Drug Dose Reduction Research Articles

A Narrative Review of Chromatographic Bioanalytical Methods for Quantifying Everolimus in Therapeutic Drug Monitoring Applications

Background: Methods for measuring drug levels in the body are crucial for improving therapeutic drug monitoring (TDM) and personalized medicine. In solid-organ transplants, TDM is essential for the management of immunosuppressive drugs to avoid toxicity and organ rejection. Everolimus is a commonly used immunosuppressant with a small range of safe doses; therefore, it is important to adjust the dose according to each patient's needs. Therefore, reliable methods are required to accurately measure everolimus levels. This study aims to conduct a comprehensive and updated narrative review of chromatographic bioanalytical methods for everolimus quantification. Methods: The authors searched for original research articles published between 2013 and 2023 in Scopus and PubMed and found 295 articles after removing duplicates. Based on their titles and summaries, 30 articles were selected for a detailed review and 25 articles were included in the final analysis. Results: Among the 25 studies, 16 used protein precipitation, mainly with methanol, to prepare the samples, 12 used high-performance liquid chromatography, 11 used ultra-performance liquid chromatography, and 2 used both. Almost all the studies (24 of 25) used tandem mass spectrometry for detection, whereas only 1 used ultraviolet. Conclusions: This comprehensive review of bioanalytical methods for measuring everolimus using chromatography is a useful resource for researchers developing bioanalytical methods for TDM applications. Future trends in everolimus measurement include achieving lower detection limits, owing to the trend of reducing drug doses in therapy by improving sample extraction techniques and using more sensitive methods.

Synergistic oral beta-lactam combinations for treating tuberculosis.

The enormous burden of tuberculosis (TB) worldwide is a major challenge to human health, but the costs and risks associated with novel drug discovery have limited treatment options for patients. Repurposing existing antimicrobial drugs offers a promising avenue to expand TB treatment possibilities. This study aimed to explore the activity and synergy of beta-lactams in combination with a beta-lactamase inhibitor, which have been underutilised in TB treatment to date. Based on inhibitory concentration, oral bioavailability and commercial availability, seven beta-lactams (cefadroxil, tebipenem, cephradine, cephalexin, cefdinir, penicillin V, flucloxacillin), two beta-lactamase inhibitors (avibactam and clavulanate), and three second-line TB drugs (moxifloxacin, levofloxacin and linezolid) were selected for combination in vitro testing against Mycobacterium tuberculosis H37Rv. Resazurin assays and colony forming unit (CFU) enumeration were used to quantify drug efficacy, Chou-Talalay calculations were performed to identify drug synergy and Chou-Martin calculations were performed to quantify drug dose reduction index (DRI). The order of activity of beta-lactams was cefadroxil>tebipenem>cephradine>cephalexin>cefdinir>penicillin V>flucloxacillin. The addition of clavulanate improved beta-lactam activity to a greater degree than the addition of avibactam. As a result, avibactam was excluded from further investigations, which focused on clavulanate. Synergy was demonstrated for cefdinir/cephradine, cefadroxil/tebipenem, cefadroxil/penicillin V, cefadroxil/cefdinir, cephalexin/tebipenem, cephalexin/penicillin V, cephalexin/cefdinir, cephalexin/cephradine and cefadroxil/cephalexin, all with clavulanate. However, combining beta-lactams with moxifloxacin, levofloxacin or linezolid resulted in antagonistic effects, except for the combinations of penicillin V/levofloxacin, penicillin V/moxifloxacin and cefdinir/moxifloxacin. Beta-lactam synergy may provide viable combination therapies for the treatment of TB.

Drug-Induced Acne in Inflammatory Bowel Disease: A Practical Guide for the Gastroenterologist.

