Drug Delivery Protocols Research Articles

Enhancing targeted tumor treatment: A novel fuzzy logic framework for precision drug delivery strategy selection

Objective:This study aims to address the challenge of selecting optimal drug delivery strategies for tumor patients by introducing a novel theoretical framework. Methods:We propose a fuzzy logic-based framework for quantitatively assessing Health States (HS) in tumor patients. This framework integrates quantified HS assessments with causality strength analyses, offering a comprehensive understanding of various drug delivery schemes’ effectiveness from pharmacokinetic and pharmacodynamic perspectives. Results:The efficacy of our approach is demonstrated through a series of real-world patient case studies, highlighting its potential to enhance the evaluation and selection of targeted drug delivery strategies. Conclusion:Our work contributes to the field by showcasing practical applications of fuzzy logic in targeted drug delivery systems (TDDs) and establishing a new benchmark for precision in drug delivery strategy selection. Significance:This study has significant implications for developing personalized medical treatments, potentially revolutionizing the field with a more nuanced and scientifically rigorous method for evaluating and selecting drug delivery protocols. Contributions:Development of a fuzzy logic framework for precise quantification of health states in tumor patients. Innovative integration of a causal system for comprehensively evaluating targeted drug delivery strategies.

Pretreatment of microneedles enhances passive transdermal administration of pilocarpine and pilocarpine-induced sweat production in humans

The development of an effective transdermal drug delivery protocol to eccrine sweat glands is important for the advancement of research on the human sweating response. We investigated whether microneedle treatment prior to the application of pilocarpine, a hydrophilic and sudorific agent that does not induce sweating due to a limited percutaneous passive diffusion by skin application alone, augments sweat production. We applied three microneedle arrays to forearm skin sites simultaneously (n = 20). Upon removal of the microneedles, 1 % pilocarpine was applied to each site for 5-, 15-, and 30-min for the assessment of sweat gland function. In parallel, pilocarpine was administered by transdermal iontophoresis (5-min) at a separate site. Sweat rate was assessed continuously via the ventilated capsule technique. Pilocarpine augmented sweat rate at the 15- and 30-min periods as compared to the application at 5-min. The sweating responses induced by the 15- and 30-min application of pilocarpine were equivalent to ∼ 80 % of that measured at the iontophoretically treated sites. Notably, we observed a correlation in sweat rate between these two transdermal drug delivery methods. Altogether, our findings show that pre-treatment of microneedle arrays can enhance transdermal delivery efficiency of pilocarpine to human eccrine sweat glands.

Radiopharmaceutical Encapsulated Liposomes as a Novel Radiotracer Im - aging and Drug Delivery Protocol.

Data are presented for 5 male New Zealand white rabbits. They were injected intravenously with the 99mTc-liposomes encapsulated MIBI through a marginal ear vein, and whole-body images were acquired using a dual-head gamma camera. Cationic PEGylated liposomes were prepared using the conventional thin-film-hydration method. The liposomes were tested for particle size, zeta potential, high-performance-liquid-chromatography (HPLC), and toxicity. The liver activity was slightly greater than or equivalent to heart uptake, using 99mTcsestamibi, MIBI, without liposome as a reference. The absorbed doses in myocardium cells after injecting rabbits with 99mTc-MIBI labeled with free positive lower pH liposomes was greater than in the liver, whereas 99mTc labeled with encapsulated MIBI within positive liposomes showed a significantly higher heart-to-liver ratio. The heart-to-spleen activity uptake ratio in 99mTc-MIBI was higher than or equal to one but increased in 99mTc labeled with MIBI and free positive liposomes. Injecting rabbits with 99mTc labeled with encapsulated MIBI raised myocardium uptake to 2-4 times more than the spleen. Heart-to-bowel activity began to rise with 99m Tc-labeld-MIBI and liposomes. This study provides findings in radiopharmaceutical biodistribution using liposomal agents. Adding free liposomes using a pH gradient technique enhanced the uptake and localization of the radiotracer. However, tracer encapsulation during the formation of the liposomes showed even better specificity.

