Drug Administration Strategies Research Articles

Chronotoxici-Plate Containing Droplet-Engineered Rhythmic Liver Organoids for Drug Toxicity Evaluation.

The circadian clock coordinates the daily rhythmicity of biological processes, and its dysregulation is associated with various human diseases. Despite the direct targeting of rhythmic genes by many prevalent and World Health Organization (WHO) essential drugs, traditional approaches can't satisfy the need of explore multi-timepoint drug administration strategies across a wide range of drugs. Here, droplet-engineered primary liver organoids (DPLOs) are generated with rhythmic characteristics in 4 days, and developed Chronotoxici-plate as an in vitro high-throughput automated rhythmic tool for chronotherapy assessment within 7 days. Cryptochrome 1 (Cry1) is identified as a rhythmic marker in DPLOs, providing insights for rapid assessment of organoid rhythmicity. Using oxaliplatin as a representative drug, time-dependent variations are demonstrated in toxicity on the Chronotoxici-plate, highlighting the importance of considering time-dependent effects. Additionally, the role of chronobiology is underscored in primary organoid modeling. This study may provide tools for both precision chronotherapy and chronotoxicity in drug development by optimizing administration timing.

Low schistosomiasis and soil-transmitted helminthiasis prevalence and intensities in selected communities in Davao de Oro and Davao del Norte, the Philippines: A setting for interruption of transmission?

Parasitic neglected tropical diseases, such as schistosomiasis and soil-transmitted helminthiasis (STH), remain as significant public health concerns in developing countries such as the Philippines. This study aimed to determine the prevalence and intensity of schistosomiasis and STH among school-age children (SAC) and adults in two co-endemic provinces in Mindanao in southern Philippines as part of monitoring of national control programs. Stool samples were collected, processed using Kato-Katz technique, and examined microscopically for presence of intestinal helminth ova. A total of 776 SAC and 526 adults participated in the study. Low schistosomiasis prevalence was generally observed in SAC (0.8%) and adults (0.4%). Generally low STH prevalence was reported in both SAC (3.9%) and adults (3.4%). Only three SAC had heavy intensity STH, which was not seen in adults. Results indicate a state of good morbidity control, which may be a result of effective implementation of mass drug administration (MDA) strategy for schistosomiasis, STH, and lymphatic filariasis in the last several years. The low prevalence and intensities of infections may also be partly attributed to the low diagnostic sensitivity of Kato-Katz technique in detecting low intensity intestinal helminth infections. While results of this study also indicate similarly low levels of both these infections in previous studies, sustaining high MDA coverage rates and addressing remaining challenges related to intensified case finding and treatment, improvements in safe water, sanitation, and hygiene, veterinary public health, and vector ecology and management will be necessary to interrupt transmission in these areas.

Comprehensive Therapeutic Approaches to Tuberculous Meningitis: Pharmacokinetics, Combined Dosing, and Advanced Intrathecal Therapies.

Tuberculous meningitis (TBM) presents a critical neurologic emergency characterized by high mortality and morbidity rates, necessitating immediate therapeutic intervention, often ahead of definitive microbiological and molecular diagnoses. The primary hurdle in effective TBM treatment is the blood-brain barrier (BBB), which significantly restricts the delivery of anti-tuberculous medications to the central nervous system (CNS), leading to subtherapeutic drug levels and poor treatment outcomes. The standard regimen for initial TBM treatment frequently falls short, followed by adverse side effects, vasculitis, and hydrocephalus, driving the condition toward a refractory state. To overcome this obstacle, intrathecal (IT) sustained release of anti-TB medication emerges as a promising approach. This method enables a steady, uninterrupted, and prolonged release of medication directly into the cerebrospinal fluid (CSF), thus preventing systemic side effects by limiting drug exposure to the rest of the body. Our review diligently investigates the existing literature and treatment methodologies, aiming to highlight their shortcomings. As part of our enhanced strategy for sustained IT anti-TB delivery, we particularly seek to explore the utilization of nanoparticle-infused hydrogels containing isoniazid (INH) and rifampicin (RIF), alongside osmotic pump usage, as innovative treatments for TBM. This comprehensive review delineates an optimized framework for the management of TBM, including an integrated approach that combines pharmacokinetic insights, concomitant drug administration strategies, and the latest advancements in IT and intraventricular (IVT) therapy for CNS infections. By proposing a multifaceted treatment strategy, this analysis aims to enhance the clinical outcomes for TBM patients, highlighting the critical role of targeted drug delivery in overcoming the formidable challenges presented by the blood-brain barrier and the complex pathophysiology of TBM.

