Reduced Drug Concentrations Research Articles

Role of ABCC5 in cancer drug resistance and its potential as a therapeutic target

Over 90% of treatment failures in cancer therapy can be attributed to multidrug resistance (MDR), which can develop intracellularly or through various routes. Numerous pathways contribute to treatment resistance in cancer, but one of the most significant pathways is intracellular drug efflux and reduced drug concentrations within cells, which are controlled by overexpressed drug efflux pumps. As a member of the family of ABC transporter proteins, ABCC5 (ATP Binding Cassette Subfamily C Member 5) reduces the intracellular concentration of a drug and its subsequent effectiveness using an ATP-dependent method to pump the drug out of the cell. Numerous studies have demonstrated that ABCC5 is strongly linked to both poor prognosis and poor treatment response. In addition, elevated ABCC5 expression is noted in a wide variety of malignancies. Given that ABCC5 is regulated by several pathways in a broad range of cancer types, it is a prospective target for cancer treatment. This review examined the expression, structure, function, and role of ABCC5 in various cancer types.

Inhibit diffusion of the small molecule drug lidocaine hydrochloride in dissolving microneedles based on a phase separation approach

Dissolving microneedles (DMNs) have emerged as a promising transdermal drug delivery modality. However, in the case of small-molecule drug delivery, there is a tendency for the drug to disperse from the needle layer into the backing layer, resulting in reduced drug concentration at the needle site and consequently compromising drug delivery efficiency. In this study, lidocaine hydrochloride (Lido) was employed as a model drug to prepare a series of Lido dissolving microneedles (Li-DMNs) through a two-step casting method. We detail their fabrication process and the composition of needle and backing solutions, conduct in vitro characterization, and investigate the impact of viscosity and phase separation effects on drug distribution. Li-DMNs exhibit excellent visual appearance, adequate mechanical strength, favorable puncture permeability, and effective transdermal release property which can effectively facilitate the transdermal delivery of Lido. The phase separation effect significantly impedes Lido diffusion into the backing layer during DMNs preparation. This approach holds immense potential for broad applications and bears great significance in enhancing both drug loading capacity and transdermal delivery efficiency of DMNs.

Antimicrobial Pharmacokinetic Considerations in Extracorporeal Membrane Oxygenation.

Critical illness creates challenges for healthcare providers in determining the optimal treatment of severe disease, particularly in determining the most appropriate selection and dosing of medications. Critically ill patients experience endogenous physiologic changes that alter the pharmacokinetics (PKs) of medications. These alterations can be further compounded by mechanical support modalities such as extracorporeal membrane oxygenation (ECMO). Specific components of the ECMO circuit have the potential to affect drug PKs through drug sequestration and an increase in the volume of distribution. Factors related to the medications themselves also play a role. These PK alterations create problems when trying to properly utilize antimicrobials in this patient population. The literature seeking to identify appropriate antimicrobial dosing regimens is both limited and difficult to evaluate due to patient variability and an inability to determine the exact role of the ECMO circuit in reduced drug concentrations. Lipophilic and highly protein bound medications are considered more likely to undergo significant drug sequestration in an ECMO circuit, and this general trend represents a logical starting point in antimicrobial selection and dosing in patients on ECMO support. This should not be the only consideration, however, as identifying infection and evaluating the efficacy of treatments in this population is challenging. Due to these challenges, therapeutic drug monitoring should be utilized whenever possible, particularly in cases with severe infection or high concern for drug toxicity.