An automated system for cattle reproductive management under the IoT framework. Part I: the e-Synch system and cow responses

The objective of this manuscript was to present the e-Synch system, integrating an intravaginal electronically controlled hormone delivery and sensing device with an IoT platform for remote programming and monitoring. Secondary objectives were to demonstrate system functionality and cow responses to e-Synch. External components of e-Synch include a 3D-printed case with retention wings, a flexible wideband antenna, and silicone membrane for pressure balancing. Internal components include a central control board, battery, wireless charging coil, and two silicone hormone reservoirs connected to individual peristaltic pumps. An accelerometer and a high-accuracy temperature sensor are integrated in the custom printed circuit board (PCB). The IoT platform includes a gateway consisting of Raspberry PI 3 and a CC1352 radiofrequency module that collects sensor data at 915 mHz. Data is transferred to the Google Cloud utilizing the IoT Core service through TCP/IP, and then is pulled by the Pub/Sub service. After routing to a BigQuery table by the Dataflow service, data visualization is provided by Data Studio. Drug delivery protocols are selected using an IOS device app that connects to e-Synch through Bluetooth. Experiments with lactating Holsteins cows were conducted to demonstrate proof-of-concept system functionality and evaluate cow responses. Despite unstable communication and signal discontinuity because of signal strength attenuation by body tissue, devices (n=6) communicated with the IoT platform in 89% (24/27) of use instances. Temperature and accelerometer data were received for at least one 15 min period during an 8 h insertion period from all devices that communicated with the IoT platform. Variation in accelerometer data (± 8.565 m/s2) was consistent with cow activity during experimentation and mean vaginal temperature of 39.1 °C (range 38.6 to 39.5 °C) demonstrated sensor functionality. Hormone release was confirmed in all instances of device use except for one. Cow behavior evaluated through signs of discomfort and pain, and tail raising scores was mostly unaltered by e-Synch. Vaginal integrity and mucus scores also remained unaltered during and after device insertion. In conclusion, the e-Synch device integrated with a controlling app and IoT platform might be used to automate intravaginal hormone delivery and sensing for controlling the estrous cycle of cattle.

Perspectives on optimizing local delivery of drugs to peripheral nerves using mathematical models.

Drug therapies for treating peripheral nerve injury repair have shown significant promise in preclinical studies. Despite this, drug treatments are not used routinely clinically to treat patients with peripheral nerve injuries. Drugs delivered systemically are often associated with adverse effects to other tissues and organs; it remains challenging to predict the effective concentration needed at an injured nerve and the appropriate delivery strategy. Local drug delivery approaches are being developed to mitigate this, for example via injections or biomaterial-mediated release. We propose the integration of mathematical modeling into the development of local drug delivery protocols for peripheral nerve injury repair. Mathematical models have the potential to inform understanding of the different transport mechanisms at play, as well as quantitative predictions around the efficacy of individual local delivery protocols. We discuss existing approaches in the literature, including drawing from other research fields, and present a process for taking forward an integrated mathematical-experimental approach to accelerate local drug delivery approaches for peripheral nerve injury repair. This article is categorized under: Neurological Diseases > Molecular and Cellular Physiology Neurological Diseases > Computational Models Neurological Diseases > Biomedical Engineering.

Computational Study of Magnetic Particle Motion inside the Nasal Cavity under the Impact of an External Magnetic Field for Biomedical Applications.

The blood-brain barrier is a highly selective semipermeable border that separates blood circulation from the brain and hinders the accumulation of substances in the central nervous system. Hence, a treatment plan aiming to combat neurodegenerative diseases may be restricted. The exploitation of the nose-brain pathway could be a promising bypass method. However, pharmaceutical uptake through the olfactory epithelium is insignificant in terms of treatment, if relying only on fluid dynamic interactions. The main reasons for this are the highly complicated geometry of the nose and the residence time of the substance. The issue can be tackled by using magnetic particles as drug carriers. With the application of an external magnetic field, further control of the particle motion can be achieved, leading to increased uptake. The present work studies this approach computationally by employing magnetite particles with a radius of 7.5 μm while a magnetic field is applied with a permanent neodymium-iron-boron magnet of 9.5×105  A/m magnetization. Through this investigation, the best drug delivery protocol achieved a 2% delivery efficiency. The most significant advantage of this protocol is its straightforward design, which does not require complex equipment, thus rendering the protocol portable and manageable for frequent dosing or at-home administration.

