Drug Dose Reduction Research Articles

Synthesis and evaluation of bone targeting PLGA nanoparticles loaded with components of traditional Chinese medicine formulas.

Targeted nanoparticles' preparation can enhance local drug concentration and reduce the side effects of drugs in non-targeted organs. At present, many patents have been applied for in the field of bone-targeted nanoparticles' preparations. They play an important role in the treatment and diagnosis of diseases. In this experiment, nanoparticles with bone targeting function were prepared by poly(lactic-co-glycolic acid) (PLGA) copolymer and tetracycline. These nanoparticles contain active ingredients in the Huangqi Sanxian decoction, a kind of Traditional Chinese Medicine (TCM) compound formula. These nanoparticles are predicted to be useful in the treatment of osteoporosis. Synthesis of tetracycline targeting groups was performed by acylation reaction, and PLGA nanoparticles were prepared by the Emulsification-solvent Evaporation Method. The appearance and particle size of the product were evaluated, and the effects of nanoparticles on the physiological activities of osteoblasts were observed. Finally, the bone-targeting ability of targeted nanoparticles in vivo and in vitro was investigated. The average particle size of the nanoparticles was about 200 nm, and the average drug entrapment was 60%. In vitro evaluation of osteoblasts assay showed that the nanoparticles can be well taken by cells. Their good biocompatibility and sustained-release properties reduce the toxic side effects of drugs when they promote osteoblasts' physiological activities. The results of the in vitro and in vivo bone targeting ability assays showed that tetracycline modified nanoparticles could effectively accumulate in the bone, indicating the great bone-targeting ability of the nanoparticles. The use of PLGA to load active components in the TCM compound formulas and remodel targeting groups is expected to improve drug efficacy, reduce drug dosage, and effects on non- action sites. This may provide new ideas for the development of TCM compound dosage forms. In summary, we prepared PLGA nanoparticles of multiple TCM ingredients with bone targeting ability, and they had good morphological appearance, and a promoting effect on various physiological activities of osteoblasts.

Synergistic effects of omega-3 polyunsaturated fatty acids and aspirin in the clinical practice – a narrative review

Abstract The review aimed to illustrate the structure, role and effects of omega-3 polyunsaturated fatty acids (omega-3 PUFAs) in combination with acetylsalicylic acid (aspirin, ASA) in various clinical cases. This verification of earlier single studies may be a guide in the further treatment of civilization diseases. The results of the presented narrative review suggest that aspirin supplementation with omega-3 fatty acids reduces pro-inflammatory biomarkers in sepsis and acute respiratory distress syndrome. Including adequate amounts of omega 3-PUFAs in therapy, rather than increasing the dose of acetylsalicylic acid, may contribute to beneficial effects in treating thrombosis and preventing myocardial infarction or other cardiovascular diseases, which is particularly important in aspirin-resistant patients. As suggested in the literature, a low daily dose of omega-3 fatty acids was effective in slowing the progression of kidney disease with IgA nephropathy. Aspirin supplementation with omega-3 fatty acids has improved clinical and immunological outcomes in the treatment of periodontitis or the therapy of colorectal cancer tumor lesions. The synergistic effect of both compounds is proposed as a new therapeutic option in the treatment of Parkinson’s disease. Further research into the synergistic effects of omega-3 fatty acids in combination with acetylsalicylic acid may provide a breakthrough in drug dose reduction, ultimately enabling more effective and safer pharmacotherapy for the patient. Therefore, studies on polyunsaturated fatty acids in combination with nonsteroidal anti-inflammatory drugs in vivo are needed.