DESIGN AND DEVELOPMENT OF NANOEMULSION OF SMILAX CHINA FOR ANTI-PSORIASIS ACTIVITY

Objective: The present investigation aimed to prepare a smilax china loaded nanoemulsion using tween 80 as a surfactant and propylene glycol as a co-surfactant. Formulation of such drugs in nanoparticulate drug delivery will be advantageous for reducing dosing frequency, longer residence time, improved permeation, and patient compliance. Methods: High-speed homogenization method. The smilax china oil was prepared by collecting the extract of smilax china leaves into the coconut oil and then used as a solvent. The authentication studies of smilax china and coconut oil were evaluated for their organoleptic and physicochemical characteristics. The quantitative estimation and pre-formulation study of quercetin was carried out which has major anti-psoriatic properties. Surfactant and co-surfactant were selected and the solubility studies of oil and Surfactants were done. The nanoemulsion was characterized by particle size, polydispersity index, zeta potential, and entrapment efficiency (%). Results: This nanoemulsion provides the particle size and entrapment efficiency range between 80.52 to 89.78 nm and 68.66 to 70.16 % respectively. Batch SC1 showed the lowest particle size, PDI, and optimized drug entrapment effectiveness (%), indicating good particle size consistency within the remaining formulation batches. The optimized formulation SC 1 was found to be stable for 90 d. Conclusion: The formulated nanoemulsion showed significant antipsoriasis activity due to the presence of quercetin which has a rhetorical yield of 1.066 mg per 5 gm powder of smilax china leaves. Formulated smilax china-loaded nanoemulsion, has the potential as an effective antipsoriasis agent with a good spreading property with faster absorption which is beneficial for reducing drug concentration with maximum therapeutic effect.

Impact of the physical-chemical properties of poly(lactic acid)–poly(ethylene glycol) polymeric nanoparticles on biodistribution

Nanoparticle (NP) formulations are inherently polydisperse making their structural characterization and justification of specifications complex. It is essential, however, to gain an understanding of the physico-chemical properties that drive performance in vivo. To elucidate these properties, drug-containing poly(lactic acid) (PLA)–poly(ethylene glycol) (PEG) block polymeric NP formulations (or PNPs) were sub-divided into discrete size fractions and analyzed using a combination of advanced techniques, namely cryogenic transmission electron microscopy, small-angle neutron and X-ray scattering, nuclear magnetic resonance, and hard-energy X-ray photoelectron spectroscopy. Together, these techniques revealed a uniquely detailed picture of PNP size, surface structure, internal molecular architecture and the preferred site(s) of incorporation of the hydrophobic drug, AZD5991, properties which cannot be accessed via conventional characterization methodologies. Within the PNP size distribution, it was shown that the smallest PNPs contained significantly less drug than their larger sized counterparts, reducing overall drug loading, while PNP molecular architecture was critical in understanding the nature of in vitro drug release. The effect of PNP size and structure on drug biodistribution was determined by administrating selected PNP size fractions to mice, with the smaller sized NP fractions increasing the total drug-plasma concentration area under the curve and reducing drug concentrations in liver and spleen, due to greater avoidance of the reticuloendothelial system. In contrast, administration of unfractionated PNPs, containing a large population of NPs with extremely low drug load, did not significantly impact the drug's pharmacokinetic behavior - a significant result for nanomedicine development where a uniform formulation is usually an important driver. We also demonstrate how, in this study, it is not practicable to validate the bioanalytical methodology for drug released in vivo due to the NP formulation properties, a process which is applicable for most small molecule-releasing nanomedicines. In conclusion, this work details a strategy for determining the effect of formulation variability on in vivo performance, thereby informing the translation of PNPs, and other NPs, from the laboratory to the clinic.

Wet-adhesive γ-PGA/ε-PLL hydrogel loaded with EGF for tracheal epithelial injury repair.

Following the global COVID-19 pandemic, the incidence of tracheal epithelial injury is increasing. However, the repair of tracheal epithelial injury remains a challenge due to the slow renewal rate of tracheal epithelial cells (TECs). In traditional nebulized inhalation treatments, drugs are enriched in the lungs or absorbed into the blood, reducing drug concentration at the tracheal injury site. In this study, we prepared an epidermal growth factor (EGF)-loaded gamma-polyglutamic acid (γ-PGA)/epsilon-poly-L-lysine (ε-PLL) (PP) hydrogel (EGF@PP) to promote the repair of tracheal epithelial injury. Epidermal growth factor promotes the proliferation of TECs and enhances vascularization, thereby accelerating injury repair. The PP hydrogel exhibits outstanding wet adhesion, slow drug release, and antibacterial and anti-inflammatory properties, making it suitable for application in the airways and creating an environment conducive to epithelial repair. Here, we established a rabbit model of tracheal injury using a laser to destroy the tracheal epithelium and delivered EGF@PP powder to the injury site under fiberoptic bronchoscopy guidance. Our findings revealed that this was an effective therapeutic strategy for accelerating the repair of tracheal epithelial injury.