32765 Regional variation in percutaneous absorption in in vitro human models: A systematic review

Percutaneous absorption is of importance given its role in topical medicaments, transdermal drug systems, and dermatotoxicology. Many factors influence percutaneous absorption, including anatomical location. Hence, this study summarizes the existing data on regional variation in percutaneous absorption in in vitro human models. PubMed, Embase, and Web of Science were explored, and literature containing quantitative data on regional differences in percutaneous absorption in humans in vitro, was collected. Eight relevant articles were identified, which together, explored 15 anatomic regions. Four studies compared percutaneous absorption between scalp and abdominal skin, and all concluded that the former was more permeable. Within those 4 studies, 10 penetrants of varying physical/chemical properties were tested, suggesting that anatomical location has a greater effect on percutaneous absorption than the penetrants’ properties. Additionally, torso was less absorptive than scrotum in both studies in which these sites were compared. In conclusion, the scrotum and scalp appear to be highly vulnerable to percutaneous absorption when compared with other regions such as the abdomen. This is thought to be largely due to the high hair follicle density in these areas, allowing for greater penetration through the appendageal pathway. However, there is a paucity of conclusive data regarding the absorptivity of other anatomical locations. Experimentation testing and ranking the vulnerability of different anatomical locations is of vital importance given its relevance in decontamination and transdermal drug delivery protocols, and understanding the mechanisms and degree of these variances should aid our pharmacologic/toxicologic judgments.

Nonlinear SDRE based adaptive fuzzy control approach for age-specific drug delivery in mixed chemotherapy and immunotherapy

Determination of a near-optimal personalized drug delivery scenario in mixed chemotherapy and immunotherapy based on the age of cancer patients was presented in this paper. For this purpose, a mathematical model for cancer dynamics is considered in the form of ordinary differential equations (ODE) which contains cancer cells, tumor cells, and chemotherapy drug intervention. This model is modified by adding immunotherapy intervention effects to alter cancer dynamics. We consider two patients with known and unknown model parameters which are mentioned as a reference and unknown patients respectively. The nonlinear composite adaptive controller is introduced by compounding State Dependent Riccati Equation (SDRE) and Model Reference Adaptive Control (MRAC) techniques for achieving the drug delivery of an unknown patient. The drug delivery scenario for a reference patient with a known mathematical model and parameters is determined via the SDRE technique and then for any unknown patient, the personalized mixed therapy protocol is achieved using the treatment regimen of the reference patient as a reference model in MRAC. To reduce the side effects of chemotherapy drugs, we determine drug maximum dose limits using fuzzy control by considering the age of cancer patients. We regarded patients in four age groups of child, young, middle-aged, and old. In the proposed methodology, unknown patients are considered as a black-box simulator and the mathematical model parameters of the patient are not essential for the design of drug administration protocol and we only need patients’ age. After chemotherapy, the treatment is completed by immunotherapy to avoid cancer relapse. The effect of reference and unknown patient ages in obtaining drug delivery protocol is deeply surveyed. Numerical simulations confirm the effectiveness, robustness, and flexibility of the proposed strategy for patients of different ages. The Proposed algorithm can be an effective tool to aid oncologists in prescribing age-specific optimal treatment protocols for cancer patients.

Intrathecal catheter implantation decreases cerebrospinal fluid dynamics in cynomolgus monkeys.

A detailed understanding of the CSF dynamics is needed for design and optimization of intrathecal drug delivery devices, drugs, and protocols. Preclinical research using large-animal models is important to help define drug pharmacokinetics-pharmacodynamics and safety. In this study, we investigated the impact of catheter implantation in the sub-dural space on CSF flow dynamics in Cynomolgus monkeys. Magnetic resonance imaging (MRI) was performed before and after catheter implantation to quantify the differences based on catheter placement location in the cervical compared to the lumbar spine. Several geometric and hydrodynamic parameters were calculated based on the 3D segmentation and flow analysis. Hagen-Poiseuille equation was used to investigate the impact of catheter implantation on flow reduction and hydraulic resistance. A linear mixed-effects model was used in this study to investigate if there was a statistically significant difference between cervical and lumbar implantation, or between two MRI time points. Results showed that geometric parameters did not change statistically across MRI measurement time points and did not depend on catheter location. However, catheter insertion did have a significant impact on the hydrodynamic parameters and the effect was greater with cervical implantation compared to lumbar implantation. CSF flow rate decreased up to 55% with the catheter located in the cervical region. The maximum flow rate reduction in the lumbar implantation group was 21%. Overall, lumbar catheter implantation disrupted CSF dynamics to a lesser degree than cervical catheter implantation and this effect remained up to two weeks post-catheter implantation in Cynomolgus monkeys.