Drug-induced acne is a common side effect to a wide array of pharmacological therapies and is characterized by a monomorphic, papulopustular eruption typically affecting the face, scalp, and the upper thorax. Corticosteroids and Janus kinase inhibitors (JAKi) are commonly used for the treatment of inflammatory bowel disease (IBD) and are known to aggravate a prior tendency to acne or trigger the development of new acneiform eruptions. Recent attention on managing drug-induced acne has been driven by the increasing use of JAKi, an expanding therapeutic class in IBD and several other immune-mediated inflammatory diseases. Both randomized controlled trials and real-world studies have identified acne as one of the most common treatment-emergent adverse events in JAKi. Left untreated, this common skin reaction can significantly impact patient self-esteem and quality of life leading to poor treatment adherence and suboptimal IBD control. This review examines the characteristics of drug-induced acne in IBD treatments, provides a practical guide for gastroenterologists to manage mild to moderate occurrences, and highlights when to seek specialist dermatology advice. Such approaches enable early treatment of a common and often distressing adverse event and optimizes the management of IBD by preventing the premature discontinuation or dose reduction of efficacious IBD drugs.

Engineered extracellular vesicles for combinatorial TNBC therapy: SR-SIM-guided design achieves substantial drug dosage reduction

Triple negative breast cancer is an aggressive subtype of breast cancer that has no therapeutic targets, relies on chemotherapeutics for treatment, and is in dire need of novel therapeutic approaches for improved patient outcomes. Extracellular vesicles serve as intercellular communicators and have been proposed as ideal drug delivery vehicles. Here, extracellular vesicles were engineered with RNA nanotechnology to develop Triple negative breast cancer tumor inhibitors. Utilizing Super Resolved-Structured Illumination Microscopy, extracellular vesicles were optimized for precise Survivin siRNA conjugated to chemotherapeutics loading and CD44 aptamer ligand decoration, thereby enhancing specificity towards triple negative breast cancer cells. Conventional treatments typically employ chemotherapy drugs Gemcitabine and Paclitaxel at dosages on the order of mg/kg respectively, per injection (IV) in mice. In contrast, engineered extracellular vesicles encapsulating these drugs saw functional tumor growth inhibition at significantly reduced concentrations: 2.2 μg/kg for Gemcitabine or 5.6 μg/kg for Paclitaxel, in combination with 21.5 μg/kg Survivin-siRNA in mice. The result is a substantial decrease of chemotherapeutic dose required, by orders of magnitude, compared to standard regimens. In vivo and in vitro evaluations in a triple negative breast cancer orthotopic xenograft mouse model demonstrated the efficacy of this reduced dosage strategy, indicating potential for decreased chemotherapy-associated toxicity.

Role of Natural Phytoconstituents as a Potential Bioenhancer of Anti-Cancer and Anti-Microbial Agents: Spotlight on the Mechanism of Action, Clinical Studies and Patents

A drug design strategy with reduced side effects and economic feasibility is desirable for fatal diseases. Increasing the bioavailability of a drug using a bioenhancer is a smart strategy. Herbal/natural bioenhancers with no probable side effects are an ideal choice to enhance the pharmacokinetics of a therapeutic drug synergistically. The mechanism of bioenhancers relies on the retention of the drug molecule in the cell without causing any changes in the metabolic activity. Most of the herbal bioenhancers achieve this feat by inhibiting metabolic enzymes such as cytochrome P450 and Uridine 5′-diphospho-glucuronosyltransferase. The efflux pump p-glycoprotein, responsible for removal of xenobiotics, is also inhibited by herbal/natural bioenhancers. The increased bioavailability because of the higher Cmax and tmax of chemotherapeutics or anti-infectious agents such as rifampicin can result in a lower drug dosage regimen. The reduction in drug dosage is directly linked to fewer side effects and economic viability. Further, there is a significant effort in clinical trials to incorporate bioenhancers in drug regimens for cancer. The role of herbal/natural bioenhancers and their potential to augment the bioavailability of therapeutics used in cancer and infectious diseases, with a focus on the mechanisms of action, clinical studies and patents, have been summarized in this review article.