530: EVALUATION OF ALTEPLASE INFUSION DELAY FOLLOWING BOLUS AND IMPACT ON OUTCOMES IN ISCHEMIC STROKE​

Introduction: Alteplase is most beneficial when given early in acute ischemic stroke (AIS) and therefore a door-to-needle time (DTN) of less than 30 minutes is recommended by the AHA. Institutions may administer the alteplase bolus immediately following results of the non-contrast CT scan, however the start of alteplase infusion may be delayed for various reasons. Delays between the alteplase bolus and infusion can result in reduced drug concentration due to a short half-life (5 minutes), but it is unknown how a prolonged delay between bolus and infusion impacts outcomes. We performed a single health-system retrospective assessment determine if a delay of more than 5 minutes between alteplase bolus and infusion impacts outcomes in patients with AIS. Methods: Adult patients who received alteplase for the treatment of AIS between March 2015 through October 2021 were included. Patients were excluded if they received alteplase at an outside hospital; underwent a mechanical thrombectomy; lacked documentation of admission or discharge NIHSS; or if pregnant. The primary outcome evaluated the change in the NIHSS from admission to discharge in patients with less than or equal to a five-minute difference compared to patients with greater than a five-minute difference from alteplase bolus to infusion. Secondary outcomes evaluated admission NIHSS compared to 90-day mRS, discharge location, in-hospital mortality, and 90-day mortality. Results: 1229 patients were included. 280 patients had a bolus to infusion delay of > 5 minutes and 949 patients had a delay of ≤ 5 minutes. There was no difference in the change in NIHSS from admission to discharge (decrease of 3 points). There was also no difference in the secondary outcomes except for 90-day mortality which was statistically higher in the group of patients with a bolus to infusion delay (6.8% vs 3.3% p-value: 0.009). The difference in 90-day mRS (n=470) was not statistically significant but did show a trend towards worse outcomes in patients with an initial NIHSS of 5-14. Conclusions: Delay in alteplase infusion following bolus did not consistently show worse patient outcomes but did show an increase in 90-day mortality and mRS. Interpretation of these study results should be taken with caution due to the retrospective nature and missing data points for 90-day mRS.

Formulation and evaluation of a smart drug delivery system of 5-fluorouracil for pH-sensitive chemotherapy

The conventional chemotherapeutic drugs have many side effects due to their non-selective tissue distribution, reduced drug concentration of the drug at the tumor site, and the drug resistance. To overcome these problems the chemotherapeutic agent should selectively accumulate the tumor site and stays there for a prolonged period of time releasing the payloads in a controlled manner. This can be achieved by the administration of a smart drug delivery system (SDDS) loaded with the active drug molecules. In this work, 5-fluorouracil (5-FU) is loaded into amine functionalised hollow mesoporous silica nanoparticles (HMSN-NH2) and then coated with a biocompatible polydopamine (PDA) to formulate SSDS for 5-FU for pH-sensitive drug release. The physiochemical properties were characterised; the structural morphology was observed by using optical microscope, scanning electron microscope and transmission electron microscope, chemical interaction between the drug and excipients were characterised from Fourier transform infrared spectroscopy, the entrapment efficiency of loaded drug and the pH-dependent drug release rate were evaluated using UV-visible spectroscopy. It was observed that, the drug is compatible with excipients by retaining all the characteristics peaks of 5-FU with negligible changes in the position in all physical mixtures. The PDA coated 5-FU loaded HMSN-NH2 also exhibits a nearly spherical and non-aggregated morphology. The release rate was showed to increase with increase in concentration of structure-directing agent (Triton X 100) in the rate of a maximum release at the end of 72 h in pH 4. The prepared novel PDA coated 5-FU HMSN-NH2 was found to be capable of delivering the anti-cancer drug 5-FU specifically at the tumor site in a pH-dependent stimuli-responsive manner. It also showed a controlled release for a period of 72 h. The enhanced cytotoxicity against HeLa cell line were found for the formulated SSD form.