Enhanced cellular uptake of platinum by a tetracationic Pt(II) nanocapsule and its implications to cancer treatment

Despite the known limitations of cisplatin chemotherapy, the treatment of cancer by platinum-based drugs remains the method of choice for many oncologists. The advancement in drug delivery formulations and protocols of combined treatments provided effective tools to ameliorate the side effects of platinum-based therapies. Another approach to improve the pharmacological profiles of anticancer platinum drugs is to properly modify their structure and composition, which has produced numerous platinum complexes with improved therapeutic effect. Recently, we have demonstrated the strong anticancer potency of supramolecular nanocapsules that form by self-assembly of four bis-anthracene ligands with two metal ions, either Pt(II) or Pd(II). Herein, we focus our study on the Pt(II) nanocapsule and its uptake by two types of cancer cells, suspension cultures of HL-60 cells and the adherent cancer cells HT-29. Comparison of the platinum uptake by cancer cells treated with the nanocapsule and with cisplatin evidenced superior uptake of platinum caused by the nanocapsule, which in HT-29 and HL-60 cells prevails by 21 and 31 times, respectively. Morphological changes in the HL-60 cells induced by the Pt(II) nanocapsule were studied by transmission electron microscopy (TEM) which provided plausible explanation of the uptake results. These data corroborate also with the known nanocapsule's very high cytotoxicity, better selectivity, and lack of cross-resistance with cisplatin. Additionally, our estimations of the drug-drug interactions in combined treatments established the propensity of the nanocapsule to exert supra-additive cytotoxicity in combination with cisplatin against the bladder cancer T-24 cells. All these findings define the scope for more detailed pharmacological characterization of the presented Pt(II) nanocapsule.

Evaluation of an Intrathecal Drug Delivery Protocol Leads to Rapid Reduction of Systemic Opioids in the Oncological Population.

Objective: The article that follows is purposed at demonstrating how IT opioid plus bupivacaine achieves sustained acceptable pain relief while simultaneously rapidly reducing oral morphine equivalents (OME). Background: Cancer patients represent a population with significant morbidity, pain, and limited life expectancy. It is, therefore, vital to achieve satisfactory analgesia quickly and safely. To date, there is limited data in the literature that discusses efficacy of combined intrathecal (IT) medication therapy in reducing systemic opioids in the oncological population. Methods: This was a retrospective analysis that reviewed cancer pain patients from day of IT pump implantation through the six-month postoperative time point. A cohort of 50 oncological patients who had intrathecal drug delivery systems (IDDSs) implanted at Memorial Sloan Kettering Cancer Center between 2017 and 2019 were studied. Median OMEs were the primary modality of analysis for this review. Mean visual analogue scale scores were secondarily reviewed. Results: Median OMEs decreased from 503 preoperative to 105 at six months postoperative time point. Median time to discharge was 6.5 days. Unfortunately, due to malignant mortality, 27 patients did not make it to the 6-month postoperative time point. Discussion: IDDSs with opioid plus bupivacaine represent a safe and efficient route toward expeditious pain relief and decreased OMEs in the cancer pain population.

Intracerebroventricular administration of N-type calcium channel blocker ziconotide displays anticonvulsant, anxiolytic, and sedative effects in rats: A preclinical and pilot study

