Continuous Drug Delivery Research Articles

Treatment of Severe Acute Bacterial Keratitis in Rabbits Using Continuous Topical Ocular Instillation with Norvancomycin.

PurposeEfficacy of norvancomycin (NVCM) through continuous topical ocular instillation drug delivery (CTOIDD) system for treating severe acute bacterial keratitis infection with Staphylococcus aureus was investigated.MethodsRabbits with bacterial keratitis were treated using CTOIDD with NVCM (n=13), topical NVCM eye drops (n=11), and CTOIDD with saline (n=8). Clinical signs of keratitis in all groups were assessed consecutively for a week. Bacterial quantification of excised corneas was counted on the fourth and eighth days. Histopathologic examinations were performed to assess inflammatory cell infiltration on the eighth day.ResultsAll signs of bacterial keratitis were alleviated in CTOIDD with NVCM according to criteria, and the CTOIDD-NVCM group had significantly less inflammation than CTOIDD-saline (p<0.05), and eye drop-NVCM (p<0.05). Two eyes in the eye drop-NVCM group, four eyes in the CTOIDD-saline group had corneal perforation (CP), while none of the rabbits showed CP in the CTOIDD-NVCM group. Bacterial counts were significantly less in the CTOIDD with NVCM group in comparison to the eye drop-NVCM (p<0.05), and CTOIDD-saline (p<0.05) groups. Severe inflammation and marked inflammatory cell infiltration were found in histopathologic examinations in the CTOIDD-saline and eye drop-NVCM groups, while significantly less inflammation was documented in the CTOIDD-NVCM (p<0.05) group.ConclusionCTOIDD with NVCM effectively reduced the severity and treated acute bacterial S. aureus keratitis infection in a rabbit model. The presented approach of CTOIDD with NVCM appears to be a promising therapeutic approach for severe acute bacterial keratitis.

ROS-Sensitive Nanoparticles Co-delivering Dexamethasone and CDMP-1 for the Treatment of Osteoarthritis Through Chondrogenic Differentiation Induction and Inflammation Inhibition.

Objective: Osteoarthritis (OA) is a common subtype of arthritis. To date, treatment of OA focuses primarily on alleviating pain and improving joint function. The lack of a vascular system within synovial joints and the rapid removal of agents due to synovial exchange hinder continuous delivery of OA drugs. However, these obstacles are being addressed by promising nanoscale drugs.Methods: We synthesize and assemble a hydrogen peroxide [H2O2, belongs to the category of active oxygen species (ROS)]-sensitive nanomicelle, which is loaded with the anti-inflammation drug dexamethasone and chondrogenic differentiation factor cartilage-derivedmor-phogeneticprotein-1. The micelle can induce bone marrow mesenchymal stem cells to repair cartilage while inhibiting joint inflammation.Results: The prepared nanoparticles were of uniform size and displayed an obvious core-shell structure. Under H2O2 stimulation, the shell layer could be removed gradually. The drug-loaded micelle effectively inhibited proliferation of activated macrophages, induced macrophage apoptosis with an anti-inflammatory effect, and caused the BMSCs to differentiate into chondrocytes.Conclusion: This work provides an experimental and theoretical basis for further development of a drug-loaded micelle in the healing of osteoarthritis.

Recent Advances in Nanomicelles Delivery Systems.

The efficient and selective delivery of therapeutic drugs to the target site remains the main obstacle in the development of new drugs and therapeutic interventions. Up until today, nanomicelles have shown their prospective as nanocarriers for drug delivery owing to their small size, good biocompatibility, and capacity to effectively entrap lipophilic drugs in their core. Nanomicelles are formed via self-assembly in aqueous media of amphiphilic molecules into well-organized supramolecular structures. Molecular weights and structure of the core and corona forming blocks are important properties that will determine the size of nanomicelles and their shape. Selective delivery is achieved via novel design of various stimuli-responsive nanomicelles that release drugs based on endogenous or exogenous stimulations such as pH, temperature, ultrasound, light, redox potential, and others. This review summarizes the emerging micellar nanocarriers developed with various designs, their outstanding properties, and underlying principles that grant targeted and continuous drug delivery. Finally, future perspectives, and challenges for nanomicelles are discussed based on the current achievements and remaining issues.