Abstract LB272: Sequential inhibition of PARP and BET as a rational therapeutic strategy for glioblastoma multiforme

Abstract Glioblastoma multiforme (GBM), characterized as one of the most aggressive brain cancers, presents significant treatment challenges due to its rapid growth, heterogeneity, and robust defensive mechanisms. Despite advancements in neuro-oncology, GBM's prognosis remains grim, with the median survival of approximately 15 months, underscoring the urgent need for innovative therapeutic strategies. Facing these challenges, PARP inhibitors (PARPi) hold substantial promise in treating GBM, evidenced by over 20 ongoing clinical trials. However, their application has been limited by side effects such as nausea, fatigue, and particularly anemia, as well as a narrow therapeutic spectrum focusing mainly on patients with homologous recombination deficiency (HRDness). Through unbiased transcriptomic and proteomic sequencing, and employing Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA), and Transcriptome-Proteome Correlation Analysis, we discovered that the BET inhibitor (BETi) Birabresib profoundly alters the processes of DNA replication and cell cycle progression in GBM cells, extending beyond the previously known impact of BET inhibition on homologous recombination repair. In vitro experiments using GBM cell lines and patient-derived primary GBM cells demonstrated that concurrent administration of PARPi and BETi can synergistically inhibit GBM. Intriguingly, we observed that DNA damage persists after the discontinuation of PARPi monotherapy. Leveraging these residual effects of PARPi, subsequent BETi administration elevated replication stress levels, leading to the inactivation of GBM cell cycle checkpoints, with efficacy comparable to concurrent treatment. The treatment-induced prolonged stalling of replication forks resulted in their collapse and the formation of double-ended double-strand breaks (DSBs). In GBM cells with elevated baseline replication stress, the sequential regimen exhibits comparable efficacy to concurrent treatment, while protecting normal glial cells with lower baseline replication stress from DNA toxicity and subsequent death. In vivo orthotopic transplantation tumor experiments in zebrafish and nude mice demonstrated consistent effects, indicating that sequential administration of PARPi followed by BETi maintained anti-tumor efficacy, similar to concurrent treatment, while reducing toxicity, as evident by the reduced impact on hemoglobin levels. Our findings provide a broader and deeper understanding of the synergistic interaction between BETi and PARPi than previously recognized. This study offers compelling preclinical evidence supporting the development of innovative drug administration strategies focusing on PARPi for GBM therapy. Citation Format: Xin Peng, Xin Huang, Shaolu Zhang, Naixin Zhang, Shengfan Huang, Yingying Wang, Zhenxing Zhong, Shan Zhu, Haiwang Gao, Zixiang Yu, Xiaotong Yan, Zhennan Tao, Yuxiang Dai, Zhe Zhang, Xi Chen, Feng Wang, Francois X. Claret, Ning Ji, Yuxu Zhong, Dexin Kong. Sequential inhibition of PARP and BET as a rational therapeutic strategy for glioblastoma multiforme [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB272.

Toward the elimination of NTDs: application of cost-effective and sensitive molecular environmental surveillance tools—a pilot study