ObjectiveZiconotide (ω-conotoxin MVIIA peptide) is a novel analgesic agent acting on voltage-gated calcium channels and is administered intrathecally for neuropathic pain. While antiepileptic activities of other types of calcium channel blockers (T- or L-type) are well established, there is no information regarding the effect of ziconotide as an N-type calcium channel antagonist in pentylenetetrazol-induced seizures or its anxiolytic and sedative activities. The present study is the first to report on these effects. MethodsTo evaluate the anticonvulsant activity of ziconotide in the pentylenetetrazol (60 mg/kg) seizure model, ziconotide was administered intracerebroventricular (i.c.v.) as a single dose (1 μg/rat) or repeatedly (chronic administration: 0.1, 0.3, or 1 μg/rat once a day for seven days). The anxiolytic and sedative actions of ziconotide were evaluated with the elevated plus maze, light/dark (LD) box, and pentobarbital-induced sleep tests. Immediately after behavioral testing, the amygdala was completely removed bilaterally to determine corticosterone levels by immunoassay. ResultsIn all dosing regimens, ziconotide significantly decreased the seizure frequency and also delayed the latency period compared with control. Chronic administration affected the percentage of mortality protection, while a single dose of ziconotide did not. In behavioral tests, ziconotide significantly increased both the number of entries and the percentage of time spent in the open arms of the elevated plus maze. Furthermore, ziconotide significantly increased the latency period and the number of entries into the light compartment during the LD box examination. Chronic administration of ziconotide significantly reduced the latency to sleep and increased sleeping time, whereas these parameters were not affected by a single dose. Additionally, amygdala corticosterone levels were significantly decreased in rats treated with ziconotide compared with control. ConclusionZiconotide displays beneficial neurobehavioral effects in a model of epilepsy with anxiety as its comorbid event. It seems that at least one of the mechanisms involved in these effects is associated with a decrease in brain corticosterone levels. The main advantage of ziconotide over benzodiazepines (routine anxiolytic and sedative drugs) is that it does not cause tolerance, dependency, and addiction. Therefore, more than ever, it is necessary to improve the convenience of drug delivery protocols and attenuate the adverse effects associated with ziconotide-based therapies.

Pilot Evaluation of Telemetered Cardiac Hemodynamics in the Setting of Fully‐Implanted Programmable Drug Delivery in Rats: A New Tool for Cardiovascular Drug Discovery?

IntroductionThe mechanistic understanding of pharmacokinetics–pharmacodynamics (PK/PD) relationships is a key component of modern cardiovascular drug discovery. However, given that both PK properties and/or experimental techniques (such as anesthesia) can alter auto‐regulatory/autonomic control in vivo (thus masking true PD responses), tools permitting the determination of translationally‐relevant PK/PD relationships for cardio‐active agents are limited. This pilot study established the feasibility of combining implantable programable infusion pumps and telemetered cardiac hemodynamic monitoring for the assessment PK‐independent PD responses in untethered conscious rats.MethodsHealthy Sprague‐Dawley rats (n = 7) were chronically instrumented with both a digital telemetered micro‐manometer catheter (HD‐S21, Data Sciences International) in the LV, and with a fully‐implanted programmable/refillable infusion pump in a femoral vein (iPRECIO® SMP‐200). The pumps were programmed, a priori, to perform (after a 21‐day recovery period) a two‐arm drug delivery protocol, consisting (each arm) of a 72h active period (ON, @12.5μL/hr) followed by a 96h washout (OFF period, on patency mode @1μL/hr); prior to each active period the pumps were loaded with either vehicle (CTRL) or a novel pure negative inotrope (MYK‐581), while normal saline was loaded prior to OFF periods. Left‐ventricular pressures (LVP) and derived functional indices were evaluated continuously (via telemetry) before/during active periods, while cardiac function/geometry were assessed (via echocardiography) prior to the end of the active period.ResultsFully implanted conscious rats had normal cardiac hemodynamics (HR: 339 ± 8 bpm, LVPmax: 119±3 mmHg) and cardiac function (EF: 76 ± 2%, FS: 47± 1%, and dLVP/dtmax: 9275 ± 369 mmHg/s), showing normal circadian oscillations. Similar observations were made during vehicle administration (e.g., EF: 77 ± 1%, and dLVP/dtmax: 9585 ± 891 mmHg/s), while marked reductions in both echocardiographic (EF: 45 ± 8.7%, FS: 24 ± 6%, P < 0.05 vs. VEH) and LVP‐derived (dLVP/dtmax: −21 ± 6%, or 7313 ± 819 mmHg/s, P < 0.05 vs. VEH) functional indices were observed during the MYK‐treatment period.ConclusionsTaken together, these data demonstrate that telemetered hemodynamics and fully‐implanted programmable/refillable infusion pump technologies can be successfully integrated in vivo in order to generate translationally‐relevant PK‐independent pharmacodynamics data in untethered conscious rats.Support or Funding InformationThese studies were supported by MyoKardia

The Binding of Drug Molecules to Serum Albumin: The Effect of Drug Hydrophobicity on Binding Strength and Protein Desolvation.