Efficacy of pembrolizumab plus lenvatinib as first‐line treatment for metastatic renal cell carcinoma with multiple brain metastases

IntroductionPatients with metastatic renal cell carcinoma have a poor prognosis and its specific pathogenesis remains unelucidated.Case presentationAt 78 years of age, a Japanese male patient was diagnosed with metastatic renal cell carcinoma (cT3N2M1 stage) and multiple brain metastases that were responsive to stereotactic radiation therapy followed by systemic combination induction therapy of pembrolizumab plus lenvatinib. Adverse events, including grade 3 hypertension, grade 2 eruption, and elevated grade 2 fever, were controlled by a dose reduction or suspension of drugs. The patient eventually showed a tolerance for continuing with 8 mg lenvatinib. Fourteen months after the initiation of treatment, and on 8 mg lenvatinib, this patient showed no sign of disease progression at the last follow‐up.ConclusionWe detail the absence of disease progression in a metastatic renal cell carcinoma case with multiple brain metastases more than 1 year after stereotactic radiation therapy followed by first‐line pembrolizumab plus lenvatinib.

Ferulic Acid-Loaded Nanostructure Maintains Brain Levels of ACh, Glutamate, and GABA and Ameliorates Anxiety and Memory Impairments Induced by the D-Galactose Aging Process in Rats.

Population aging is a global reality driven by increased life expectancy. This demographic phenomenon is intrinsically linked to the epidemic of cognitive disorders such as dementia and Alzheimer's disease, posing challenges for elderly and their families. In this context, the search for new therapeutic strategies to prevent or minimize cognitive impairments becomes urgent, as these deficits are primarily associated with oxidative damage and increased neuroinflammation. Ferulic acid (FA), a natural and potent antioxidant compound, is proposed to be nanoencapsulated to target the central nervous system effectively with lower doses and an extended duration of action. Here, we evaluated the effects of the nanoencapsulated FA on d-galactose (d-Gal)- induced memory impairments. Male Wistar adult rats were treated with ferulic acid-loaded nanocapsules (FA-Nc) or non-encapsulated ferulic acid (D-FA) for 8weeks concurrently with d-Gal (150mg/kg s.c.) injection. As expected, our findings showed that d-Gal injection impaired memory processes and increased anxiety behavior, whereas FA-Nc treatment ameliorated these behavioral impairments associated with the aging process induced by d-Gal. At the molecular level, nanoencapsulated ferulic acid (FA-Nc) ameliorated the decrease in ACh and glutamate induced by d-galactose (d-Gal), and also increased GABA levels in the dorsal hippocampus, indicating its therapeutic superiority. Additional studies are needed to elucidate the mechanisms underlying our current promising outcomes. Nanoscience applied to pharmacology can reduce drug dosage, thereby minimizing adverse effects while enhancing therapeutic response, particularly in neurodegenerative diseases associated with aging. Therefore, the strategy of brain-targeted drug delivery through nanoencapsulation can be effective in mitigating aging-related factors that may lead to cognitive deficits.

Decision Aid-Led Tapering of Biologic and Targeted Synthetic Disease-Modifying Antirheumatic Drugs in Rheumatoid Arthritis: A Qualitative Study.

To explore the experiences and perspectives of patients and rheumatologists on decision aid (DA)-led tapering of advanced therapy in rheumatoid arthritis (RA). Semistructured interviews were completed with patients and rheumatologists, embedded within a pilot study of DA-led tapering (ie, dose reduction) of biologic disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs) in RA. All patients were in sustained (≥ 6 mos) remission and had chosen to reduce their therapy after a DA-led shared decision with their rheumatologist. The rheumatologists included those participating in the pilot (n = 4), and those who were not (n = 8). Reflexive thematic analysis of audiotaped and transcribed interviews identified themes in the group experiences. Patients (n = 10, 6 female) unanimously found the DA easy to understand and felt confident in shared decision making about treatment tapering and managing flares. Rheumatologists' (n = 12, 5 female) perspectives on tapering bDMARDs and tsDMARDs varied widely, from very supportive to completely opposed, and influenced their views on the DA. Rheumatologists expressed concerns about patient comprehension, destabilizing a stable situation, risks of flare, and extending appointment times. Despite their initial reservations about sending the DA to all eligible patients ahead of appointments, 3 of 4 participating rheumatologists adopted this approach during the pilot, which had the benefit of facilitating patient-led conversations. A DA-led strategy for tapering advanced therapy in RA was acceptable to patients and feasible in practice. Sending patients a DA ahead of their appointment facilitated patient-led conversations about tapering.