Quantitative systems pharmacology modeling of HER2-positive metastatic breast cancer for translational efficacy evaluation and combination assessment across therapeutic modalities

HER2-positive (HER2+) metastatic breast cancer (mBC) is highly aggressive and a major threat to human health. Despite the significant improvement in patients’ prognosis given the drug development efforts during the past several decades, many clinical questions still remain to be addressed such as efficacy when combining different therapeutic modalities, best treatment sequences, interindividual variability as well as resistance and potential coping strategies. To better answer these questions, we developed a mechanistic quantitative systems pharmacology model of the pathophysiology of HER2+ mBC that was extensively calibrated and validated against multiscale data to quantitatively predict and characterize the signal transduction and preclinical tumor growth kinetics under different therapeutic interventions. Focusing on the second-line treatment for HER2+ mBC, e.g., antibody-drug conjugates (ADC), small molecule inhibitors/TKI and chemotherapy, the model accurately predicted the efficacy of various drug combinations and dosing regimens at the in vitro and in vivo levels. Sensitivity analyses and subsequent heterogeneous phenotype simulations revealed important insights into the design of new drug combinations to effectively overcome various resistance scenarios in HER2+ mBC treatments. In addition, the model predicted a better efficacy of the new TKI plus ADC combination which can potentially reduce drug dosage and toxicity, while it also shed light on the optimal treatment ordering of ADC versus TKI plus capecitabine regimens, and these findings were validated by new in vivo experiments. Our model is the first that mechanistically integrates multiple key drug modalities in HER2+ mBC research and it can serve as a high-throughput computational platform to guide future model-informed drug development and clinical translation.

Haemodynamic response to pre-hospital emergency anaesthesia in trauma patients within an urban helicopter emergency medical service.

Pre-hospital emergency anaesthesia is routinely used in the care of severely injured patients by pre-hospital critical care services. Anaesthesia, intubation, and positive pressure ventilation may lead to haemodynamic instability. The aim of this study was to identify the frequency of new-onset haemodynamic instability after induction in trauma patients with a standardised drug regime. A retrospective database analysis was undertaken of all adult patients treated by a physician-led urban pre-hospital care service over a 6-year period. The primary outcome measure was the frequency of new haemodynamic instability following pre-hospital emergency anaesthesia. The association of patient characteristics and drug regimes with new haemodynamic instability was also analysed. A total of 1624 patients were included. New haemodynamic instability occurred in 231 patients (17.4%). Patients where a full-dose regime was administered were less likely to experience new haemodynamic instability than those who received a modified dose regime (9.7% vs 24.8%, p < 0.001). The use of modified drug regimes became more common over the study period (p < 0.001) but there was no change in the rates of pre-existing (p = 0.22), peri-/post-anaesthetic (p = 0.36), or new haemodynamic instability (p = 0.32). New haemodynamic instability within the first 30min following pre-hospital emergency anaesthesia in trauma patients is common despite reduction of sedative drug doses to minimise their haemodynamic impact. It is important to identify non-drug factors that may improve cardiovascular stability in this group to optimise the care received by these patients.

Reservoir Microneedle Patch Mitigates Postsurgical Atrial Fibrillation

AbstractOral amiodarone for 3–6 months is commonly required for the prevention and treatment of atrial fibrillation (AF) after surgical ablation of refractory AF. However, clinical data show that oral administration is likely to cause systemic toxicity, especially pulmonary fibrosis. Here, a new strategy is described for the treatment and prevention of postsurgical AF via the epicardial application of a monolithic reservoir microneedle device. These findings demonstrate that this strategy enables a sustained transport of amiodarone directly to the atrium, thereby maximizing therapeutic efficacy and minimizing systemic drug distribution. Notably, a significantly reduced drug dosage (only one dose of 6.3 mg for reservoir MNs versus a daily dose of ≈10 mg for oral administration) achieves therapeutic efficacy over a long period of 24 weeks in a rat AF model, circumventing the risks of pulmonary fibrosis associated with oral administration. This device can serve as a promising alternative to oral amiodarone, providing a robust therapeutic strategy for the prevention and treatment of postsurgical AF is antipicated.

Revealing Changes in Celecoxib Nanostructured Lipid Carrier's Bioavailability Using Hyaluronic Acid as an Enhancer by HPLC-MS/MS.