In this work, dual polarization interferometry (DPI) and quartz crystal microgravimetry with dissipation monitoring (QCM-D) were used to examine the binding characteristics and structure-activity relationships of 12 common drugs on a model bovine serum albumin (BSA) film. By taking advantage of the different hydration sensitivities of DPI and QCM-D, we were able to quantify changes in the solvent state upon drug binding to BSA. Quantifying the changes in water mass within binding pockets and upon drug-protein binding allows for a more complete understanding of binding phenomena between drug molecules and serum proteins. For the drugs tested, a quantitative structure-activity relationship (QSAR) was used to establish a correlation between drug binding (KD) and hydrophobicity (ClogP), with the latter being related to the drug's ability to desolvate the BSA upon binding. Understanding these relationships provides insight into the role of water at the protein-ligand interface and is of particular importance in the area of ligand binding within the field of drug design. This study underscores the importance of hydrophobicity to drug binding kinetics and may be used to further understand and improve drug design and delivery protocols.

Facile Green Synthesis of Silver Bionanocomposite with Size Dependent Antibacterial and Synergistic Effects: A Combined Experimental and Theoretical Studies

The application of nanoparticles is largely rely on the size of the nanoparticle. This investigation reports a one pot size specific green synthesis with a study of comparative antibacterial activity of silver bionanocomposite (AgBNC). The variations of concentration of silver nitrate (AgNO3) with eco-friendly reducing agent (citric acid) and stabilizer (gelatin), leads to the synthesis of different size AgBNCs (~ 37, 46 and 58 nm) with extended stability up to 4 months and the size of the AgBNC increases with increasing the concentration of AgNO3. UV–Vis spectrophotometry, dynamic light scattering (DLS), Fourier transform infrared (FTIR) spectroscopy, field emission scanning electron microscopy (FESEM), studies were conducted to explain particle size, shape and stability of AgBNC. Furthermore, as capping of silver nanoparticle (AgNP) is major issue regarding the stability of AgBNC, electronic structure of gelatin-AgNP complex is presented using density functional theory (DFT) for better understanding of interaction energies of AgNPs and gelatin. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were investigated against five different pathogenic bacteria which showed that lowest sized AgBNC is more effective than other samples with an increased 3–30-fold activity when it combined with different antibiotics. Highest antibacterial activity was observed for ciprofloxacin with lowest size AgBNC against S. mutans. These observations have immense importance in the context of providing guidelines for efficient biomedical drug delivery protocol.

Cochlear pharmacokinetics - Micro-computed tomography and learning-prediction modeling for transport parameter determination

Inner ear disorders such as sensorineural deafness and genetic diseases may one day be treated with local drug delivery to the inner ear. Current pharmacokinetic models have been based on invasive methods to measure drug concentrations, limiting them in spatial resolution, and restricting the research to larger rodents. We developed an intracochlear pharmacokinetic model based on an imaging, learning-prediction (LP) paradigm for learning transport parameters in the murine cochlea. This was achieved using noninvasive micro-computed tomography imaging of the cochlea during in vivo infusion of a contrast agent at the basal end of scala tympani through a cochleostomy. Each scan was registered in 3-D to a cochlear atlas to segment the cochlear regions with high accuracy, enabling concentrations to be extracted along the length of each scala. These spatio-temporal concentration profiles were used to learn a concentration dependent diffusion coefficient, and transport parameters between the major scalae and to clearance. The LP model results are comparable to the current state of the art model, and can simulate concentrations for cases involving different infusion molecules and different drug delivery protocols. Forward simulation results with pulsatile delivery suggest the pharmacokinetic model can be used to optimize drug delivery protocols to reduce total drug delivered and the potential for toxic side effects. While developed in the challenging murine cochlea, the processes are scalable to larger animals and different drug infusion paradigms.

Active diffusion limited reactions.

We investigate the one- and two-dimensional diffusion limited reactions A + A → 0 and A + B → 0 with A active Janus particles and B passive particles in thermal equilibrium. We show that by increasing the self-propulsion time of the A particles, the reactant densities decay faster, at least for time transients of potential interest for chemical applications, e.g., to develop smart drug delivery protocols. Asymptotic and transient density decays obey power laws with exponents that depend on the actual annihilation reaction and its dimensionality.

