Drug Dose Reduction Research Articles

Starting stiripentol in adults with Dravet syndrome? Watch for ammonia and carnitine.

Dravet syndrome (DS) is a rare cause of severe and pharmacoresistant epileptic encephalopathy. Stiripentol (STP) has a significant therapeutic benefit in the pediatric DS population. However, STP effects on adult patients have not been well studied. In our adult STP-naive DS patient population, STP initiation was associated with encephalopathy, despite decreases in valproate and clobazam dosage. Here we explored the cause and treatment of encephalopathic manifestations associated with STP in adults. Twenty-eight patients with a confirmed clinical and genetic diagnosis of DS who attended the Adult Epilepsy Genetics Clinic were identified retrospectively. Patients who declined or discontinued STP after fewer than 3months of use, patients who were deceased before starting STP or seizure-free when the genetic diagnosis was confirmed, and those who started STP before leaving the pediatric system (<18years) were excluded. Levels of ammonia, carnitine, and other anti-epileptic drugs (AEDs) were observed for patients receiving STP. Patients with high ammonia levels who received carnitine supplementation were reevaluated. They were also offered an increased dosage of stiripentol if treatment with carnitine improved the encephalopathy. We observed hyperammonemic encephalopathy in 77% of patients treated with STP. In seven of nine patients, we observed a rate of improvement in ammonia levels of 35% (95% confidence interval [CI] 21%-49%) at a mean carnitine dose of 991±286mg/d (range 660-1320mg/d). Five patients whose ammonia levels normalized were also offered an increase in STP dose and they were able to tolerate higher doses with improvement in side effects. Despite such adjustments, the mean maximum stiripentol dose reached was 14.89±8.72mg/kg/d, which is lower than what is typically recommended in children (50mg/kg/d). We report hyperammonemia in adult STP-naive patients who were on valproate and clobazam, despite dose reduction of the latter drugs. We also report that treatment with carnitine improved hyperammonemia, allowing the continuation of STP.

Immunosuppressive and metabolic agents that influence allo- and xenograft survival by in vivo expansion of T regulatory cells.

The transplanted organs or cells survive if the recipient receives adequate long-term immunosuppressive therapy. Immunosuppressive therapy combined with cell-based strategies (eg, regulatory T cell [Treg]-based therapy) promotes graft survival. A combination of Treg-based therapy and minimal or no immunosuppressive drug therapy would have the potential to minimize the risks of the complications and side effects of these drugs. Fortunately, some immunosuppressive and other agents not only impede the effector T cell response, but also help generate new CD4+ Tregs from conventional effector T cells. These agents include IL-2, TGF-β, agents that block the CD40/CD40L costimulation pathway, mTOR inhibitors, and histone deacetylase inhibitors. Consequently, a state of relative unresponsiveness to the transplanted organ may be induced through the expansion of Tregs. We here review the effect of these various agents on expansion of CD4+ Tregs in allo- and xenotransplantation. The expansion of Tregs might allow a dose reduction of the standard immunosuppressive drugs.

Outcome Measures for Interventions to Reduce Inappropriate Chronic Drugs: A Narrative Review.

Inappropriate prescribing is a highly important problem, given the growing aging multimorbid population with associated polypharmacy. An increasing number of studies have recently developed and tested interventions to withdraw inappropriate drugs, a process called deprescribing. However, we still lack complete information on the types and prevalence of measures used to assess the success of such interventions. To categorize and synthesize the full spectrum of measures used in intervention studies focused on reducing inappropriate prescribing of chronic drugs in adults, to standardize measurements in future studies and help researchers design studies inclusive of the important measure types. We searched Ovid/MEDLINE to identify intervention studies focused on deprescribing chronic drugs in adults, published between 2010 and 2019. We extracted data on study characteristics, intervention components, and outcome measures. We categorized and synthesized the measures using a comprehensive and systematic framework, separating measures of intended and unintended consequences. Most (90/93) studies used measures of appropriate prescribing, such as drug cessation or dose reduction. The following measures were used infrequently across studies: patient-reported experience, preferences, and outcome (12 (13%), 2 (2%), and 25 (27%) studies, respectively); provider-reported experience (11 (12%) studies); patient-provider interaction (4 (4%) studies); and measures of unintended consequences (24 (26%) studies). Studies varied in the type and number of measures assessed, ranging from 1 to 20 different measures by study. To ensure initiation, success, and long-term sustainability of deprescribing, it is important to assess the success of intervention studies using clinically relevant patient- and provider-centered measures. This categorized synthesis of outcome measures used in deprescribing studies may facilitate implementation of important measure types (e.g., patient-reported measures and measures of unintended consequences) in future studies. J Am Geriatr Soc 68:2390-2398, 2020.