Hydrogen bond-enhanced nanogel delivery system for potential intranasal therapy of Parkinson's disease

Parkinson's disease (PD) is a severe neurodegenerative disease with a high incidence in the elderly and is mainly treated by drugs. The blood–brain barrier (BBB) limits the entry of oral neuroactive drugs to the brain, reducing drug concentration and affecting the treatment of PD. Nanotechnology-based drug delivery systems, especially thermosensitive systems, allow drug access to the brain via the nose-brain pathway, which is not limited by the presence of BBB. These delivery systems demonstrate outstanding performance in enhancing brain accumulation of active drugs, improving the loading capacity and stability. In this study, a nano-hydrogel delivery system composed of hydrogen bond-enhanced nanogel and thermosensitive gel is prepared for the effective delivery of albiflorin to treat PD. Importantly, the glycyrrhizic acid acts as a hydrogen bond crosslinker and adjunctive drug to prevent the premature release of albiflorin and achieve synergistic therapeutic performance. Compared to free drugs, the nano-hydrogel delivery system provides superior efficacy due to the enhanced stability. Moreover, this nano-hydrogel delivery system exhibits a selective brain distribution and accumulation and good antioxidant and anti-inflammation effects. This work demonstrates that this intranasal nanogel may function as a promising drug delivery system in treating PD.

Challenges and solutions in polymer drug delivery for bacterial biofilm treatment: A tissue-by-tissue account.

To tackle the emerging antibiotic resistance crisis, novel antimicrobial approaches are urgently needed. Bacterial communities (biofilms) are a particular concern in this context. Biofilms are responsible for most human infections and are inherently less susceptible to antibiotic treatments. Biofilms have been linked with several challenging chronic diseases, including implant-associated osteomyelitis and chronic wounds. The specific local environments present in the infected tissues further contribute to the rise in antibiotic resistance by limiting the efficacy of systemic antibiotic therapies and reducing drug concentrations at the infection site, which can lead to reoccurring infections. To overcome the shortcomings of systemic drug delivery, encapsulation within polymeric carriers has been shown to enhance antimicrobial efficacy, permeation and retention at the infection site. In this Review, we present an overview of current strategies for antimicrobial encapsulation within polymeric carriers, comparing challenges and solutions on a tissue-by-tissue basis. We compare challenges and proposed drug delivery solutions from the perspective of the local environments for biofilms found in oral, wound, gastric, urinary tract, bone, pulmonary, vaginal, ocular and middle/inner ear tissues. We will also discuss future challenges and barriers to clinical translation for these therapeutics. The following Review demonstrates there is a significant imbalance between the research focus being placed on different tissue types, with some targets (oral and wound biofims) being extensively more studied than others (vaginal and otitis media biofilms and endocarditis). Furthermore, the importance of the local tissue environment when selecting target therapies is demonstrated, with some materials being optimal choices for certain sites of bacterial infection, while having limited applicability in others.

Immunogenicity of Tumor Necrosis Factor Antagonists and Effect of Dose Escalation on Anti-Drug Antibodies and Serum Drug Concentrations in Inflammatory Bowel Disease.