EXTH-26. SECONDARY STRUCTURE ANALYSIS OF THE EGFR PRE-mRNA TRANSCRIPT TO IDENTIFY TARGETABLE REGIONS AND OPTIMIZE RNA THERAPY

Abstract Individuals diagnosed with glioblastoma multiforme (GBM) have a short life expectancy of 12–15 months. Current strategies are often limited by the blood-brain barrier. This project is to develop therapies to bypass challenges to effective and continuous drug delivery to the brain, targeting cancer-driving genes. Epidermal growth factor receptor (EGFR) is dysregulated in 57% of all GBM. Our approach uses an adeno-associated virus gene transfer vector encoding RNA therapeutics targeting critical elements of the EGFR pre-mRNA transcript. The ‘pre-mRNA structurome’ can be used to uncover and determine the accessibility of targetable regions. Our approach has the potential to deliver one single dose of gene therapy directly to the GBM tumor environment and block the production of EGFR and activate the expression of a stable therapeutic isoform of EGFR. To advance our therapeutic strategy, we have analyzed the EGFR secondary structure using selective 2’ hydroxyl acylation and primer extension followed by mutational profiling (SHAPE-MaP). SHAPE-MaP reactivity profiles were generated revealing the structure of splicing and cryptic polyadenylation signal (PAS) elements within the targeted region. We identified enhancer binding motifs surrounding the 5’ splice site and hidden elements of the cryptic PAS. Based on these structural profiles, we generated RNA therapies to unravel the hidden PAS to activate expression of the short therapeutic isoform.

Population pharmacokinetics of levodopa gel infusion in Parkinson\u2019s disease: effects of entacapone infusion and genetic polymorphism

Levodopa-entacapone-carbidopa intestinal gel (LECIG) provides continuous drug delivery through intrajejunal infusion. The aim of this study was to characterize the population pharmacokinetics of levodopa following LECIG and levodopa-carbidopa intestinal gel (LCIG) infusion to investigate suitable translation of dose from LCIG to LECIG treatment, and the impact of common variations in the dopa-decarboxylase (DDC) and catechol-O-methyltransferase (COMT) genes on levodopa pharmacokinetics. A non-linear mixed-effects model of levodopa pharmacokinetics was developed using plasma concentration data from a double-blind, cross-over study of LCIG compared with LECIG in patients with advanced Parkinson’s disease (n = 11). All patients were genotyped for rs4680 (polymorphism of the COMT gene), rs921451 and rs3837091 (polymorphisms of the DDC gene). The final model was a one compartment model with a high fixed absorption rate constant, and a first order elimination, with estimated apparent clearances (CL/F), of 27.9 L/h/70 kg for LCIG versus 17.5 L/h/70 kg for LECIG, and apparent volume of distribution of 74.4 L/70 kg. Our results thus suggest that the continuous maintenance dose of LECIG, on a population level, should be decreased by approximately 35%, to achieve similar drug exposure as with LCIG. An effect from entacapone was identified on all individuals, regardless of COMT rs4680 genotype. The individuals with higher DDC and COMT enzyme activity showed tendencies towards higher levodopa CL/F. The simultaneous administration of entacapone to LCIG administration results in a 36.5% lower apparent levodopa clearance, and there is a need for lower continuous maintenance doses, regardless of patients’ COMT genotype.

Long-Term Stability of Anti-Vascular Endothelial Growth Factor (a-VEGF) Biologics Under Physiologically Relevant Conditions and Its Impact on the Development of Long-Acting Delivery Systems.