Oral drug administration is the most common and convenient route, offering good patient compliance but drug solubility limits oral applications. Celecoxib, an insoluble drug, requires continuous high-dose oral administration, which may increase cardiovascular risk. The nanostructured lipid carriers prepared from drugs and lipid excipients can effectively improve drug bioavailability, reduce drug dosage, and lower the risk of adverse reactions. In this study, we prepared hyaluronic acid-modified celecoxib nanostructured lipid carriers (HA-NLCs) to improve the bioavailability of celecoxib and reduce or prevent adverse drug reactions. Meanwhile, we successfully constructed a set of FDA-compliant biological sample test methods to investigate the pharmacokinetics of HA-NLCs in rats. The pharmacokinetic analysis confirmed that HA-NLCs significantly enhanced drug absorption, resulting in an AUC0-t 1.54 times higher than the reference formulation (Celebrex®). Moreover, compared with unmodified nanostructured lipid carriers (CXB-NLCs), HA-NLCs enhance the retention time and improve the drug's half-life in vivo. HA-NLCs significantly increased the bioavailability of celecoxib. The addition of hyaluronic acid prolonged the drug's in vivo duration of action and reduced the risk of cardiovascular adverse effects associated with the frequent administration of oral celecoxib.

Niraparib in Japanese patients with heavily pretreated, homologous recombination-deficient ovarian cancer: final results of a multicenter phase 2 study.

To evaluate the long-term efficacy and safety of niraparib in Japanese women with heavily pretreated ovarian cancer. This was the follow-up analysis of a phase 2, multicenter, open-label, single-arm study in Japanese women with homologous recombination-deficient, platinum-sensitive, relapsed, high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who had completed 3-4 lines of chemotherapy and were poly(ADP-ribose) polymerase inhibitor naïve. Participants received niraparib (starting dose, 300 mg) once daily in continuous 28-day cycles until objective disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was confirmed objective response rate (ORR), as assessed using Response Evaluation Criteria in Solid Tumors version 1.1. Safety evaluations included treatment-emergent adverse events (TEAEs). 20 patients were enrolled in the study and included in both efficacy and safety analyses. Median total study duration was 759.5 days. Median dose intensity was 201.3 mg/day. Confirmed ORR was 60.0% (90% confidence interval [CI]=39.4-78.3); 2 patients had complete response and 10 patients had partial response. Median duration of response was 9.9 months (95% CI=3.9-26.9) and the disease control rate was 90.0% (95% CI=68.3-98.8). The most common TEAEs were anemia (n=15), nausea (n=12), and decreased platelet count (n=11). TEAEs leading to study drug dose reduction, interruption, or discontinuation were reported in 16 (80.0%), 15 (75.0%), and 2 patients (10.0%), respectively. The long-term efficacy and safety profile of niraparib was consistent with previous findings in the equivalent population in non-Japanese patients. No new safety signals were identified. ClinicalTrials.gov Identifier: NCT03759600.

PH-responsive Photinia glabra-zinc oxide-protoporphyrin IX nanoconjugates with enhanced cellular uptake for photodynamic therapy towards cancer cells.

Background: Photodynamic therapy (PDT) of cancer has been limited by thepoor solubility of most photosensitizers, use of high drug dosages, and the pH difference between the tumor tissue microenvironment (slightly acidic) and the bloodstream. These affect cellular uptake, selectivity and singlet oxygen generation. Materials & methods: We formulated Photinia glabra-green synthesized zinc oxide-protoporphyrin IX(PG-ZnO-PP)nanoconjugates by conjugating the ZnO nanoparticles enriched with amino groupsand PP. Results: PG-ZnO-PP nanoconjugates showed higher rate of reactive oxygen species generation, improved cellular uptake in the acidic pH and lower IC50 toward Eca-109 cells for PDT. Conclusion: PG-ZnO-PP nanoconjugates are a potential solution to reducing drug dosage of PP through improved drug uptake, for enhanced targetability and reduced skin photosensitivity with improved PDT efficacy.

Cell Membrane-Derived Nanovehicles for Targeted Therapy of Ischemic Stroke: From Construction to Application.