Infliximab and adalimumab concentrations are associated with important outcomes in inflammatory bowel disease (IBD). Antibodies to infliximab (ATI) and adalimumab (ATA) are associated with reduced drug concentrations and worse outcomes. Because the efficacy of dose escalation to overcome antibodies is unclear, we assessed the impact of this strategy to overcome immunogenicity in IBD. Infliximab and adalimumab dosing, drug, and antibody concentrations were extracted from a database of patients with IBD having specimens collected for therapeutic drug monitoring. The primary outcome compared proportions with either infliximab ≥5 μg/mL or adalimumab ≥7.5 μg/mL and undetectable antibodies between dose-escalated and non-escalated patients. Area under the receiver operating characteristic curve analyses determined antibody concentrations below which dose escalation was associated with the primary outcome. The study included 63,176 patients treated with infliximab and 46,429 patients treated with adalimumab. We detected ATI and ATA in 23.6% (n = 14,900) of patients treated with infliximab and 19.6% (n = 9101) of patients treated with adalimumab. In patients with ATI, infliximab dose escalation (n = 453) yielded higher proportions achieving the primary outcome (47.5% vs 30.9%; P < 0.001), greater drug concentration increases (5.9 μg/mL vs 0.2 μg/mL; P < 0.001), and ATI reductions (4.3 U/mL vs 1.9 U/mL; P = 0.002) compared to no escalation (n = 204). An ATI threshold of 8.55 U/mL was associated with achieving the primary outcome with dose escalation (area under the curve = 0.66). For patients with ATI ≤8.55 U/mL (n = 274), higher proportions (59.1% vs 29.6%; P < 0.001) achieved the primary outcome compared with those with ATI >8.55 U/mL (n = 179). No patients treated with adalimumab achieved the primary outcome (0/390), regardless of dose escalation (n = 87). Dose escalation increased drug concentrations and eliminated antibodies with infliximab but not adalimumab. Initial ATI ≤8.55 U/mL was associated with increased efficacy of dose escalation using this assay.

Effect of aging on heat transfer, fluid flow and drug transport in anterior human eye: A computational study

There are a lot of geometrical and morphological changes that happen in the human eye with age. Primary open-angle glaucoma, which is caused by the increase in intraocular pressure inside the anterior chamber of the eye is also associated with the physiological aging of the eye. Therefore, it is crucial to understand the effects of aging on drug delivery in the human eye when applied topically. Consequently, a numerical model of topical drug delivery for an aging human eye has been developed using commercial software COMSOL Multiphysics in the current study. Three different age groups (young, middle and old) have been considered and the changes in geometrical and tissue properties of different domains of the eye with age have been included in the numerical model. The effect of aging on heat transfer, aqueous humor flow, intraocular pressure and drug concentration in different domains and orientations of the eye have been investigated. Additionally, an attempt has been made to predict the best class of anti-glaucomatic treatment in silico that should be preferred to treat primary open-angle glaucoma effectively. Results illustrate that there is a decrease in the average corneal temperature and an increase in the temperature deviation across the cornea with age. Further, there is a decrease in the aqueous humor flow magnitude in the anterior chamber of the eye and an increase in intraocular pressure in the anterior chamber of older age groups, which leads to primary open-angle glaucoma. The reduced aqueous humor flow leads to increased drug concentration in the anterior chamber as well as iris and reduced drug concentration in the trabecular mesh of the older age groups, thereby affecting the treatment efficacy. Additionally, our simulated results demonstrate that anti-glaucomatic treatments should be more focused on treating the trabecular mesh rather than the ciliary body of the eye.

Formation of Antihyperlipidemic Nano-Ezetimibe from Volatile Microemulsion Template for Enhanced Dissolution Profile.

Nanostructures play an important role in targeting sparingly water-soluble drugs to specific sites. Because of the structural flexibility and stability, the use of template microemulsions (μEs) can produce functional nanopharmaceuticals of different sizes, shapes, and chemical properties. In this article, we report a new volatile oil-in-water (o/w) μE formulation comprising ethyl acetate/ethanol/brij-35/water to obtain the highly water-dispersible nanoparticles of an antihyperlipidemic agent, ezetimibe (EZM-NPs), to enhance its dissolution profile. A pseudoternary phase diagram was delineated in a specified brij-35/ethanol ratio (1:1) to describe the transparent, optically isotropic domain of the as-formulated μE. The water-dilutable μE formulation, comprising an optimum composition of ethyl acetate (18.0%), ethanol (25.0%), brij-35 (25.0%), and water (32.0%), showed a good dissolvability of EZM around 4.8 wt % at pH 5.2. Electron micrographs showed a fine monomodal collection of EZM-loaded μE droplets (∼45 nm) that did not coalesce even after lyophilization, forming small spherical EZM-NPs (∼60 nm). However, the maturity of nanodrug droplets observed through dynamic light scattering suggests the affinity of EZM to the nonpolar microenvironment, which was further supported through peak-to-peak correlation of infrared analysis and fluorescence measurements. Moreover, the release profile of the as-obtained EZM-nanopowder increased significantly >98% in 30 min, which indicates that a reduced drug concentration will be needed for capsules or tablets in the future and can be simply incorporated into the multidosage formulation of EZM.