The port delivery system with ranibizumab (PDS) is an investigational long-acting drug delivery system for the continuous release of ranibizumab, an anti-VEGF biologic, in the vitreous humor. The efficacy of the PDS implant relies on the maintenance of long-term drug stability under physiological conditions. Herein, the long-term stability of three anti-VEGF biologics - ranibizumab, bevacizumab and aflibercept - was investigated in phosphate buffered saline (PBS) at 37°C for several months. Comparison of stability profiles shows that bevacizumab and aflibercept are increasingly prone to aggregation whereas ranibizumab undergoes minimal aggregation. Ranibizumab also shows the smallest loss in antigen binding capacity after long-term incubation in PBS. Even though the aggregated forms of bevacizumab and aflibercept bind to VEGF, the consequences of aggregation on immunogenicity, implant function and efficacy are unknown. These results highlight the importance of maintaining long-term drug stability under physiologically relevant conditions which is necessary for achieving efficacy with an invivo continuous drug delivery device such as the PDS implant.

P57 Continuous drug delivery is significantly affected by relative height changes between patient and syringe driver

AimsSyringe drivers are the principle method of giving continuous infusions of important drugs to patients. Many of these drugs are critical for the maintenance of normal physiology. Anecdotal evidence abounds of severe patient instability on movement of syringe drivers during infusion. Our objective was to define the variation in drug delivery seen in three different syringe drivers, with changes in relative height between the syringe driver and the end of the giving set.MethodsThree syringe drivers (Alaris CC (Becton Dickinson), Perfusor Space (B Braun), and Synamed μSP6000 (Arcomed)) were analysed for reliability of flow at 0.5, 1, 2, and 5 ml/hr. A small air bubble was introduced into the giving set, and the progression of this was documented before and after a vertical movement of the syringe driver by 25 or 50 cm upwards or downwards relative to the delivery port.ResultsFor all pumps, delivery was interrupted on movement of the pumps downwards, and a bolus was given with movement of the pump upwards. Delivery halted at lower pump speeds for longer than higher pump speeds. The maximum delivery interruption was 11.8 minutes. Boluses given on moving the pump up were calculated as the equivalent number of minutes needed to deliver the bolus volume at steady state. The maximum bolus given was equivalent to 15.8 minutes of delivery. We were unable to eliminate the effects seen by very slow, steady movement of the pumps up or down. Static height differences made no difference to delivery.ConclusionsSyringe drivers should not be moved vertically in relation to the patient. Critical drug delivery is interrupted for up to 12 minutes with relative downward movements, and significant boluses of drugs are given with relative upward movements. As far as possible, elimination of relative height movements is advised, and extreme caution is necessary if any movements are unavoidable.

Dermal pharmacokinetics of rivastigmine-loaded liposomes: an ex vivo–in vivo correlation study

The aim of the present study was to develop a topical liposomal formulation as a transdermal delivery of rivastigmine for the treatment of Alzheimer’s disease as an alternative to the oral dosage form and to achieve smooth continuous drug delivery and maintain plasma levels within the therapeutic window. Rivastigmine-loaded liposomes were prepared by a thin layer hydration technique that was applied in ex vivo–in vivo correlation study. Permeability parameters through rat skin in ex vivo study and pharmacokinetic parameters in the in vivo study were evaluated. The ex vivo permeation study showed that liposomes provided steady-state flux 0.11 ± 0.01 mg/cm.h that were more than 2-fold the aqueous control. In the in vivo experiments, after topical application of optimized rivastigmine liposomes, the C max 208 ng/ml and AUC0–24 3605 (ng.h/ml) were also significantly higher than the control group (both p < 0.01). A point-to-point significant linear correlation was found between ex vivo and in vivo parameters, meaning in vivo pharmacokinetic parameters can be predicted by ex vivo permeation parameters. These data suggest that a liposomal formulation could be an effective carrier to enhance rivastigmine permeation through the skin and maintain plasma levels within the therapeutic window.