Ischemic stroke (IS) is a prevalent form of stroke and a leading cause of mortality and disability. Recently, cell membrane-derived nanovehicles (CMNVs) derived from erythrocytes, thrombocytes, neutrophils, macrophages, neural stem cells, and cancer cells have shown great promise as drug delivery systems for IS treatment. By precisely controlling drug release rates and targeting specific sites in the brain, CMNVs enable the reduction in drug dosage and minimization of side effects, thus significantly enhancing therapeutic strategies and approaches for IS. While there are some reviews regarding the applications of CMNVs in the treatment of IS, there has been limited attention given to important aspects such as carrier construction, structural design, and functional modification. Therefore, this review aims to address these key issues in CMNVs preparation, structural composition, modification, and other relevant aspects, with a specific focus on targeted therapy for IS. Finally, the challenges and prospects in this field are discussed.

Effects of yogic practices on polypharmacy

The occurrence and concurrency of Noncommunicable chronic diseases increase with age, and therefore, the number of medications used increases correspondingly. Polypharmacy is a scenario in which five medications or more are consumed concurrently (regardless of dose and duration of consumption), which leads to reduced quality of life, physical problems, increased drug interactions, adverse effects, and medical complications and increases the cost of treatment. Moreover, polypharmacy increases the incidence of falls, frequency of hospital admission, length of stay, and the death rate among patients, especially in the elderly population. This would allow therapies like Yoga, pranayama, and meditation to act as an effective mainstay or adjunctive or alternative therapy for many disorders, as it can be cost-effective, patient-compliant, and clinically efficacious with the most negligible side effects. However, very few studies have focused on the impact of yogic practices on reducing drug dosage or polypharmacy among patients. Hence, a Medline English literature search was planned to review all the studies demonstrating a dose-response effect between yogic practices and the number/dosage of medication reduction in different disorders. Data extracted and analyzed depicted that the practice of Yoga, pranayama, and meditation can result not only in reducing the number of medications but also the dosages in hypertension, type 2 diabetes mellitus, bronchial asthma, arthritis, sleep disorders, obsessive-compulsive disorder (OCD), gastrointestinal disorders like constipation and irritable bowel syndrome.

Niraparib maintenance in newly diagnosed advanced ovarian cancer — review and case series

Introducing PARP inhibitors maintenance therapy into clinical practice significantly improved treatment outcomes in patients with high-grade platinum-sensitive advanced ovarian cancer, the most lethal gynecological malignancy. Niraparib is a potent PARP inhibitor whose safety and efficacy were assessed in the placebo-controlled, randomized clinical trial PRIMA. Niraparib significantly prolonged progression-free survival in the overall population of high-grade advanced ovarian cancer regardless of BRCA and homologous deficiency status compared to placebo. However, the most significant benefit was observed in BRCA mutated and homologous recombination deficient subgroups. Niraparib has a manageable toxicity profile and is well-tolerated by patients. Most common toxicities are hematological and can be managed with drug interruption and dose reduction that do not decrease efficacy. Niraparib is recommended for patients who responded to the first-line chemotherapy with platinum compound regardless of homologous recombination status. This review will discuss the use of niraparib in newly diagnosed advanced ovarian cancer patients focusing on its efficacy and tolerability. Additionally, a case series will be presented to further discuss this drug use in clinical practice in Poland.

Design, Development and Evaluation of Tetracycline Controlled Release Microspheres

Microsphere drug delivery methods have been used to boost efficacy, reduce toxicity, and improve patient compliance. Additional benefits of using microspheres to deliver medications include controlled drug release, improved bioavailability, and targeted drug delivery to the desired location. In order to achieve the required therapeutic effect, hydroxypropyl methyl cellulose K4M and sodium alginate are used as a polymer in microsphere delivery system and different concentration of aluminium chloride is used as cross linking agent. The advantage of microsphere formulations over traditional tablet or capsule formulations is that they increase the surface area exposed to the absorption site, boosting medication absorption and reducing drug dose frequency. Tetracycline is a broad-spectrum antibiotic that is frequently used to treat illnesses like pneumonia and respiratory tract infections. The encapsulation effectiveness, particle size, in -vitro release analysis and release kinetics of the microsphere formulations was assessed.