The Modern State of Prevention and Treatment of Chikungunya Fever

The Chikungunya virus (CHIKV) is an alphavirus transmitted to people by Aedes mosquitoes, usually Aedes aegypti and Aedes albopictus. The virus causes Chikungunya fever, a disease characterized by fever, nausea, headaches, rash, and persistent arthral­gia. Chikungunya fever may be associated with severe complications, including death. Since 2005, CHIKV has spread worldwide, leading to epidemics in Africa, Indian Ocean islands, Asia, and, most recently, in the Americas. Globally expanding pandemics with CHIKV rheumatic disorders and post-infectious complications are exacerbating public health problems. There is no specific vac­cine or drug to treat this viral infection. Analysis of the search for effective drugs in relation to CHIKV showed that, despite the diversity of research areas, as well as the use of modern advances in molecular biology, there are no etiotropic treatments or medic­inal immunobiological preparations (MIBPs) approved for use in practical medicine. However, new strategies for antiviral research are encouraging (inspire optimism?). Combined chemotherapy with interferons and antiviral agents is an appealing ther­apeutic strategy for providing increased antiviral activity and reducing drug concentrations.

Impact of metastases directed radiation therapy on CDK4/6 inhibitors dose reduction and treatment discontinuation for metastatic HR+/HER2- breast cancer (MBC).

562 Background: Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6i) represent the standard I-II line for hormonal receptors positive/human epidermal growth factor receptor 2 negative metastatic breast cancer (MBC) patients. Metastases directed radiotherapy (RT) for these patients is commonly used with palliative or radical schedules during systemic treatment. Although encouraging preliminary results were published, there is still a lack of robust data on the safety concerning RT during CDK4/6i treatment. Methods: we analyzed at Our Institution 85 consecutive patients treated in I (n=47) and II line (n=38) for MBC with CDK4/6i between April 2017 and September 2019 (22 ribociclib, 63 palbociclib). Overall, 25 (29.4%) patients received metastases directed RT during CDK4/6i treatment, including 14 concomitant (16.5%) and 11 sequential (12.9%). Estimated CDK4/6i half-life is 26 and 30 hours for palbociclib and ribociclib, respectively. Five half-lives are required to reduce drug concentration by 95-97%; thus, we also analyzed CDK4/6i treatment as non-concomitant or sequential to RT. Main endpoints of our analysis were impact of RT on CDK4/6i dose reduction and discontinuation, overall adverse events rate (any grade and grade ≥2), and neutropenia grade ≥2 as per CTCAE scale version 5.0. Results: at a median follow up of 12 months (range 3-29), we observed a CDK4/6i dose reduction in 35 patients (41.2%) and 5 patients (5.9%) discontinued treatment due to adverse events; 82 patients (96.5%) experienced any grade of toxicity, 72 (84.7%) a grade ≥2 and 70 patients (82.4%) neutropenia grade ≥2. We did not observe significant difference in terms of CDK4/6i dose reduction or discontinuation, any grade or grade ≥2 toxicity, neutropenia grade ≥2 in the comparison between patients receiving RT versus no RT and between patients receiving concomitant RT versus sequential RT versus no-RT (Table). Conclusions: our results showed that the prescription of a metastases directed RT during treatment with a CDK4/6i as I-II line for MBC did not significantly impact on dose reduction or discontinuation caused by an exceeding in adverse event rate. Although these promising results, caution should be used and cooperative initiatives strongly encouraged. [Table: see text]

MA17.09 5-Azacytidine Inhaled Dry Powder Formulation Profoundly Improves Pharmacokinetics and Efficacy for Lung Cancer Therapy