Formulation Designing Factors for Development of Repaglinide Transdermal Therapeutic System

Repaglinide, a blood-glucose-lowering drug, has a shorter half-life (~1 hour), low oral bioavailability (LOB) (~56 %) due to the first-pass metabolism, and required frequent dosing (Three to four times daily) to control blood glucose level. Repaglinide transdermal therapeutic system (TTS) was prepared to provide continuous drug delivery for a prolonged time. Designing factors for development are selection and optimization of product ingredients, optimization of drug load, types of TTS, matrix thickness, and optimization of drug delivery. During development, repaglinide TTS were evaluated for physicochemical characteristics and ex-vivo skin flux at different stages. Based on the pre-formulation study data, Durotak 87-2516® was selected as a pressure-sensitive adhesive. Different formulations of a drug in adhesive matrix and reservoir type repaglinide TTS were evaluated for ex-vivo skin permeation (flux) study. The skin flux results show that sandwiched reservoir type repaglinide TTS can provide average cumulative drug permeation and flux rate of 379.75 ± 47.89 μg/cm2 and 4.62 ± 1.00 μg/cm2/hr respectively for sustain drug delivery over the time of 72 hours. Developed sandwiched reservoir type repaglinide TTS has the potential to sustain delivery of drug for 72 hours, which reduce frequent dosing and thereby improve patient compliance.

Continuous Drug Delivery is Significantly Affected by Relative Height Changes Between Patient and Syringe Driver.

Syringe drivers are the principle method of giving small-volume continuous infusions of important drugs to patients. Many of these drugs are critical for the maintenance of normal physiology. Anecdotal evidence abounds of severe patient instability on movement of syringe drivers during infusion. We aimed to define the variation in drug delivery seen in three syringe drivers, with changes in relative height between the syringe driver and the end of the giving set. Three syringe drivers (Alaris CC [Becton Dickinson], Perfusor Space [B Braun], and Synamed μSP6000 [Arcomed]) were analyzed for reliability of flow at 0.5, 1, 2, and 5 mL/h. This is an in vitro investigation. A small air bubble was introduced into the giving set, and the progression of this was documented before and after a vertical movement of the syringe driver by 25 or 50 cm upward or downward relative to the delivery port. For all pumps, delivery was interrupted on movement of the pumps downward, and a bolus was given with movement of the pump upward. Delivery halted at lower pump speeds for longer than higher pump speeds. The maximum delivery interruption was 11.8 minutes. Boluses given on moving the pump up were calculated as the equivalent number of minutes needed to deliver the bolus volume at steady state. The maximum bolus given was equivalent to 15.8 minutes of delivery. We were unable to eliminate the effects seen by very slow, steady movement of the pumps up or down. Static height differences made no difference to delivery. Syringe drivers should not be moved vertically in relation to the patient. Critical drug delivery is interrupted for up to 12 minutes with relative downward movements, and significant boluses of drugs are given with relative upward movements. As far as possible, elimination of relative height movements is advised, and extreme caution is necessary if any movements are unavoidable.

A Comprehensive Review of Concentrated Growth Factors and Their Novel Applications in Facial Reconstructive and Regenerative Medicine.

Concentrated growth factors (CGFs) are the latest generation of platelet concentrates. The objective of developing CGF is to increase therapeutic efficacy. However, few studies have supported the superiority of CGF in composition and efficacy. The reconstruction and regeneration process is complicated and long term, whereas bioactivity of CGF is not durable. The purpose of this review is threefold. The first is to recommend more comparative studies between CGF and other platelet concentrates. The second is to constitute a continuous drug delivery system by combining CGF with other biomaterials. Finally, the novel use of CGF in facial regenerative and reconstructive medicine will be highlighted. A comprehensive review of literature regarding the use of CGF in facial regenerative and reconstructive medicine was performed. Based on the inclusion and exclusion criteria, a total of 135 articles were included. The use of CGF involving facial rejuvenation, cartilage grafting, facial bone defects, facial peripheral nerve injury and wounding is reviewed. The reconstructive and regenerative principles lie in firm fibrin scaffolds and continuous in situ delivery of multiple growth factors. CGF represents an advance in personalized medicine concept. However, the current scientific evidences about the use of CGF are limited. More basic and clinical studies should be conducted to understand the characteristics and clinical application of CGF. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Validation of Nanoparticle Response to the Sound Pressure Effect during the Drug-Delivery Process.

