release Devices (CRDs) were tested with different concentrations of metofluthrin and tested against An. quadrimaculatus mosquitoes using arm-in cage, semi-field, and outdoor studies. Arm-in-cage trials showed an approximate mean values for mosquito knockdown of 40% and mosquito bite reduction of 80% for the optimal metofluthrin formulation for a 15-minute trial. Semi-field outdoor studies showed a mean mortality of a 50% for 24 hour trial and 75% for a 48 hour trial for optimal concentrations. Outdoors studies showed an approximate mean mortality rate of 50% for a 24 hour trial for optimal concentrations. Numerical simulations based on Computational Fluid Dynamics (CFD) were performed in order to obtain spatial concentration profiles for 24 hour and 48 hour periods. Experimental results were correlated with simulation results in order to obtain a functional model that linked mosquito mortality with the estimated spatial concentration for a given period of time. Such correlation provides a powerful insight in predicting the effectiveness of the CRDs as a vector-control tool. While CRDs represent an alternative to current spatial repellent delivery methods, such as coils, candles, electric repellents, and passive emanators based on impregnated strips, the presented method can be applied to any spatial vector control treatment by correlating entomological endpoints, i.e. mortality, with in-silico simulations to predict overall efficacy. The presented work therefore presents a new methodology for improving design, development and deployment of vector-control tools to reduce transmission of vector-borne diseases, including malaria and dengue

Rapid Reconstitution Packages (RRPs) implemented by integration of computational fluid dynamics (CFD) and 3D printed microfluidics

Rapid Reconstitution Packages (RRPs) are portable platforms that integrate microfluidics for rapid reconstitution of lyophilized drugs. Rapid reconstitution of lyophilized drugs using standard vials and syringes is an error-prone process. RRPs were designed using computational fluid dynamics (CFD) techniques to optimize fluidic structures for rapid mixing and integrating physical properties of targeted drugs and diluents. Devices were manufactured using stereo lithography 3D printing for micrometer structural precision and rapid prototyping. Tissue plasminogen activator (tPA) was selected as the initial model drug to test the RRPs as it is unstable in solution. tPA is a thrombolytic drug, stored in lyophilized form, required in emergency settings for which rapid reconstitution is of critical importance. RRP performance and drug stability were evaluated by high-performance liquid chromatography (HPLC) to characterize release kinetics. In addition, enzyme-linked immunosorbent assays (ELISAs) were performed to test for drug activity after the RRPs were exposed to various controlled temperature conditions. Experimental results showed that RRPs provided effective reconstitution of tPA that strongly correlated with CFD results. Simulation and experimental results show that release kinetics can be adjusted by tuning the device structural dimensions and diluent drug physical parameters. The design of RRPs can be tailored for a number of applications by taking into account physical parameters of the active pharmaceutical ingredients (APIs), excipients, and diluents. RRPs are portable platforms that can be utilized for reconstitution of emergency drugs in time-critical therapies.United States. Army Research Office. Institute for Soldier Nanotechnologies (contract: W911NF-07-D-0004

Comparison of detachment.

The proportion of ticks that detached from their stick was assessed and shown as a percentage for each group. All ticks were included in the analysis. Only exposure to metofluthrin was associated with a small, significant increase in detachment in I. scapularis. Significance indicator: NS = Not significant, * P < 0.05, ** P < 0.01, *** P < 0.001.</p

Comparison of climbing deterrence.

The proportion of ticks deterred was described as a percentage. All ticks were included in the analysis. Significant deterrence was observed with transfluthrin and metofluthrin in all species. Significance indicator: NS = Not significant, * P < 0.05, ** P < 0.01, *** P < 0.001.</p