Epigenetic therapy through its ability to activate hundreds of genes silenced by promoter hypermethylation in lung cancer could produce durable and sustained tumor regression. The demethylating agent 5-azacytidine (5AZA) is unstable in aqueous solution and subject to hydrolysis and catabolism by cytidine deaminase (CDA) in liver, thereby reducing drug concentration after systemic administration prior to reaching the lung. Delivering 5AZA by inhalation could mitigate these barriers. A stable, respirable (3.5 μM) dry powder formulation of 5AZA was generated. Pharmacokinetic (PK) studies in rats compared systemic dosing to inhaled delivery of a dry powder or aqueous formulation of 5AZA in the presence and absence of the CDA inhibitor tetrahyroduridine (THU). An orthotopic nude rat lung cancer model compared efficacy of inhaled dry powder versus aqueous 5AZA for treatment of engrafted human adenocarcinoma (Calu6, Calu3), adenocarcinoma in situ (H358), and squamous cell (RH2) tumor lines. Three weeks following engraftment (lungs contain multiple tumors), rats were treated 4 times weekly for 4 weeks, then sacrificed to assess tumor burden and genome-wide effects on the methylome in vehicle and treated tumors using the Illumina EPIC array. Plasma PK showed a ∼10-fold increase in area under the curve (AUC) and a 1.5 and 5-fold increase in maximum concentration (Cmax) comparing inhaled dry powder (0.6 mg/kg) to systemic (2 mg/kg, equivalent to the human injectable dose of 75 mg/m2) and inhaled aqueous (0.6 mg/kg) 5AZA that was augmented by THU. Inhaled dry powder and aqueous 5AZA PK in lung were similar and greatly exceeded systemic (30-fold Cmax; 47-fold AUC). PK in liver and brain were superior for dry powder with 7- and 26-fold increase in AUC and 7- and 3.3-fold increase in Cmax compared to systemic or aqueous dosing. The efficacy study comparing inhaled delivery of equivalent doses (0.6 mg/kg lung dose) showed dry powder was significantly better than aqueous with a 70–80% compared to 33–50% reduction in tumor burden for Calu6, Calu3, and RH2 and equally effective in largely curing H358 tumors. A significantly increased median number of genes (175–320 versus 25–270) exhibiting ≥30% demethylation of CpGs across their promoter region was seen for Calu6, Calu3, and H358 tumors exposed to dry powder versus aqueous 5AZA, with equivalent numbers of genes demethylated for RH2. Delivery of a dry powder formulation of 5AZA via an inhaler could be used to treat local and metastatic lung cancer (Support–CA196590).

Chemotherapy drug regimen optimization using deterministic oscillatory search algorithm

Purpose : To schedule chemotherapy drug delivery using Deterministic Oscillatory Search algorithm, keeping the toxicity level within permissible limits and reducing the number of tumor cells within a predefined time period. Methods : A novel metaheuristic algorithm, deterministic oscillatory search, has been used to optimize the Gompertzian model of the drug regimen problem. The model is tested with fixed (fixed interval variable dose, FIVD) and variable (variable interval variable dose, VIVD) interval schemes and the dosage presented for 52 weeks. In the fixed interval, the treatment plan is fixed in such a way that doses are given on the first two days of every seven weeks such as day 7, day 14, etc. Results : On comparing the two schemes, FIVD provided a higher reduction in the number of tumor cells by 98 % compared to 87 % by VIVD after the treatment period. Also, a significant reduction in the number was obtained half way through the regimen. The dose level and toxicity are also reduced in the FIVD scheme. The value of drug concentration is more in FIVD scheme (50) compared to VIVD (41); however, it is well within the acceptable limits of concentration. The results proved the effectiveness of the proposed technique in terms of reduced drug concentration, toxicity, tumor size and drug level within a predetermined time period. Conclusion : Artificial intelligent techniques can be used as a tool to aid oncologists in the effective treatment of cancer through chemotherapy. Keywords : Deterministic Oscillatory Search, Chemotherapy scheduling, Drug schedule, Artificial intelligence

Iron Oxide Nanoparticles for Biomedical Applications: A Perspective on Synthesis, Drugs, Antimicrobial Activity, and Toxicity.