Effect of moderate-intensity statin with ezetimibe combination vs. high-intensity statin therapy according to sex in patients with atherosclerosis

We aimed to evaluate sex differences in the effects of moderate-intensity statin with ezetimibe combination therapy (rosuvastatin 10 mg plus ezetimibe) versus high-intensity statin (rosuvastatin 20 mg) monotherapy in patients with atherosclerotic cardiovascular disease (ASCVD). This was a sex-specific subgroup analysis of the RACING trial that evaluated the interaction between sex and treatment strategies for the primary outcome (composite of cardiovascular death, major cardiovascular events, or nonfatal stroke at 3 years). Of 3780 patients in the RACING trial, 954 (25.2%) were women. Regardless of sex, the effect of moderate-intensity statin with ezetimibe combination therapy on primary outcome compared with high-intensity statin monotherapy was similar (hazard ratio [HR] 0.98 [0.63–1.52] in women; HR 0.90 [0.71–1.14] in men). The rate of discontinuation or dose reduction of study drugs due to intolerance was lower in the ezetimibe combination group than in the high-intensity statin monotherapy group in both women (4.5% vs. 8.6%, P = 0.014) and men (4.8% vs. 8.0%, P < 0.001). LDL cholesterol levels of < 70 mg/dL at 1, 2, and 3 years were more frequently achieved in the ezetimibe combination group than in the high-intensity statin monotherapy group (all P < 0.001) in both sexes. There were no significant interactions between sex and treatment groups regarding the primary outcome, discontinuation, or dose reduction of study drugs, or the proportion of achievement of LDL cholesterol levels < 70 mg/dL. The effect of ezetimibe combination therapy for the 3-year composite outcomes was not different in both men and women. The benefits of ezetimibe combination therapy on LDL cholesterol lowering and drug tolerance were similarly observed regardless of sex.Trial registration: https://clinicaltrials.gov; Unique identifier: NCT03044665.

Efficacy of bepridil as a periprocedural support drug in atrial fibrillation patients with left ventricular systolic dysfunction undergoing catheter ablation

Abstract We previously reported that sinus restoration either with drugs or DC cardioversion prior to catheter ablation (CA) was associated with a better outcome in persistent atrial fibrillation (AF). As an antiarrhythmic agent for persistent AF, amiodarone is recommended for patients with structural heart disease. Bepridil, a unique multichannel inhibitor, has a comparable defibrillation efficacy and fewer extracardiac complications than amiodarone, although safety and efficacy of bepridil has not been established in those with left ventricular (LV) systolic dysfunction. We compared the safety and efficacy of bepridil and amiodarone as periprocedural support drugs for CA in patients with persistent AF with LV systolic dysfunction. Method and result: Persistent AF patients with LVEF ≤50% taking bepridil or amiodarone as periprocedural support drugs for CA were retrospectively analyzed; 51 patients in the bepridil group and 17 patients in the amiodarone group. There were 20 (39%) in the bepridil group and 17 (100%) in the amiodarone group with LVEF less than 40%. The amiodarone group had more history of heart failure hospitalizations, higher BNP, and lower LVEF than the bepridil group (HF; Bep 35.8% vs Amio 94.1% [p&amp;lt;0.01], BNP; Bep 306.4±422.8 pg/ml vs Amio 645.2±456.3 [p&amp;lt;0.01], LVEF; Bep 39.9±8.4% vs Amio 26.7±7.9% [p&amp;lt;0.01]). Bepridil was used at a dose of 126±39 mg and amiodarone at 153±60 mg before CA. Successful pharmacological defibrillation before CA was more prevalent in the bepridil group (Bep; 15:29.4% vs Amio; 2:11.8%, p=0.14). The time from drug induction to CA was 41±38 days in the bepridil group and 66±59 days in the amiodarone group. At 1-year after CA, doses of both drugs could be reduced (Bep: 72±53mg, Amio: 67±49mg), and 12 (23.5%) in the bepridil group and 3 (17.6%) in the amiodarone group were able to discontinue the drug. AF recurred in 6 (11%) in the bepridil group, and 2 (11%) in the amiodarone group. QTc was the longest immediately before CA in the both groups (Bep: 462±36ms, Amio: 462±32ms), but was shortened at 1-year with the drug dose reduction (Bep: 435±40ms, Amio: 444±29ms). LVEF significantly improved following maintenance of sinus rhythm in the both groups (Bep: 39.9±8.4% to 52.6±10.2% [p&amp;lt;0.01], Amio: 26.7±7.9% to 49.5±14.5% [p&amp;lt;0.01]), which was comparable between the 2 groups. Fatal ventricular arrhythmia occurred in 1 (5%) in the amiodarone group but not in the bepridil group. Hospitalization for heart failure occurred in 2 (3.9%) in the bepridil group. Discussion: Bepridil could be used safely at a short-term high dose before ablation and then reducing the dose after ablation. There is also a trend toward selecting bepridil in patients with relatively preserved cardiac function and less severe conditions. Conclusion: Bepridil can be used rather safely in AF patients with LV systolic dysfunction undergoing CA as a periprocedural support drug.