Intravenous delivery is the fastest conventional method of delivering drugs to their targets in seconds, whereas intramuscular and subcutaneous injections provide a slower continuous delivery of drugs. In recent years, nanoparticle-based drug-delivery systems have gained considerable attention. During the progression of nanoparticles into the blood, the sound waves generated by the particles create acoustic pressure that affects the movement of nanoparticles. To overcome this issue, the impact of sound pressure levels on the development of nanoparticles was studied herein. In addition, a composite nanostructure was developed using different types of nanoscale substances to overcome the effect of sound pressure levels in the drug-delivery process. The results demonstrate the efficacy of the proposed nanostructure based on a group of different nanoparticles. This study suggests five materials, namely, polyimide, acrylic plastic, Aluminum 3003-H18, Magnesium AZ31B, and polysilicon for the design of the proposed structure. The best results were obtained in the case of the movement of these molecules at lower frequencies. The performance of acrylic plastic is better than other materials; the sound pressure levels reached minimum values at frequencies of 1, 10, 20, and 60 nHz. Furthermore, an experimental setup was designed to validate the proposed idea using advanced biomedical imaging technologies. The experimental results demonstrate the possibilities of detecting, tracking, and evaluating the movement behaviors of nanoparticles. The experimental results also demonstrate that the lowest sound pressure levels were observed at lower frequency levels, thus proving the validity of the proposed computational model assumptions. The outcome of this study will pave the way to understand the interaction behaviors of nanoparticles with the surrounding biological environments, including the sound pressure effect, which could lead to the useof such an effect in facilitating directional and tactic movements of the micro- and nano-motors.

Ultrasound-guided serratus plane block with continuous postoperative drug delivery system for acute nociceptive and neuropathic pain after mastectomy

ABSTRACT Objectives The study compared the effect of pre-emptive serratus plane block, with postoperative continuous drug delivery: into the serratus plane (bupivacaine 0.125% CDB), or around the wound (lidocaine 5% patches LP) on acute nociceptive and neuropathic pain after mastectomy. Methods This randomized-controlled blinded study was conducted on 43 women scheduled for mastectomy for breast cancer, under standard general anaesthesia and pre-emptive serratus plane block. Patients were randomly assigned to 2 groups according to postoperative analgesia: Group (S) received a 6 ml hourly doses of bupivacaine (0.125%) for 24 hrs using an epidural catheter inserted into the serratus plane and Group (L) received 2 LP around the wound for 12 hrs/24 hrs. IV morphine (3 mg) was given to patients with visual analogue scale >3 and repeated at 10 min intervals if needed. Measurements Primary outcome was visual analogue scale (VAS) for nociceptive pain at rest and arm movement for 24 hrs postoperatively. Secondary outcomes included incidence, characters and severity of acute neuropathic pain, using DN4 questionnaire and Neuropathic Pain Scale (NPS) for 4 weeks. Hypothesia to touch and temperature, mechanical allodynia and hyperalgesia were assessed between T2-T6 compared to the other side for 4 weeks. Patient satisfaction was measured by satisfaction score. Results There was no significant difference between the two groups regarding VAS at rest and movement, incidence, duration and sites of neuropathic pain and its effect on sleep, mood and work. The intensity of numbness measured by NPS was significantly less in Group L than Group S in the third postoperative week (P ≤ 0.05). Patients ‘satisfaction with postoperative pain relief was higher in Group L (P ≤ 0.05). Conclusion LP are as effective in reducing acute nociceptive pain as continuous bupivacaine delivery into the serratus plane. They are superior in reducing numbness and favoured by patients postmastectomy.