Fire needle therapy for the treatment of cancer pain: a protocol for the systematic review and meta-analysis.

Cancer patients frequently suffer pain as one of their symptoms. It includes acute and chronic pain and is one of the most feared symptoms for patients. About one-third of adults actively undergoing cancer treatment suffer from pain related to their condition. Cancer pain control remains suboptimal due to a lack of assessment, knowledge, and access. Fire needle therapy, a traditional Chinese medicine, offers a potentially beneficial addition to current pain management approaches. This protocol outlines a systematic review and meta-analysis to compile evidence and examine the pain-relieving effects and safety of fire needle therapy for cancer patients. We will systematically search China National Knowledge Infrastructure (CNKI), Wanfang Database, China Biology Medicine disc (CBM), China Science and Technology Journal Database (CSTJ or VIP), PubMed, Web of Science, Embase, Cochrane Central Registry of Controlled Trials (CENTRAL), Chinese Clinical Trial Registry (Chictr), Opengrey, Worldcat, and Scopus from inception through July 2023. Random control trials (RCTs) include all types of cancer patients (age ≥ 18 years) complaining of pain. The primary outcome will be changes in pain intensity measured by Visual Analogue Scale (VAS), Numerical Rating Scale (NRS), Neuropathic Pain Scale (NPS), or Brief Pain Inventory (BPI). Secondary outcomes include quality of life (EORTC QLQ-C30 and GCQ), performance status (KPS), times of burst pain, treatment response rate, the dose reduction of analgesic drugs, and side effects rates. Utilizing the Cochrane risk bias measurement tool: Risk of Bias 2 (RoB 2), the trials' quality will be evaluated, and meta-analysis will be performed using RevMan software (version 5.4). This systematic review will be the first comprehensive review of the literature to provide a meta-analysis of fire needle therapy for cancer pain, including only Random control trials (RCTs). For the sake of transparency and to avoid future duplication, the publication of this protocol offers a clear illustration of the procedures utilized in this evaluation. The results of our future studies may provide a new approach and theoretical basis for the treatment of cancer pain by medical oncology professionals. https://www.crd.york.ac.uk/prospero/, identifier CRD42023418609.

Perception and coping mechanisms of patients with diabetes mellitus during the COVID-19 pandemic in Ibadan, Nigeria.

The 2019 coronavirus disease (COVID-19) ushered in a period of fear and uncertainty, resulting in structural instability across the globe. Vulnerable individuals, such as patients with diabetes mellitus, are predispose to have adverse effects and complications of COVID-19 when infected. We explored the perception of diabetes mellitus patients during the COVID-19 pandemic and their coping mechanisms at the University College Hospital, Ibadan. We employed an exploratory qualitative study design to explore diabetes mellitus patients' perceptions and coping mechanisms during the COVID-19 pandemic. A purposive sampling technique was used to recruit 32 participants (2 health professionals and 30 diabetes mellitus patients). In-depth interviews were used to collect the data from the participants. All the recorded audio data were transcribed verbatim and exported to NVivo software for thematic data analyses. Most diabetes mellitus patients were not fearful of the pandemic but were optimistic that it would not affect their health. Mechanisms such as the usage of herbal medicines and adherence to COVID-19 precautionary measures were noticed among patients. The study also revealed that the hospital's coping mechanism during the COVID-19 pandemic include prolonged appointments, limiting the number of patients attended per clinic day, and the provision of telehealth service. Patients in our study utilised negative coping mechanisms such as reduced drug dosages, subscriptions to cheaper drug brands, and reliance on religious institutions rather than a clinic for health instructions. The study has shown that diabetes mellitus patients were not fearful of the COVID-19 pandemic. The utilisation of telehealth, encouragement of daily monitoring of sugar levels, provision of avenues for a medication review, and adherence to the safety protocols were coping mechanisms employed by the health system and diabetes mellitus patients. We recommend that the government and other healthcare stakeholders reinforce the resilience of diabetes mellitus patients by alleviating their health burdens during the pandemic. This could be done by subsidizing the prices of drugs, tests, and consultation fees for patients with diabetes mellitus. Also, more efforts should be made to elevate the health system through the reduction in waiting and appointment times in the diabetes clinic and employing more health personnel in the clinic.