Initial Findings from a First-in-Human Phase 1a/b Trial of NX-5948, a Selective Bruton's Tyrosine Kinase (BTK) Degrader, in Patients with Relapsed/Refractory B Cell Malignancies

Introduction: Although BTK inhibitors (BTKi) are effective therapeutics in the treatment of B cell malignancies, emerging BTK resistance mutations in chronic lymphocytic leukemia (CLL), as well as potential growth-promoting kinase-independent scaffolding function of BTK, present a need for improved or new approaches. NX-5948 is a novel, orally administered small molecule that induces specific BTK protein degradation by the cereblon E3 ligase complex without degradation of other cereblon neo-substrates. Importantly, NX-5948 induces degradation of wild-type and mutant forms of BTK in B-cells [Noviski et al. 2023] at sub-nanomolar potencies and exhibits potent tumor growth inhibition in TMD8 xenograft models that contain either wild-type BTK or BTKi-resistant mutations [Robbins 2021]. Here we provide the first disclosure of preliminary safety and efficacy findings from a Phase 1a trial of NX-5948 in patients with relapsed/refractory B cell malignancies. Methods: NX-5948-301 is a Phase 1, first-in-human, dose-escalation and cohort-expansion trial evaluating the safety, tolerability, and clinical activity of NX-5948 in relapsed/refractory CLL and various subtypes of non-Hodgkin's lymphoma (NHL). Key eligibility criteria: ≥2 prior lines of therapy; measurable or other evaluable disease per indication-specific response criteria; Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1. Phase 1a (dose escalation) evaluates safety and tolerability of NX-5948 via a standard 3+3 dose escalation in patients with relapsed/refractory B cell malignancies. Approximately 110 patients (30 in Phase 1a, 80 in Phase 1b) may be enrolled and treated until confirmed disease progression or unacceptable toxicity. Endpoints include dose-limiting toxicities (DLTs); treatment-emergent adverse events (TEAEs); deaths; changes in safety parameters; objective response rate per disease-specific response criteria. Phase 1b (dose expansion) will include up to four expansion cohorts. Results: As of June 9, 2023, 14 patients were enrolled in Phase 1a and received NX-5948 at 50 mg (n=7), 100 mg (n=4), or 200 mg (n=3) orally once daily. Median age was 65 (range 46-79) years; female/male ratio 28.6%/71.4%; white 92.9%; ECOG PS 0/1 21.4%/78.6%; primary diagnoses were CLL (n=4), diffuse large B cell lymphoma (DLBCL, n=4), mantle cell lymphoma (MCL, n=3), marginal zone lymphoma (MZL, n=2), and follicular lymphoma (FL, n=1). Median number of prior therapies was 4.5 (range 2-10), which included: for CLL - BTKi (n=4/4) and BCL2 inhibitor (n=3/4); for NHL - BTKi (n=5/10), bispecific antibody (n=3/10), and CAR-T (n=2/10). NX-5948 was well tolerated with no DLTs and no TEAEs resulting in drug discontinuation or dose reduction. In addition, there were no NX-5948-related grade ≥3 TEAEs or related serious adverse events. The most common TEAEs were purpura/contusion (57.1%, all below grade 3), nausea (35.7%), and thrombocytopenia (35.7%). No atrial fibrillation/flutter or hypertension was reported. Median duration of treatment was 2.8 (range 0.5-9.6) months with 9/14 patients remaining on treatment. Current data indicate that NX-5948 exhibits dose-dependent pharmacokinetics (PK) and a half-life of ~24 hours, supporting once daily dosing (Figure a). Rapid, robust and sustained BTK degradation was observed in all patients, regardless of absolute BTK starting level, tumor type, or NX-5948 dose (Figure b). Of three evaluable patients with CLL receiving the lowest dose of 50 mg, early signs of clinical activity were observed including one confirmed partial response (PR; at 8 and 16 weeks) and 2 patients with stable disease (SD; at 8 weeks). Further treatment responses will be reported at the time of presentation. Summary/conclusion: Current findings in this heavily pre-treated population of patients with CLL and NHL are encouraging and indicate that NX-5948 is safe and well tolerated and has clinical activity, supporting continuation of its development in CLL and NHL. NX-5948 also exhibits dose-proportional PK, resulting in rapid, robust and sustained BTK degradation. Additional data with higher dose levels and longer treatment duration will be presented at the meeting.