Neglected tropical diseases (NTDs) affect over a billion people worldwide. The 2021–2030 NTD road map calls for innovative and highly efficient interventions to eliminate or significantly reduce the burden of NTDs. These include sensitive and cost-effective diagnostic techniques for disease surveillance. Environmental surveillance has been employed effectively in this regard to measure and track infectious diseases such as polio on a population-wide scale. In this study, environmental surveillance was used as a cost-effective tool for the detection of soil-transmitted helminths (STHs) in Accra, Ghana, in an area that is populated by urban vegetable farmers. The activities of urban farmers expose them to the risk of STH infection, as well as impact the transmission in urban areas since leafy vegetables could carry infective stages of STHs. A total of 32 wastewater samples were collected from eight points on the Nima Creek (the main source of irrigation for the farmers) over a 7-week period. Real-time PCR and melt peak analysis were used to screen four STHs (i.e., Ascaris lumbricoides, Necator americanus, Ancylostoma duodenale, and Trichuris trichiura). This study revealed that A. lumbricoides (17 out of 32 wastewater samples, 53.3%) was the most prevalent STH, followed by A. duodenale (31.2%), T. trichiura (21.9%), and N. americanus (12.5%). Environmental surveillance helps in the detection of the types of STH pathogens circulating within the community and in the design of mass drug administration (MDA) strategies. This surveillance technique can also provide preliminary information for environmental modifications to help reduce STH transmission in line with the One Health approach recommended in the 2021–2030 NTD road map.

Is a mass drug administration deworming programme for school-aged children enough to reduce the prevalence of soil-transmitted helminths and Schistosoma mansoni in adults: a cross-sectional study from Togo

BackgroundThe world health organization (WHO) introduced the mass drug administration (MDA) strategy in order to reduce the prevalence of soil-transmitted helminths (STHs) and Schistosoma mansoni in endemic areas. However, this strategy is not implemented in adult population in Togo. Thus, the question arose if the present MDA strategy contributes to the reduction of transmission rates. The present study aimed to monitor the prevalence of STHs and S. mansoni among adult’s, between 2017 and 2022, in the central region of Togo.MethodsTwo cross-sectional studies were conducted in six villages in the central region of Togo in 2017 and 2022. Stool samples were collected from adults over the age of 18 years. To assess STHs and S. mansoni infections, real-time multiplex qPCR and Kato-Katz techniques were performed. Data were analysed using SPSS software version 21 and GraphPad PRISM version 9.2.0. A p-value less than 0.05 was considered statistically significant.ResultsA total of 210 and 289 individuals were recruited in 2017 and 2022, respectively. We detected significant increase in the prevalence of STHs and S. mansoni from 7.61% to 24.56% (p=0.0008) and from 27.62% to 46.36% (p=0.0014) by Kato-Katz and RT-qPCR, respectively. The prevalence of Ancylostoma duodenale infection was the highest with an increase from 7.14% to 23.53% by Kato-Katz and 9.09% to 40.0% by RT-qPCR.ConclusionThe prevalence of STHs and S. mansoni increased in the adult population in the central region of Togo from 2017 to 2022, despite the implementation of MDA in school-aged children. Hence, there is an urgent need to include adult individuals and adapt the MDA programme in the central region of Togo.

Inhaled immunoantimicrobials for the treatment of chronic obstructive pulmonary disease.

Effective therapeutic modalities and drug administration strategies for the treatment of chronic obstructive pulmonary disease (COPD) exacerbations are lacking. Here, mucus and biofilm dual-penetrating immunoantimicrobials (IMAMs) are developed for bridging antibacterial therapy and pro-resolving immunotherapy of COPD. IMAMs are constructed from ceftazidime (CAZ)-encapsulated hollow mesoporous silica nanoparticles (HMSNs) gated with a charge/conformation-transformable polypeptide. The polypeptide adopts a negatively charged, random-coiled conformation, masking the pores of HMSNs to prevent antibiotic leakage and allowing the nebulized IMAMs to efficiently penetrate the bronchial mucus and biofilm. Inside the acidic biofilm, the polypeptide transforms into a cationic and rigid α helix, enhancing biofilm retention and unmasking the pores to release CAZ. Meanwhile, the polypeptide is conditionally activated to disrupt bacterial membranes and scavenge bacterial DNA, functioning as an adjuvant of CAZ to eradicate lung-colonizing bacteria and inhibiting Toll-like receptor 9 activation to foster inflammation resolution. This immunoantibacterial strategy may shift the current paradigm of COPD management.

Real-Time Measurement of Antiglaucoma Drugs in Porcine Eyes Using Boron-Doped Diamond Microelectrodes.