Biopsy-proven BK virus nephropathy inrenal transplant recipients: A multi-central study from Turkey (BK-TURK STUDY).

BK polyomavirus infection is a challenging complication of renal transplantation. The management is not standardized and is based on reports from transplantation centers' experiences, usually with small sample sizes. Therefore, we aimed to present our countrywide experience with BK virus nephropathy (BKVN) in renal transplant recipients. Our study was carried out with the participation of 30 transplantation centers from all regions of Turkey. Only cases with allograft biopsy-proven BKVN were included in the study. 13,857 patients from 30 transplantation centers were screened, and 207 BK nephropathy cases were included. The mean age was 46.4± 13.1 years, and 146 (70.5%) patients were male. The mean time to diagnosis of BK nephropathy was 15.8±22.2 months after transplantation. At diagnosis, the mean creatinine level was 1.8± 0.7 mg/dL, and the mean estimated glomerular filtration rate was 45.8 ± 19.6 mL/min/1.73m2. In addition to dose reduction or discontinuation of immunosuppressive drugs, 18 patients were treated with cidofovir, 11 patients with leflunomide, 17 patients with quinolones, 15 patients with intravenous immunoglobulin (IVIG), 5 patients with cidofovir plus IVIG, and 12 patients with leflunomide plus IVIG. None of the patients receiving leflunomide or leflunomide plus IVIG had allograft loss. During follow-up, allograft loss occurred in 32 (15%) out of 207 patients with BK nephropathy. BKVN is still a frequent cause of allograft loss in kidney transplantation and is not fully elucidated. The results of our study suggest that leflunomide treatment is associated with more favorable allograft outcomes.

Designing Microneedle Patch for Prophylaxis of Postoperative Atrial Fibrillation.

Postoperative atrial fibrillation (POAF) is a common complication following cardiac surgery, which often occurs within 30 postoperative days, especially peaking at 2-3 days. Antiarrhythmic medications such as amiodarone are recommended in clinical practice for the prophylaxis and treatment of POAF. However, conventional oral administration is hindered due to delayed drug action and high risks of systemic toxicity, and emerging localized delivery strategies suffer from a limited release duration (less than 30 days). Herein, we develop a microneedle (MN) patch for localized delivery of amiodarone to the atria in a "First Rapid and Then Sustained" dual-release mode. Specifically, this patch is composed of a needle array integrated with an amiodarone-loaded reservoir for a sustained and steady release for over 30 days; and an amiodarone-containing coating film deposited on the needle surface via the Langmuir-Blodgett technique for a rapid release at the first day. Upon this design, only one MN patch enables a higher drug accumulation in the atrial tissue at the first day than oral administration and simultaneously remains therapeutical levels for over 30 days, despite at a significantly reduced drug dosage (5.08 mg in total versus ∼10 mg per day), thereby achieving ideal preventive effects and safety in a rat model. Our findings indicate that this MN device provides a robust and efficient delivery platform for long-term prophylaxis of POAF.