A randomized comparative study to evaluate efficacy and safety of transdermal buprenorphine patch with transdermal fentanyl patch as Pre-emptive analgesia in postoperative pain control in patients undergoing mastectomy surgery

Introduction: Amongst the various modes of delivery, transdermal route has several potential benefits over other routs of administration for perioperative analgesia. These include noninvasive dosing, better absorption and lack of first pass metabolism. It provides steady and continuous drug delivery resulting in steady plasma concentration. Experimental approach: 60 patients undergoing mastectomy surgery were randomly divided in 2 groups (n=30). Group A received buprenorphine 10 mcg/h TDS and group B received 25 mcg/h fentanyl TDS, 4 hours prior to surgery. Patients were followed for three days for postoperative pain relief and adverse effects. Major findings: The mean level of VAS was significantly lower in group B. The mean level of sedation score was significantly lower in Group B. 13.3% patients in group A required single dose of rescue analgesic while 0.00% in group B. 18% patient in fentanyl group and 13.3% patients in buprenorphine group experienced some adverse effects. Conclusion: Fentanyl and buprenorphine TDS were safe and effective in controlling postoperative pain. Fentanyl is better than buprenorphine in this respect.

A gum Arabic assisted sustainable drug delivery system for adult Drosophila.

ABSTRACTLarge-scale compound screening in adult flies is hampered by the lack of continuous drug delivery systems and poor solubility of numerous compounds. Here we found that gum Arabic (Acacia/Senegal gum), a widely used stabilizer, can also emulsify lipophilic compounds and profoundly increase their accessibility to target tissues in Drosophila and mice. We further developed a gum Arabic-based drug delivery system, wherein the drug was ground into gum Arabic and emulsified in liquid food fed to flies by siphoning through a U-shape glass capillary. This system did not affect food intake nor cell viability. Since drugs were continuously delivered by siphoning, minimal compound waste and less frequent food changes make this system ideal for large-scale long-term screenings. In our pilot screening for antitumor drugs in the NCI DTP library, we used a Drosophila model of colorectal cancer and identified two drugs that are especially hydrophobic and were not identified in previous screenings. Our data demonstrated that gum Arabic facilitates drug delivery in animal models and the system is suitable for long-term high-throughput drug screening in Drosophila. This system would accelerate drug discovery for chronic and cognitive conditions.

Evaluation of a novel flow-controlled syringe infusion pump for precise and continuous drug delivery at low flow rates: a laboratory study.

Syringe infusion pumps are used for the administration of short-acting drugs in anaesthesia and critical care medicine, but are prone to flow irregularities at low flow rates. A flow-controlled syringe infusion pump using an integrated flow sensor for feedback control represents a new approach to overcoming these limitations. This study compares the performance of a prototype flow-controlled syringe pump both at start-up, and during vertical displacement manoeuvres, with that of a standard infusion syringe pump. The novel pump almost completely eliminated delays at start-up and flow irregularities during hydrostatic pressure changes. Related fluctuations in plasma drug concentration were minimised and the known disadvantages of standard syringe infusion pumps currently used in clinical practice were reduced. Besides providing fast start-up to steady-state flow and precise continuous drug delivery at low flow rates during hydrostatic pressure changes, the new pump offers the potential for the development of target-controlled infusion algorithms for short-acting cardiovascular and other drugs.

SDF-1/CXCR4 axis coordinates crosstalk between subchondral bone and articular cartilage in osteoarthritis pathogenesis.