The primary treatment for glaucoma, the most common cause of intermediate vision impairment, involves administering ocular hypotensive drugs in the form of topical eye drops. Observing real-time changes in the drugs that pass through the cornea and reach the anterior chamber of the eye is crucial for improving and developing safe, reliable, and effective medical treatments. Traditional methods for measuring temporal changes in drug concentrations in the aqueous humor employ separation analyzers such as LC-MS/MS. However, this technique requires multiple measurements on the eyes of various test subjects to track changes over time with a high temporal resolution. To address this issue, we have developed a measurement method that employs boron-doped diamond (BDD) microelectrodes to monitor real-time drug concentrations in the anterior chamber of the eye. First, we confirmed the electrochemical reactivity of 13 antiglaucoma drugs in a phosphate buffer solution with a pH of 7.4. Next, we optimized the method for continuous measurement of timolol maleate (TIM), a sympathetic beta-receptor antagonist, and generated calibration curves for each BDD microelectrode using aqueous humor collected from enucleated porcine eyes. We successfully demonstrated the continuous ex vivo monitoring of TIM concentrations in the anterior chambers of these enucleated porcine eyes. The results indicate that changes in intracameral TIM concentrations can be monitored through electrochemical measurements using BDD microelectrodes. This technique holds promise for future advancements in optimizing glaucoma treatment and drug administration strategies.

Praziquantel-related visual disorders among recipients in mass drug administration campaigns in schistosomiasis endemic settings: Systematic review and meta-analysis protocol.

Hundreds of millions of doses of Praziquantel (PZQ) have been administered to persons with and without schistosomiasis living in schistosomiasis endemic settings, through the mass drug administration (MDA) strategy which started in the early 2000s. A recent publication suggested high risk of PZQ-related visual disorders, raising public health concerns. We aim to systematically synthesize evidence on the magnitude of PZQ-related visual disorders. We will search PubMed, Google Scholar, CINAHL, SCOPUS, CENTRAL and LILACS from 1977 (when the first human clinical trials on PZQ started) to 31st May 2024, with no language restrictions. The key search terms will include "Praziquantel", "PZQ", "visual disorder", "adverse events", "side effects", "blurry vision" and "visual impairment" together with alternative terms and synonyms. All the countries endemic for schistosomiasis will be included as search terms. We will also search HINARI, Africa Journals Online, Thesis Databases and Preprint Repositories. Where necessary, we will contact expert researchers working in the field of schistosomiasis, UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR), pharmaceutical industries, country-specific Food and Drug Authorities (FDAs) and the European Medicines Agency databases. We will search Conference Proceedings and reference lists of relevant studies for additional studies. At least two authors will independently select studies, extract data and assess risk of bias in the included studies. Any disagreements or discrepancies will be resolved through discussion between the reviewers. Heterogeneity will be explored graphically, and statistically using the I2-statistic. We will conduct random-effects meta-analysis when heterogeneity is appreciable, and express dichotomous outcomes (visual adverse events including excessive lacrimation, blurry vision and visual impairments) as risk ratio (RR) or Odds Ratio (OR) with their 95% confidence interval (CI). We will perform subgroup analysis to assess the impact of heterogeneity, and sensitivity analyses to test the robustness of the effect estimates. The overall level of evidence will be assessed using GRADE. The present review expects to identify and categorize visual disorders occurring after administration of PZQ, alone or in combination with other drugs. By synthesizing the data from multiple studies, the review aims to present a quantitative assessment of the risk or odds of experiencing a visual disorder in different populations after ingesting PZQ. The review will also generate insights into whether PZQ in combination with other drugs are associated with increased odds of visual disorders and whether the occurrence of visual disorders correlates with dosage or treatment duration. Policymakers, public health experts and stakeholders could rely on the review findings to deliver context-sensitive preventive chemotherapy programs by adjusting drug combinations or dosing schedules to reduce risk of visual adverse effects in populations treated with PZQ. The review aims to identify gaps in the current evidence regarding visual disorders following PZQ administration in schistosomiasis endemic settings which can serve as the basis for future research on important but unanswered questions. The findings of this study will be disseminated through stakeholder forums, conferences, and peer-review publications. The review protocol has been registered in the International Prospective Register for Systematic Reviews (PROSPERO)- CRD42023417963.