Hand-foot syndrome in sorafenib and lenvatinib treatment for advanced thyroid cancer.

The aim of this study was to assess the clinical impact of hand-foot syndrome (HFS) during treatment with two multikinase inhibitors, sorafenib and lenvatinib, in a large group of patients with advanced thyroid cancer. Moreover, we looked for possible associations between HFS occurrence and clinical and pathological features. We retrospectively evaluated 239 patients with advanced thyroid cancer: 165 treated with lenvatinib and 74 with sorafenib. Statistical analyses were performed to verify which features could be correlated with HFS development. HFS was observed in 35/74 (47.4%) and in 43/165 (26.7%) patients treated with sorafenib or lenvatinib, respectively. The median latency from the drug beginning and HFS appearance was 27 days for sorafenib and 2.9 months for lenvatinib. G3/G4 toxicity was observed in 16/35 (45.7%) patients treated with sorafenib and only in 3/43 (7%) treated with lenvatinib. Drug dose reduction due to HFS was required in 19/74 (25.7%) and 3/165 (1.8%) patients treated with sorafenib and lenvatinib, respectively. HFS occurrence was significantly associated with a longer duration of therapy in both groups. HFS was a frequent adverse event during both lenvatinib and sorafenib therapy, with a higher frequency and toxicity grade during sorafenib treatment. HFS was the most frequent reason for drug reduction or discontinuation in patient treated with sorafenib. Early diagnosis of HFS is important to allow early intervention, possibly in a multidisciplinary setting, and to avoid treatment discontinuation, which is highly relevant to obtain the maximum effectiveness of systemic therapy.

Antimicrobial Potential of Polyphenols: An Update on Alternative for Combating Antimicrobial Resistance.

The last decade has encountered an increasing demand for plant-based natural antibiotics. This demand has led to more research-based investigations for natural sources of antimicrobial agents and published reports demonstrating that plant extracts are widely applied in modern medicine, reporting potential activity that may be due to polyphenol compounds. Interestingly, the effects of polyphenols on the sensitivity of bacteria to antibiotics have not been well-studied. Hence, the current review encompasses the prospective application of plant-based phenolic extracts from plants of Indian origin. The emergence of resistance to antimicrobial agents has increased the inefficacy of many antimicrobial drugs. Several strategies have been developed in recent times to overcome this issue. A combination of antimicrobial agents is employed for the failing antibiotics, which restores the desirable effect but may have toxicity-related issues. Phytochemicals such as some polyphenols have demonstrated their potent activity as antimicrobial agents of natural origin to work against resistance issues. These agents alone or in combination with certain antibiotics have been shown to enhance the antimicrobial activity against a spectrum of microbes. However, the information regarding the mechanisms and structure-activity relationships remains elusive. The present review also focuses on the possible mechanisms of natural compounds based on their structure- activity relationships for incorporating polyphenolic compounds in the drug-development processes. Besides this work, polyphenols could reduce drug dosage and may diminish the unhidden or hidden side effects of antibiotics. Pre-clinical findings have provided strong evidence that polyphenolic compounds, individually and in combination with already approved antibiotics, work well against the development of resistance. However, more studies must focus on in vivo results, and clinical research needs to specify the importance of polyphenol-based antibacterials in clinical trials.

Research Progress on the Treatment of Qi Deficiency and Blood Stasis Type Hand-foot Syndrome by Buyang Huanwu Decoction