Co-delivery of IR-768 and daunorubicin using mPEG-b-PLGA micelles for synergistic enhancement of combination therapy of melanoma

Malignant melanoma is an emerging problem worldwide due to the high degree of lethalness. Its aggressiveness and the ability to metastasize along with the heterogeneity at the molecular and cellular levels, limit the overall therapeutic efficacy. Despite significant advances in melanoma treatment over the last decade, there is still a need for improved therapeutic modalities. Thus, we demonstrate here a combinatorial approach that targets multiple independent therapeutic pathways, in which polymeric micelles (PMs) were used as efficacious colloidal nanocarriers loaded with both daunorubicin (DRB) as a cytotoxic drug and IR-768 as a photosensitizer. This afforded the dual drug loaded delivery system IR-768 + DRB in PMs. The fabricated mPEG-b-PLGA micelles (hydrodynamic diameters ≈ 25 nm) had a relatively narrow size distribution (PdI > ca. 0.3) with uniform spherical shapes. CLSM study showed that mPEG-b-PLGA micelles were uptaken by mitochondria, which further contributed to excellent singlet oxygen generation capacity for PDT in A375 melanoma cells. Furthermore, the PMs were efficiently internalized by tested cells through endocytosis, resulting in much higher cellular uptake comparing to the free drug. As a result of these properties, IR-768 + DRB in PMs exhibited very potent and synergistically enhanced anticancer activity against A375 cells. Additionally, this combination approach allowed to reduce drug doses and provided low side effects towards normal HaCaT. This study indicates excellent properties of mPEG-b-PLGA micelles resulting in great therapeutic potential possessed by the developed nanoscale drug delivery system for combined chemo-photodynamic therapy of melanoma.

Cutaneous Immune-Related Adverse Events (irAEs) to Immune Checkpoint Inhibitors: A Dermatology Perspective on Management [Formula: see text

Immune checkpoint inhibitors have proven to be efficacious for a broad spectrum of solid organ malignancies. These monoclonal antibodies lead to cytotoxic T-cell activation and subsequent elimination of cancer cells. However, they can also lead to immune intolerance and immune-related adverse event (irAEs) that are new and specific to these therapies. Cutaneous irAEs are the most common, arising in up to 34% of patients on PD-1 inhibitors and 43% to 45% on CTLA-4 inhibitors. The most common skin manifestations include maculopapular eruption, pruritus, and vitiligo-like lesions. A grading system has been proposed, which guides management of cutaneous manifestations based on the percent body surface area (BSA) involved. Cutaneous irAEs may prompt clinicians to reduce drug doses, add systemic steroids to the regiment, and/or discontinue lifesaving immunotherapy. Thus, the goal is for early identification and concurrent management to minimize treatment interruptions. We emphasize here that the severity of the reaction should not be graded based on BSA involvement alone, but rather on the nature of the primary cutaneous pathology. For instance, maculopapular eruptions rarely affect <30% BSA and can often be managed conservatively with skin-directed therapies, while Stevens-Johnson syndrome (SJS) affecting even 5% BSA should be managed aggressively and the immunotherapy should be discontinued at once. There is limited literature available on the management of the cutaneous irAEs and most studies present anecdotal evidence. We review the management strategies and provide recommendations for psoriatic, immunobullous, maculopapular, lichenoid, acantholytic eruptions, vitiligo, alopecias, vasculitides, SJS/toxic epidermal necrolysis, and other related skin toxicities.

Oral mucositis among Chinese cancer patients receiving chemotherapy: Effects and management strategies.