Discussion on the Treatment Methods and Value of the No-Reflow Phenomenon During Percutaneous Coronary Intervention

Objective: To explore the treatment methods and value of the no-reflow phenomenon during percutaneous coronary intervention (PCI). Methods: 180 patients with acute myocardial infarction (AMI) who underwent PCI treatment at the First Hospital of Hebei Medical University from November 2020 to December 2022 were selected and divided into Group A, Group B, and Group C by random number table extraction method, each group included 60 cases. Group A received intracoronary injection of recombinant human urokinase and Group B received intracoronary injection of diltiazem. Group C adopted a targeted drug administration strategy of “front and back pinch method,” where targeted thrombolysis was performed in the target vessel before the stent was released to quickly dissolve the residual thrombus near the lesion and the small distal thrombus; recombinant human urokinase was subsequently injected in the targeted vessel. The incidence of cardiovascular events, cardiac function, and quality of life of the three groups were analyzed. Results: After the intervention, the incidence rates of angina pectoris, heart failure, and recurrent myocardial infarction in Group C were lower than those in Group B (P < 0.05); the overall incidence rate was the lowest in Group C, followed by Group A and Group B; after intervention, left ventricular end-diastolic diameter, end-systolic diameter, and ejection fraction in Groups A and C were all better than those of group B (P < 0.05), and Group C was better than Group A; after intervention, the scores of different dimensions of quality of life in Groups A and C were higher than those of Group B (P < 0.05). Conclusion: AMI patients are prone to the no-reflow phenomenon after PCI treatment. Using recombinant human urokinase to complete the “front and back pinch method” can effectively improve the no-reflow phenomenon, reduce the incidence of cardiovascular events, optimize cardiac function, and improve the patient’s quality of life and survival rate.

Latest development of approved COVID-19 drugs and COVID-19 drugs undergoing late stage clinical trials

As the world adapts to living with SARS-CoV-2, the continuous emergence of new variants has become a primary focus of current studies. In this review, we examined a range of available COVID-19 drugs, including FDA-regulated drugs and those undergoing late-stage clinical trials. Some FDA-regulated drugs, such as Veklury (remdesivir), Olumiant (baricitinib), and Actemra (tocilizumab), have garnered primary clinical status in treatment guidelines, supported by sufficient clinical evidence. Conversely, EUA-authorized therapies, such as some antiviral agents, have demonstrated lower efficacy due to the virus’s constant mutation. We also focused on COVID-19 drugs undergoing late-stage clinical trials, some of which have raised controversy in their administration, such as colchicine and corticosteroids, while others are worth exploring regarding their timing. Several ongoing multi-drug clinical trials are of particular interest, including the “MEDIC-LAUMC” trial that explores drug co-administration, and “ACTIV-2” and “ACTIV-3” trials that compare the effects of different drugs for non-hospitalized and hospitalized patients, respectively. These ongoing clinical trials at a late stage provide essential clinical evidence for future drug authorization and have the potential to provide better drug administration strategies for COVID-19 variants. We look forward to the continued exploration of drug co-administration, comprehensive clinical evidence for treatment, and the investigation of different potential drug utilization.

Hydrogel-Based Microneedle as a Drug Delivery System.

The skin is considered the largest and most accessible organ in the human body, and allows the use of noninvasive and efficient strategies for drug administration, such as the transdermal drug delivery system (TDDS). TDDSs are systems or patches, with the ability and purpose to deliver effective and therapeutic doses of drugs through the skin. Regarding the specific interaction between hydrogels (HG) and microneedles (MNs), we seek to find out how this combination would be applied in the context of drug delivery, and we detail some possible advantages of the methods used. Depending on the components belonging to the HG matrix, we can obtain some essential characteristics that make the combination of hydrogels-microneedles (HG-MNs) very advantageous, such as the response to external stimuli, among others. Based on multiple characteristics provided by HGMNs that are depicted in this work, it is possible to obtain unique properties that include controlled, sustained, and localized drug release, as well as the possibility of a synergistic association between the components of the formulation and the combination of more than one bioactive component. In conclusion, a system based on HG-MNs can offer many advantages in the biomedical field, bringing to light a new technological and safe system for improving the pharmacokinetics and pharmacodynamics of drugs and new treatment perspectives.