Hand-foot syndrome (HFS) is one of the common adverse reactions in the treatment of malignant tumors, and its incidence is gradually increasing with the widespread use of antitumor drugs. HFS seriously affects patients' daily social and life, and even leads to drug dosage reduction or early discontinuation of medication, which delays treatment. Modern medicine has not yet fully clarified the understanding of its etiology and pathogenesis, the lack of uniform standards for the evaluation of therapeutic efficacy, and the poor effect of targeted systemic therapy. Chinese medicine classifies HFS into the category of "blood paralysis", and considers that the disease is located in the hands and feet, with deficiency as the main cause, and the deficiency as the underlying cause, and the mixture of deficiency and reality. BHD is from the book "Reform and Error Correction of Medical Forests" written by Qing Dynasty physician Wang Qingren, which has the effects of tonifying qi, activating blood and clearing collaterals. The formula is rigorous and well formulated, and is now widely used in all kinds of diseases with qi deficiency and blood stasis, with remarkable results. In recent years, with the rapid development of modern pharmacology, the research on the microscopic mechanism of action of BHD has been developing and deepening, which provides new ideas for the treatment of the disease. In this paper, we review BHD in HFS in the treatment of malignant tumors from the aspects of its formula and modern pharmacological research, with a view to providing clinical basis and reference for the future treatment of HFS of qi deficiency and blood stasis type by BHD.

Hematological Malignancies in Older Patients: Focus on the Potential Role of a Geriatric Assessment Management.

Geriatric assessment management is a multidimensional tool used to evaluate prognosis for clinical outcomes and targets for interventions in older adults with cancer receiving chemotherapy. In this review, we evaluated the possible application of geriatric assessment management (GAM) in hematological malignancies. In older patients with Diffuse Large B Cell Lymphoma, GAM might be helpful in both predicting planned hospital admissions and improving quality of life. In chronic myeloid leukemia, the Charlson Comorbidity Index demonstrates how comorbidities could affect treatment compliance and overall outcomes. In multiple myeloma, the application of different scores such as the International Myeloma Working Group Frailty Index and the Revised Myeloma Comorbidity Index can identify frail patients who need suitable interventions in treatment plan (reducing drug dose or changing treatment). Therefore, including GAM in the management plan of older patients with hematological malignancies may direct and optimize cancer care.

Development of Inhaled Tuberculosis Microparticle using Polysaccharide Polymers Containing Rifamycin Groups: In-vitro and In-vivo Study

Tuberculosis (TB) is one of the urgent global health problems. TB therapy involves the use of antibiotics, but unwanted side effects often accompany the treatment of TB with high doses and long periods of time. In an effort to increase the effectiveness of TB treatment and reduce side effects, direct drug delivery to the lungs is the focus of research. One of the approaches used is the development of drug delivery systems that use natural polymers in dry powder inhalation (DPI) formulations. Natural polymers, especially polysaccharides, have various advantages, such as biodegradability, biocompatibility and non-toxicity. This review discusses the use of rifamycin microparticle tuberculosis inhalation using polysaccharide polymers and reviews relevant in-vitro and in-vivo studies. The use of natural polymers, especially polysaccharides, is expected to increase the efficiency of TB therapy by reducing drug doses and systemic side effects and increasing direct drug delivery to infected organs.

Oxytetracycline dose reduction in salmon farming: Assessing a micro encapsulated novel formulation in an in vivo model

Oxytetracycline (OTC) is used in Chilean salmonid farming for bacterial pathogens treatment, mainly orally administered. Oral bioavailability of OTC in salmonids is low, so a high percentage of the dose is excreted by fishes. To increase OTC oral absorption, Zn-alginate microparticles were developed by spray drying, with a yield of 59.09%. An in vivo study was performed using Oncorhynchus mykiss (Rainbow trout) to compare OTC Zn-alginate micro-particles oral absorption in plasma and muscle matrices. Seven sampling points for plasma and four for muscle were considered. OTC was quantified in both matrices by UPLC-MS/MS. Results indicated a statistically significant difference between plasma concentrations of the OTC microparticles with respect to the commercial OTC formulation, reflecting a higher absorption of the microencapsulated drug, reaching maximum concentration 4 h earlier than the commercial formulation. In addition, the microparticles showed a release of OTC that remained constant for 12 h. In muscle, OTC microparticles reached twice the maximum concentration than the commercial formulation at 8 h. In conclusion, OTC microparticles improve the oral absorption of the molecule, which could allow drug delivery optimization and dose reduction in bacterial pathogens treatment in salmon production, consequently, decrease contamination of the environment with OTC residues.