Additive Effects of Helix aspersa Mucus Fractions with Chemotherapy Drugs in Breast Cancer: Exploring Anti-proliferative Potential

This study investigated the anti-proliferative effects of biologically active substances (BAS) derived from the mucus of the garden snail Helix aspersa on breast cancer cell lines (MCF-7 and MDA-MB-231) and a non-cancerous cell line (MCF-10A). Two mucus fractions with different molecular weights (Mw) were examined, and their interactions with the chemotherapy drugs cisplatin and tamoxifen were evaluated.&#x0D; The results showed that the mucus fractions exhibited a slight anti-proliferative effect on breast cancer cells, with the fraction having Mw above 50 kDa demonstrating stronger activity compared to the fraction with Mw above 20 kDa. Furthermore, the combination of the mucus fractions with cisplatin or tamoxifen resulted in significant reductions in the half effective dose, indicating possible synergistic effects which were more pronounced with the fraction having Mw above 20 kDa. Dose-response curves and microscopic images supported the presence of such effects, revealing lower IC50 values and significant cell death when the cancer cells were treated with the combination of the mucus fractions and chemotherapy drugs. However, the analysis using the (highest single agent) HSA model indicated mostly additive interactions between the mucus fractions and chemotherapy drugs.&#x0D; These findings suggest the potential of biologically active substances derived from Helix aspersa mucus in enhancing the anti-proliferative effects of chemotherapy drugs in breast cancer treatment. The identification of additive interactions provides insights into the development of combination therapies with reduced drug dosage. Overall, this study contributes to the understanding of the anti-proliferative effects of Helix aspersa mucus fractions and their interactions with chemotherapy drugs, highlighting their potential as novel therapeutic approaches in breast cancer treatment.

Selected neurological complications of oncological treatment — literature overview

Treatment in oncology may lead to several adverse side effects, including those affecting the nervous system. These side effects may reduce the quality of life of patients, both during and after treatment, and may necessitate changes in the treatment regimen or reduction of drug doses, thus reducing the effectiveness of therapy. The knowledge of therapy-induced side effects is essential for their early recognition and differentiation from symptoms resulting from the progression of neoplastic disease, metabolic disorders, or infections, requiring prompt initiation of causal treatment. This article presents the current state of knowledge regarding central and peripheral neurotoxicity of treatment in oncology. Adverse effects described after chemo- and radiotherapy are better known but still limit the potential possibilities of the applied treatment. Neurotoxicities of targeted therapy and immunotherapy, which are of increasing importance in the era of personalization of treatment, are presented.

Stimuli-responsive “theranostic” nanocomposite hydrogels based on β-cyclodextrin containing Fe3O4 and Bi2O3 nanoparticles for targeted delivery of methotrexate