Crosstalk between subchondral bone and articular cartilage is considered a central feature of osteoarthritis (OA) initiation and progression, but its underlying molecular mechanism remains elusive. Meanwhile, specific administration of drugs in subchondral bone is also a great challenge during investigation of the process. We here explore the role of stromal cell-derived factor 1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4) axis in the crosstalk between subchondral bone and articular cartilage in OA pathogenesis, using osmotic infusion pumps implanted in tibial subchondral bone directly to ensure quantitative, continuous and steady drug delivery over the entire experiment. We found that increased SDF-1 in subchondral bone firstly induced subchondral bone deterioration by erroneous Mesenchymal Stem Cells (MSCs) recruitment and excessive bone resorption in anterior cruciate ligament transection (ACLT) mice. Deterioration of subchondral bone then led to the traverse of SDF-1 from subchondral bone to overlying cartilage. Finally, SDF-1 from underlying subchondral bone combined with CXCR4 in chondrocytes to induce articular cartilage degradation by promoting the shift of transforming growth factor-β receptor type I (TβRI) in chondrocytes from activin receptor-like kinase 5 (ALK5) to activin receptor-like kinase 1 (ALK1). More importantly, specific inhibition of SDF-1/CXCR4 axis in ACLT rats attenuated OA by stabilizing subchondral bone microarchitecture, reducing SDF-1 in cartilage and abrogating the shift of TβRI in chondrocytes. Our data demonstrate that the SDF-1/CXCR4 axis may coordinate the crosstalk between subchondral bone and articular cartilage in OA pathogenesis. Therefore, specific inhibition of SDF-1/CXCR4 axis in subchondral bone or intervention in SDF-1 traverse may be therapeutic targets for OA.

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.

Treatment Strategies in Diffuse Midline Gliomas With the H3K27M Mutation: The Role of Convection-Enhanced Delivery in Overcoming Anatomic Challenges.

Diffuse midline gliomas harboring the H3 K27M mutation—including the previously named diffuse intrinsic pontine glioma (DIPG)—are lethal high-grade pediatric brain tumors that are inoperable and without cure. Despite numerous clinical trials, the prognosis remains poor, with a median survival of ~1 year from diagnosis. Systemic administration of chemotherapeutic agents is often hindered by the blood brain barrier (BBB), and even drugs that successfully cross the barrier may suffer from unpredictable distributions. The challenge in treating this deadly disease relies on effective delivery of a therapeutic agent to the bulk tumor as well as infiltrating cells. Therefore, methods that can enhance drug delivery to the brain are of great interest. Convection-enhanced delivery (CED) is a strategy that bypasses the BBB entirely and enhances drug distribution by applying hydraulic pressure to deliver agents directly and evenly into a target region. This technique reliably distributes infusate homogenously through the interstitial space of the target region and achieves high local drug concentrations in the brain. Moreover, recent studies have also shown that continuous delivery of drug over an extended period of time is safe, feasible, and more efficacious than standard single session CED. Therefore, CED represents a promising technique for treating midline tumors with the H3K27M mutation.

Comparison of postoperative analgesic efficacy of transdermal and epidural buprenorphine following major abdominal surgeries: a prospective randomized study

Introduction A transdermal delivery system provides steady and continuous drug delivery as compared with epidural route. The aim of the present study was to compare the efficacy of transdermal and epidurally administered buprenorphine in providing adequate postoperative analgesia in patients undergoing major abdominal surgeries. Patients and methods The present study was a prospective, randomized, open-label study conducted in 30 patients aged between 18 and 70 years undergoing major abdominal surgeries. Patients were randomized equally into two groups. T group received a transdermal buprenorphine 10-mg patch, with a delivery rate of 10 μg/h, which was applied ∼20–24 h before surgery. On day of the surgery for patients belonging to E group, an epidural catheter was placed at the start of the surgery and buprenorphine 150 μg in 10-ml saline was given epidurally. All patients received general anesthesia following standardized anesthesia protocol. In the postoperative period, pain relief was checked using numerical rating scale. Results Mann–Whitney U test and independent t test were used as applicable. Numerical rating score was significantly higher in group T at 0, 6, 12, 18, 24, and 30 h as compared with group E. It became comparable at 36, 42, and 48 h. The need for rescue analgesia was significantly higher in group T as compared with group E. Conclusion Epidurally administered buprenorphine is superior in providing adequate analgesia in the early postoperative period in patients undergoing major abdominal surgeries as compared with the transdermal route.