Oral mucositis is a painful and distressing complication of chemotherapy-induced toxicity in cancer patients that can develop early during the treatment regimen. Previous studies have demonstrated that both oxidative stress and inflammation play a role in the development of the ulceration that is a characteristic of oral mucositis. To date, a few studies have investigated the effect of this complication on the well-being of patients, demonstrating its negative impact on patients' functional ability and quality of life. This effect may entail chemotherapeutic drug dose reduction among patients, in turn reducing their cancer survival rates. Therefore, interventions to address the detrimental effects of oral mucositis on the well-being of cancer patients are required. This review provides an overview of the studies that have examined the negative effects of oral mucositis on Chinese cancer patients undergoing chemotherapy, as well as the interventions shown to be effective in treating this complication, with a focus on interventions utilizing traditional Chinese medicine. Overall, both traditional Chinese medicine-based interventions and interventions involving patient education about effective oral care led by trained nurses were found to be useful in reducing the incidence and severity of oral mucositis among Chinese patients undergoing chemotherapy. Future oral mucositis management plans aiming at effective oral care among cancer patients undergoing chemotherapy should incorporate these types of interventions as integral components to enhance the well-being of these patients.

Cytotoxic and biomechanical effects of clinical dosing schemes of paclitaxel on neurons and cancer cells.

Chemotherapy-induced peripheral neuropathy often results in a reduction in drug dose. However, the serum level of anticancer drugs varies with time after intravenous infusion, and this factor has seldom been considered in previous in vitro studies. The goals of this study were to build an automatic dosage control system and to evaluate the influence of drug infusion rate on the cells. Neurons and melanoma cells were used as the samples. The 3-h (average and peak concentration: 0.024 and 0.287μM) and 24-h infusion (average and peak concentration: 0.020 and 0.042μM) schemes were investigated. For evaluations, cell indentation tests by an atomic force microscope, serial immunofluorescent images, and cell viability analysis was performed. For the neurons, Young's modulus first increased and then remained unchanged in the 3-h scheme, but was stationary throughout the observation period in the 24-h scheme. For the cancer cells, Young's modulus increased in both infusion schemes, and the increase was larger in the 3-h scheme. Morphologically, axons swelled and shortened, and the number of their branches decreased in the 3-h scheme. In contrast, there was only slowed growth of axons without obvious morphological changes in the 24-h scheme. Viability analysis of the cancer cells revealed that the 3-h scheme had a better anticancer effect. A dosage-control system simulating the pharmacodynamic changes of drugs was successfully constructed for in vitro cell cultures. The 3-h scheme of paclitaxel showed better anticancer effects but more adverse effects on neuronal growth and morphology.

Dermatologic management of oncotherapy side effects: A proposed algorithm.

Since the introduction of the first chemotherapeutic regimens for the treatment of oncological disease, hundreds of drugs have been approved for cancer treatment and many more are under investigation. The development of newer drugs such as target therapies, immuno-oncotherapies, and hormonal therapies has increased in specificity with the development of smaller molecules and more selective targets. Cutaneous side effects are now well known for both standard chemotherapy and targeted therapies. The correct diagnosis and management of these effects are of vital importance both to optimize therapeutic success rates and to reduce the patient's suffering. In fact, the appearance of a cutaneous adverse event can be responsible for a reduction in drug dosage or worse its suspension. In order to achieve this objective, we propose a management algorithm, based on three different steps, before, during, and after the oncological treatments, respectively. Our proposal underlines the importance of correct skin care measures to limit or reduce the severity of side effects.

The learned placebo response in the immune system

The learned placebo response of the immune system is based on the mutual interaction between the brain and the immune system; both systems continually exchange information via humoral and neural communication pathways. This communication network enables the modification, i.e. suppression or stimulation, of peripheral immune functions by classical or Pavlov's conditioning. The present article provides an overview of the results of recent experimental animal studies, which also document the potential clinical relevance of learned immune responses. Learned immunological responses mediated by classical conditioning have also been demonstrated in humans. The knowledge gained from experimental data and clinical observations paves the way for apotential implementation of learned immune responses as supportive measures to standard immunopharmacological treatment strategies to reduce drug dosage as well as adverse side effects while simultaneously maximizing the therapeutic effect.