LGG-51. SYSTEMIC IMMUNE TOXICITY OF BRAF AND MEK-INHIBITORS IN CHILDREN: A PAN-CANADIAN SERIES

Abstract BACKGROUND BRAF/MEK-inhibitors have been transformative for pediatric gliomas with RAS/MAPK pathway aberrations. The RAS/MAPK pathway has a complex role in immune regulation. Though well-known in adults, the systemic immune-related adverse effects (irAE) of BRAF/MEKi in children are not widely reported. METHODS We performed a retrospective chart review for irAE following BRAF/MEKi in children treated at SickKids between 2016-2023. Additional patients were included through a pan-Canadian survey. RESULTS 136 patients on BRAF/MEKi were included (MEKi: 74%, BRAFi: 13%, BRAF+MEKi: 13%); irAE was reported in 6/136 (4.5%). One additional patient was included through the national survey. Median age was 14 years (range: 7-16). Male:female was 3:4. Three patients were on BRAFi, and two each on MEKi, and BRAF+MEKi. Early events developing within weeks of drug initiation included hyper-immune systemic inflammatory responses in three children on BRAFi and one child on MEKi. There was no evidence of any concomitant infection. Two children needed intensive care and showed evidence of multi-organ dysfunction. Delayed irAE developing after months to years on therapy included multi-systemic sarcoid-like reaction, parasympathetic dysautonomia (both on BRAF+MEKi) and brachial neuritis/Parsonage-Turner syndrome (MEKi). Management included drug holidays, dose reductions, and immunosuppressive treatment with steroids. Long-term steroids were needed in two of these seven patients. CONCLUSIONS Pediatric oncologists need to be aware of rare yet possibly under-reported systemic immune toxicity in children treated with BRAF/MEKi. They can present acutely, or while on chronic therapy. Management may be challenging in view of issues with rebound tumor growth on stopping some of these drugs, with select patients needing concomitant, long-term immunosuppressive therapy. Genetic susceptibility and biomarkers may need to be systematically studied in future clinical trials of novel RAS/MAPK inhibitors. Continued surveillance and reporting are needed for the marketed compounds, especially for children on long-term use of these inhibitors.

Advances in the targeted theragnostics of osteomyelitis caused by Staphylococcus aureus.

Bone infections caused by Staphylococcus aureus may lead to an inflammatory condition called osteomyelitis, which results in progressive bone loss. Biofilm formation, intracellular survival, and the ability of S. aureus to evade the immune response result in recurrent and persistent infections that present significant challenges in treating osteomyelitis. Moreover, people with diabetes are prone to osteomyelitis due to their compromised immune system, and in life-threatening cases, this may lead to amputation of the affected limbs. In most cases, bone infections are localized; thus, early detection and targeted therapy may prove fruitful in treating S. aureus-related bone infections and preventing the spread of the infection. Specific S. aureus components or overexpressed tissue biomarkers in bone infections could be targeted to deliver active therapeutics, thereby reducing drug dosage and systemic toxicity. Compounds like peptides and antibodies can specifically bind to S. aureus or overexpressed disease markers and combining these with therapeutics or imaging agents can facilitate targeted delivery to the site of infection. The effectiveness of photodynamic therapy and hyperthermia therapy can be increased by the addition of targeting molecules to these therapies enabling site-specific therapy delivery. Strategies like host-directed therapy focus on modulating the host immune mechanisms or signaling pathways utilized by S. aureus for therapeutic efficacy. Targeted therapeutic strategies in conjunction with standard surgical care could be potential treatment strategies for S. aureus-associated osteomyelitis to overcome antibiotic resistance and disease recurrence. This review paper presents information about the targeting strategies and agents for the therapy and diagnostic imaging of S. aureus bone infections.