Robust Control of Repeated Drug Administration with Variable Doses Based on Uncertain Mathematical Model.

The aim of this paper was to design a repeated drug administration strategy to reach and maintain the requested drug concentration in the body. Conservative designs require an exact knowledge of pharmacokinetic parameters, which is considered an unrealistic demand. The problem is usually resolved using the trial-and-error open-loop approach; yet, this can be considered insufficient due to the parametric uncertainties as the dosing strategy may induce an undesired behavior of the drug concentrations. Therefore, the presented approach is rather based on the paradigms of system and control theory. An algorithm was designed that computes the required doses to be administered based on the blood samples. Since repeated drug dosing is essentially a discrete time process, the entire design considers the discrete time domain. We have also presented the idea of applying this methodology for the stabilization of an unstable model, for instance, a model of tumor growth. The simulation experiments demonstrated that all variants of the proposed control algorithm can reach and maintain the desired drug concentration robustly, i.e., despite the presence of parametric uncertainties, in a way that is superior to that of the traditional open-loop approach. It was shown that the closed-loop control with the integral controller and stabilizing state feedback is robust against large parametric uncertainties.

Optimal administration strategy in chemotherapy regimens using multi-drug cell-cycle specific tumor growth models

During the last decades, various chemotherapeutic drugs have been developed to treat cancer, which makes the chemotherapy design more complicated. To determine optimal drug regimens for patients with colorectal cancer, this study extends two multi-drug cell-cycle specific tumor growth models with distinct action mechanisms. To this end, two of the most commonly used drugs in treating colorectal cancer, namely 5-FU and CPT-11, are assumed. In the extended compartmental models, drug resistance and toxicity are taken into account, and two constraints are imposed to limit the drug dosages during the therapy. Two different drug administration strategies are proposed. In the first strategy, drugs are injected sequentially, while in the second, drugs are simultaneously administered. To minimize the tumor size at the end of therapy or equivalently to prolong the patient’s survival time, an optimal control problem is defined and solved using the genetic algorithm (GA). The in silico results for a variety of scenarios based on the patient’s health conditions demonstrate that the simultaneous approach outperforms the sequential strategy and yields superior results. To verify the resultant findings, a robust evaluation with uncertain model parameters is also performed, which again shows the superiority of the simultaneous strategy.

Prevalence of Plasmodium falciparum gametocytaemia in asymptomatic school children before and after treatment with dihydroartemisinin-piperaquine (DP)

BackgroundAsymptomatic Plasmodium carriers form the majority of malaria-infected individuals in most endemic areas. A proportion of these asymptomatically infected individuals carry gametocytes, the transmissible stages of malaria parasites, that sustain human to mosquito transmission. Few studies examine gametocytaemia in asymptomatic school children who may form an important reservoir for transmission. We assessed the prevalence of gametocytaemia before antimalarial treatment and monitored clearance of gametocytes after treatment in asymptomatic malaria children. MethodsA total of 274 primary school children were screened for P. falciparum parasitaemia by microscopy. One hundred and fifty-five (155) parasite positive children were treated under direct observation with dihydroartemisinin-piperaquine (DP). Gametocyte carriage was determined by microscopy seven days prior to treatment, day 0 before treatment, and on days 7, 14 and 21 post initiation of treatment. ResultsThe prevalence of microscopically-detectable gametocytes at screening (day −7) and enrolment (day 0) were 9% (25/274) and 13.6% (21/155) respectively. Following DP treatment, gametocyte carriage dropped to 4% (6/135), 3% (5/135) and 6% (10/151) on days 7, 14 and 21 respectively. Asexual parasites persisted in a minority of treated children, resulting in microscopically detectable parasites on days 7 (9%, 12/135), 14 (4%, 5/135) and 21 (7%, 10/151). Gametocyte carriage was inversely correlated with the age of the participants (p = 0.05) and asexual parasite density (p = 0.08). In a variate analysis, persistent gametocytaemia 7 or more days after treatment was significantly associated with post-treatment asexual parasitaemia at day 7 (P = 0.027) and presence of gametocytes on the day of treatment (P < 0.001). ConclusionsThough DP provides both excellent cure rates for clinical malaria and a long prophylactic half-life, our findings suggest that after treatment of asymptomatic infections, both asexual parasites and gametocytes may persist in a minority of individuals during the first 3 weeks after treatment. This indicates DP may be unsuitable for use in mass drug administration strategies towards malaria elimination in Africa.