Mixed therapy in cancer treatment for personalized drug administration using model reference adaptive control

The paper presents Model Reference Adaptive Control (MRAC) design strategy to determine personalized drug delivery protocol for mixed therapy with chemotherapy and immunotherapy in cancer treatment. We consider a nonlinear mathematical ODE set for cancer dynamics that includes tumor, natural killers, circulating lymphocytes and cytotoxic T-cells population together with the interaction of chemotherapy and immunotherapy. For researchers and physicians, the main challenge in mathematical models is the determination of the exact model parameters. In order to have a drug administration policy for a patient with unknown parameter set, we develop State Dependent Riccati Equations (SDRE) based MRAC design approach to determine the personalized drug delivery protocol for patients with unknown model parameters. First of all, we determine the optimal drug delivery scenario for a reference patient with known dynamics parameters using SDRE approach. Then for any patient with unknown parameters, the personalized mixed therapy protocol is determined based on the treatment regimen of the reference patient. In the proposed methodology, unknown patients are considered as a black-box simulator in the design and the mathematical model parameters of the patient are not essential for the design of drug administration protocol. In addition, the Bang-Bang and continuous drug delivery regimens could be obtained using proper adaptation gains in the presented MRAC methodology. The simulation results demonstrate the effectiveness of the proposed MRAC approach for prescribing a treatment regimen of chemo-immunotherapy.

Neuronal calcium channels blocker, ziconotide (ɷ-conotoxin MVIIA), reverses morphine withdrawal-induced memory impairments via alteration in hippocampal NMDA receptor expression in rats

ɷ-Conotoxin MVIIA (ziconotide or SNX-111) is an atypical analgesic drug with the water-soluble formulation and routinely is injected into the brain and spinal regions in human and animal model studies. The aim of the current study was to investigate the neurobehavioral protection of this agent as a selective N-type calcium channels antagonist following spontaneous morphine withdrawal in rats. Male rats were administered morphine (10–50 mg/kg) intraperitoneal (IP) twice daily for 7 days. Ziconotide was injected intrathecal (IT) either in chronic form (0.1, 0.3 and 1 µg/rat) concurrent with daily doses of morphine or it was injected as a single dose (1 µg/rat) on the last day. Novel object recognition task (NOR) and radial arm maze (RAM) were used in order to evaluation of the recognition and spatial working/reference memory performances, respectively. The amount of N-methyl-D-aspartate (NMDA) receptor subunits including NR2A and NR2B in the hippocampus and prefrontal cortex were determined by western blotting. We observed that abrupt cessation after chronic exposure to morphine led to decrease in both recognition and working/reference memory performances (p < .01). Spontaneous withdrawal also significantly suppressed the amount of NR2A and NR2B. This impairment was attenuated by single and chronic doses of ziconotide (p < .05). Also, expression of NR2A and NR2B were significantly increased during both drug delivery protocols. Our findings suggest that ziconotide prevents morphine withdrawal-induced memory deficits through alteration in glutamatergic transmission and regulation of NMDA receptors (NMDARs).

Hearing Changes After Intratympanic Steroids for Secondary (Salvage) Therapy of Sudden Hearing Loss: A Meta-Analysis Using Mathematical Simulations of Drug Delivery Protocols.

The use of glucocorticoids for secondary (salvage/rescue) therapy of idiopathic sudden hearing loss (ISSHL), including controlled and uncontrolled studies with intratympanic injections or continuous, catheter mediated applications, were evaluated by means of a meta-analysis in an attempt to define optimal local drug delivery protocols for ISSHL. A total of 30 studies with 33 treatment groups between January 2000 and June 2014 were selected based on sufficiently detailed description of application protocols. Cochlear drug levels were calculated by a validated computer model of drug dispersion in the inner ear fluids based on the concentration and volume of glucocorticoids applied, the time drug remained in the middle ear, and on the specific timing of injections. Various factors were compared with hearing outcome, including baseline data, individual parameters of the application protocols, calculated peak concentration (Cmax), and total dose (area under the curve, AUC). There was no dependence of hearing outcome on individual parameters of the application protocol, Cmax or AUC. Hearing gain and final hearing thresholds were independent of treatment delay. Based on the available data from uncontrolled and controlled randomized and non-randomized studies no clear recommendation can be made so far for a specific application protocol for either primary or secondary (salvage) intratympanic steroid treatment in patients with ISSHL. For meta-analyses, change in pure tone average (PTA) may not be an adequate outcome parameter to assess effectiveness of the intervention especially with inhomogeneity of patient populations. Final PTA might provide a better outcome parameter.