The present study aimed to design and development of novel “theranostic” hydrogels-based drug delivery system (DDSs) composed of beta-cyclodextrin (β-CD), poly(N,N´-dimethylamino)ethyl methacrylate) (PDMAEMA), and Fe3O4 and Bi2O3 nanoparticles (NPs). Methotrexate (MTX) was loaded into the fabricated hydrogels as an anti-cancer drug. Drug encapsulation efficiencies for S1 and S2 samples were obtained as 77.74 and 81 %, respectively. In vitro drug release study verified pH-dependent and sustained drug release behavior of the formulated S1/MTX and S2/MTX. Cytocompatibilities of the hydrogels were approved using MTT-assay on MCF-7 cells. In contrast, the drug-loaded hydrogels showed time- and concentration-dependence cytotoxicities. As MTT-assay results, IC50 in time period of 48 h for free MTX, S1/MTX, and S2/MTX were quantified as 55, 27 and 27 µgmL−1 based on concentration of MTX. Therefore, S1/MTX and S2/MTX possesses higher anti-cancer activities owing to sustained and “smart” release of drug that could reduce drug dosage and side effects. The presence of Fe3O4 NPs and Bi2O3 NPs in the hydrogels allows diagnosis by MRI and CT, respectively. In addition, Bi2O3 NPs is suggested as efficient X-ray radiosensitizer for increasing the efficiency of radiotherapy. Therefore, the fabricated hydrogels have potential for synergistic chemoradiotherapy and can be exploited in medical imaging.

QbD-driven development of phospholipid-embedded lipidic nanocarriers of raloxifene: extensive in vitro and in vivo evaluation studies.

Raloxifene (RLX) is popularly indicated in treatment of osteoporosis and prevention of breast cancer. Owing to its poor aqueous solubility, high pre-systemic metabolism, intestinal glucuronidation, and P-glycoprotein (P-gp) efflux, however, it demonstrates low (< 2%) and inconsistent oral bioavailability. The current work, Quality by Design (QbD)-driven development of phospholipid-embedded nanostructured lipidic carriers (NLCs) of RLX, accordingly, was undertaken to potentiate its lymphatic uptake, augment oral bioavailability, and possibly reduce drug dosage. Factor screening and failure mode effect analysis (FMEA) studies were performed to delineate high-risk factors using solid lipid (glyceryl monostearate), liquid lipid (vitamin E), and surfactant (Tween 80). Response surface optimization studies were performed employing the Box-Behnken design. Mathematical and graphical methods were adopted to embark upon the selection of optimized NLCs with various critical quality attributes (CQAs) of mean particle size as 186nm, zeta potential of - 23.6mV, entrapment efficiency of 80.09%, and cumulative drug release at 12h of 83.87%. The DSC and FTIR studies, conducted on optimized NLCs, indicated successful entrapment of drug into the lipid matrix. In vitro drug release studies demonstrated Fickian diffusion mechanism. In vivo pharmacokinetic studies in rats construed significant improvement in AUC0-72h (4.48-folds) and in Cmax (5.11-folds), unequivocally indicating markedly superior (p < 0.001) oral bioavailability of RLX-NLCs vis-à-vis marketed tablet formulation. Subsequently, level "A" in vitro/in vivo correlation (IVIVC) was also successfully attempted between the percentages of in vitro drug dissolved and of in vivo drug absorbed at the matching time points. In vitro cytotoxicity and cellular uptake studies also corroborated higher efficacy and successful localization of coumarin-6-loaded NLCs into MG-63 cells through microfluidic channels.

Nanocarriers in Tuberculosis Treatment: Challenges and Delivery Strategies.

The World Health Organization identifies tuberculosis (TB), caused by Mycobacterium tuberculosis, as a leading infectious killer. Although conventional treatments for TB exist, they come with challenges such as a heavy pill regimen, prolonged treatment duration, and a strict schedule, leading to multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. The rise of MDR strains endangers future TB control. Despite these concerns, the hunt for an efficient treatment continues. One breakthrough has been the use of nanotechnology in medicines, presenting a novel approach for TB treatment. Nanocarriers, such as lipid nanoparticles, nanosuspensions, liposomes, and polymeric micelles, facilitate targeted delivery of anti-TB drugs. The benefits of nanocarriers include reduced drug doses, fewer side effects, improved drug solubility, better bioavailability, and improved patient compliance, speeding up recovery. Additionally, nanocarriers can be made even more targeted by linking them with ligands such as mannose or hyaluronic acid. This review explores these innovative TB treatments, including studies on nanocarriers containing anti-TB drugs and related patents.