Modelling mass drug administration strategies for reducing scabies burden in Monrovia, Liberia.

Scabies is a parasitic infestation with high global burden. Mass drug administrations (MDAs) are recommended for communities with a scabies prevalence of >10%. Quantitative analyses are needed to demonstrate the likely effectiveness of MDA recommendations. In this study, we developed an agent-based model of scabies transmission calibrated to demographic and epidemiological data from Monrovia. We used this model to compare the effectiveness of MDA scenarios for achieving scabies elimination and reducing scabies burden, as measured by time until recrudescence following delivery of an MDA and disability-adjusted-life-years (DALYs) averted. Our model showed that three rounds of MDA delivered at six-month intervals and reaching 80% of the population could reduce prevalence below 2% for threeyears following the final round, before recrudescence. When MDAs were followed by increased treatment uptake, prevalence was maintained below 2% indefinitely. Increasing the number of and coverage of MDA rounds increased the probability of achieving elimination and the number of DALYs averted. Our results suggest that acute reduction of scabies prevalence by MDA can support a transition to improved treatment access. This study demonstrates how modelling can be used to estimate the expected impact of MDAs by projecting future epidemiological dynamics and health gains under alternative scenarios.

Intranasally administered thermosensitive gel for brain-targeted delivery of rhynchophylline to treat Parkinson’s disease

The aim of this study is to overcome the obstacle of the blood-brain barrier (BBB) in therapeutic drugs of Parkinson's disease (PD), like rhynchophylline (RIN) entry by intranasal administration and to solve the problem of short residence time of drugs in the nasal cavity by the dosage form design of thermosensitive gel. We first conducted a study of the screening of absorption enhancers and 3% hydroxypropyl-β-cyclodextrin (HP-β-CD) was effective to improve the nasal mucosal permeability of RIN. By adjusting the ratio of different components in order to make the gel with adhesion and rapid gelation which were determined to be Poloxamer 407 (P407) 20%, Poloxamer 188 (P188) 1%, polyethylene glycol 6000 (PEG-6000) 1% and HP-β-CD 3%. In addition, the characterization showed that the thermosensitive gel was network cross-linked, rapidly gelation upon entry into the nasal cavity and was stable as semi-solid state with adhesion as well as sustained release properties. Moreover, pharmacokinetic study was performed to evaluate the bioavailability and brain targeting of RIN thermosensitive gel and which were 1.6 times and 2.1 times higher than those of oral administration. We also evaluated the anti-PD effects of RIN thermosensitive gel in-vitro as well as in-vivo. The results showed that RIN thermosensitive gel was effective in repairing the motor function impairment, dysregulated expression levels of oxidative stress factors, and positive neuronal damage within the substantia nigra and dopamine caused by PD. The constructed intranasal drug administration strategy through thermosensitive gel provided a new choice for targeted treatment of PD together with other central nervous system diseases.

A bibliometric research based on hotspots and frontier trends of denosumab.

Denosumab is a monoclonal antibody that targets and inhibits the osteoclast activating factor receptor activator for nuclear factor-κB ligand (RANKL). It has been widely used in the treatment of osteoporosis, giant cell tumors of bone, and in the prevention of malignant skeletal-related events (SREs). We collected the research results and related MeSH terms of denosumab from 2011 to 2021 through the Web of Science and PubMed, respectively. The literature was visualized and analyzed by CiteSpace and bibliometric online analysis platforms. The MeSH terms were biclustered using the Bibliographic Co-Occurrence Analysis System (BICOMB) and graph clustering toolkit (gCLUTO). The results show that the number of denosumab-related annual publications had increased from 51 to 215, with the United States leading and Amgen Inc. being the most influential in the past 10 years. Articles published in the Journal of Bone and Mineral Research had the highest total citations. Three scholars from Shinshu University in Matsumoto, Yukio Nakamura, Takako Suzuki, and Hiroyuki Kato, joined the field relatively late but produced the most. The clinical comparison and combination of denosumab with other drugs in the treatment of osteoporosis was the most significant focus of research. Drug withdrawal rebound and management strategies have gained more attention and controversy recently. MeSH analysis revealed eight major categories of research hotspots. Among them, exploring the multiple roles of the RANK-RANKL-OPG system in tumor progression, metastasis, and other diseases is the potential direction of future mechanism research. It is a valuable surgical topic to optimize the perioperative drug administration strategy for internal spinal fixation and orthopedic prosthesis implantation. Taken together, the advantages of denosumab were broad and cost-effective. However, there were still problems such as osteonecrosis of the jaw, severe hypocalcemia, a high recurrence rate of giant cells in the treatment of bone and individual sarcoidosis, and atypical femoral fractures, which need to be adequately solved.