Medical applications and biotechnological advances, including magnetic resonance imaging, cell separation and detection, tissue repair, magnetic hyperthermia and drug delivery, have strongly benefited from employing iron oxide nanoparticles (IONPs) due to their remarkable properties, such as superparamagnetism, size and possibility of receiving a biocompatible coating. Ongoing research efforts focus on reducing drug concentration, toxicity, and other side effects, while increasing efficacy of IONPs-based treatments. This review highlights the methods of synthesis and presents the most recent reports in the literature regarding advances in drug delivery using IONPs-based systems, as well as their antimicrobial activity against different microorganisms. Furthermore, the toxicity of IONPs alone and constituting nanosystems is also addressed.

Use of Pinus sylvestris L. (Pinaceae), Origanum vulgare L. (Lamiaceae), and Thymus vulgaris L. (Lamiaceae) essential oils and their main components to enhance itraconazole activity against azole susceptible/not-susceptible Cryptococcus neoformans strains

BackgroundCryptococcal infections, besides being a problem for immunocompromised patients, are occasionally being a problem for immunocompetent patients. In addition, the lower susceptibility of this yeast to azoles is a growing problem in health care. To date, there are very few molecules with any activity towards Cryptococcus neoformans, leading to heightened interest in finding new alternatives or adjuvants to conventional drugs for the treatment of mycosis caused by this yeast. Since the essential oils (EOs) are considered as a potential rich source of bioactive antimicrobial compounds, we evaluated the antifungal activity of Origanum vulgare (oregano), Pinus sylvestris (pine), and Thymus vulgaris (thyme red) EOs, and their components (α-pinene, carvacrol, thymol) compared with fluconazole, itraconazole, and voriconazole, against C.neoformans clinical strains. Then, we investigated the effect of EOs and components in combination with itraconazole.MethodsEO composition was analysed by Gas chromatography-mass spectrometry (GC-MS). A broth microdilution method was used to evaluate the susceptibility of C.neoformans to azoles, EOs and components. Checkerboard tests, isobolograms and time-kill assays were carried out for combination studies.ResultsSix C.neoformans isolates were susceptible to azoles, while one C.neoformans exhibited a reduced susceptibility to all tested azole drugs. All EOs exerted a good inhibitory activity against all C.neoformans strains. Pine EO was the most effective. Among components, thymol exerted the most remarkable activity. By checkerboard testing and isobolographic analysis, combinations of itraconazole with oregano, pine, or thyme EOs, and carvacrol were found to be synergistic (FICI≤0.5) against azole susceptible C.neoformans. Regarding the azole not susceptible C.neoformans strain, the synergistic effect with itraconazole was observed with thyme EO (chemotype: thymol 26.52%; carvacrol 7.85%), and carvacrol. Time-kill assays confirmed the synergistic effects of itraconazole and oregano or thyme EO against azole susceptible C.neoformans. Binary mixtures of itraconazole/thyme EO or carvacrol yielded additive effects on the azole not susceptible C.neoformans.ConclusionsOur findings highlight the potential effectiveness of thyme, oregano EOs, and carvacrol as natural and cost-effective adjuvants when used in combination with itraconazole. Identification of EOs exerting these effects could be one of the feasible ways to overcome drug resistance, reducing drug concentration and side effects.

Determination of the release mechanism of Theophylline from pellets coated with Surelease®—A water dispersion of ethyl cellulose

The aim of this study was to investigate the water transport over free standing films based on the aqueous ethyl cellulose (EC) coating Surelease® and the drug (Theophylline) release mechanism from coated pellets. It was found that the main drug release rate from pellets was controlled by a diffusion mechanism. However, the drug release rate was altered by addition of sodium chloride to the external release medium. A decrease in the drug release rate when sodium chloride is added to the release medium has traditionally been used to indicate an osmotic drug release mechanism. However, our findings that the release rate decreased by sodium chloride addition could be explained by sodium chloride diffusing through the coating layer into the inner parts of the pellets, decreasing the solubility of Theophylline. This gave a reduced drug concentration gradient over the coating layer and thus a slower release rate. Furthermore, this study shows, as expected, that the transport of water through Surelease® films into the pellets was faster than the transport out of Theophylline (approx. seven times), which was the reason why the pellets were swelling during the release. It was also shown that the drug release rate, determined for both whole dose release and for single pellets, decreased with increasing thickness (from 16 to 51μm) of the coating layer controlling the drug release rate.