Physiologically based pharmacokinetic (PBPK) modeling of flurbiprofen in different CYP2C9 genotypes.

The aim of this study was to establish the physiologically based pharmacokinetic (PBPK) model of flurbiprofen related to CYP2C9 genetic polymorphism and describe the pharmacokinetics of flurbiprofen in different CYP2C9 genotypes. PK-Sim® software was used for the model development and validation. A total of 16 clinical pharmacokinetic data for flurbiprofen in different CYP2C9 genotypes, dose regimens, and age groups were used for the PBPK modeling. Turnover number (kcat) of CYP2C9 values were optimized to capture the observed profiles in different CYP2C9 genotypes. In the simulation, predicted fraction metabolized by CYP2C9, fraction excreted to urine, bioavailability, and volume of distribution were similar to previously reported values. Predicted plasma concentration-time profiles in different CYP2C9 genotypes were visually similar to the observed profiles. Predicted AUCinf in CYP2C9*1/*2, CYP2C9*1/*3, and CYP2C9*3/*3 genotypes were 1.44-, 2.05-, and 3.67-fold higher than the CYP2C9*1/*1 genotype. The ranges of fold errors for AUCinf, Cmax, and t1/2 were 0.84-1.00, 0.61-1.22, and 0.74-0.94 in development and 0.59-0.98, 0.52-0.97, and 0.61-1.52 in validation, respectively, which were within the acceptance criterion. Thus, the PBPK model was successfully established and described the pharmacokinetics of flurbiprofen in different CYP2C9 genotypes, dose regimens, and age groups. The present model could guide the decision-making of tailored drug administration strategy by predicting the pharmacokinetics of flurbiprofen in various clinical scenarios.

Penetrating-peptide-mediated non-invasive Axitinib delivery for anti-neovascularisation.

The unique physiological makeup of the eye limits the use of small-molecule drugs for treating the posterior segment of the eye. Nevertheless, transmembrane-peptide-mediated non-invasive drug delivery can serve as an ideal treatment strategy, as it is capable of delivering small-molecule drugs across the membrane in the form of eye drops, thereby achieving the effective treatment of neovascularisation in the posterior cavity. In this study, we screened and compared the posterior segment distribution of two poly(ethylene glycol)-distearoylphosphatidylethanolamine carriers modified using targeting-peptides. Thereafter, a transmembrane peptide (i.e., PENE) with a greater ability of transmembrane delivery was selected for delivering the anti-vascular drug (i.e., Axitinib) to the posterior segment of the eye. Using two different mouse models with fundus neovascular diseases, the complete non-invasive delivery of Axitinib to the posterior segment of the eye was confirmed using the targeted system; the designed eye drops (i.e., PENE-nanoparticles) could achieve drug distribution to the retina and veins of the eye as well as good drug permeability for renewal. Moreover, using the eye-drop treatment, neovascularisation was substantially reduced, demonstrating the high efficacy of this drug delivery system. This study, which combines nanodrug-loading technology and the transmembrane delivery of penetrating-peptides to achieve the goal of the non-invasive delivery of small-molecule drugs through the dense blood vessels of the sclera, shows wide applicability and considerably expands the use of ocular drugs. Thus, this study is expected to help develop a more acceptable drug administration strategy for the drug treatment of the posterior segment of the eye.