Oxymatrine loaded nitric oxide-releasing liposomes for the treatment of ulcerative colitis.

Oxymatrine (OM) is the biologically active ingredient of Chinese medicinal herb Sophora flavescens, which is reported to be effective on alleviating ulcerative colitis (UC) due to its anti-inflammatory property. However, its highly effective dose is an obstacles to its application. Therefore, liposome was used to encapsulate OM, realize targeting delivery to colitis and thus reduce drug dosage. Meanwhile, considering the potential anti-inflammatory ability of nitric oxide (NO), a NO donor, d-α-tocopheryl polyethylene glycol succinate nitrate (TN), was introduced into the liposomal system and OM loaded NO-releasing liposomes (OM@TN-lip) were prepared in order to co-deliver OM and NO to the inflammatory lesions of DSS-induced UC mice to achieve the combination therapy. OM@TN-lip was multilamelar sphere with the encapsulation efficiency of ~70%, the diameter of ~200nm and ζ-potential of about -13mV. Bio-distribution results revealed the liposomes could efficiently accumulate in the inflammatory colon by diffusion and maintain for more than 36h. In UC mice model, OM@TN-lip showed significant alleviation of inflammation and the treatment was highly related to down-regulation of pro-inflammatory cytokines TNF-α, IFN-γ, IL-1β and IL-6, decrease of macrophages infiltration, activity decrease of myeloperoxidase (MPO) and cyclooxygenase-2 (COX-2), and rebuilding antioxidant/oxidation balance by reducing reactive oxygen species (ROS) and increasing Glutathione (GSH) in colon.

Nanoparticles in Colorectal Cancer Therapy: Latest In Vivo Assays, Clinical Trials, and Patents.

Colorectal cancer (CRC) is the third most common cancer worldwide. Its poor response to current treatment options in advanced stages and the need for efficient diagnosis in early stages call for the development of new therapeutic and diagnostic strategies. Some of them are based on the use of nanometric materials as carriers and releasers of therapeutic agents and fluorescent molecules, or even on the utilization of magnetic materials that provide very interesting properties. These nanoformulations present several advantages compared with the free molecular cargo, including increased drug solubility, bioavailability, stability, and tumor specificity. Moreover, tumor multidrug resistance has been decreased in some cases, leading to improved treatment effectiveness by reducing drug dose and potential side effects. Here, we present an updated overview of the latest advances in clinical research, in vivo studies, and patents regarding the application of nanoformulations in the treatment of CRC. Based on the information gathered, a wide variety of nanomaterials are being investigated in clinical research, even in advanced phases, i.e., close to reaching the market. In sum, these novel materials can offer remarkable advantages with respect to current therapies, which could be complemented or even replaced by these nanosystems in the near future.

HERBAL NANOSUSPENSION: IN VITRO CANCER STUDY AGAINST DIFFERENT CELL LINES

Herbal formulations marketed in India for many years providing its therapeutic benefits in health problems. Medicinal plants or their phytoconstituents are less toxic and free from side effects than synthetic drugs. However, formulation aspects of these phytoconstituents are limited due to its low solubility. Nanotechnology is a promising technique to increase the solubility of herbal drugs. This will lead to a subsequent reduction in drug dose. Nanoformulations such as nanosuspension increase the solubility of poorly soluble drugs and also have good targeting effects on different cells. The efficacy of herbal nanosuspensions evaluated using different cell lines. Here, hepatocellular carcinoma cell line (SMMC-7721), human prostate cancer cell line, human myelogenous leukemia cell line, human epithelial cell line, human breast cancer cell lines (4T1, MCF-7, and MDA-MB-453), carcinomic human alveolar basal epithelial cell line (A549), human umbilical vein endothelial cell line, human colorectal adenocarcinoma cell line (HT-29), and human epithelial carcinoma cell line (HeLa) are used in the evaluation procedures. In vitro assays help in the determination of the dose range of drugs for the activity. The present review highlights the in vitro cancer studies of herbal nanosuspensions using different cell lines.

Momordica charantia and Cisplatin Treatment Increase the Cytotoxic Effects on Acute Leukemia Cells

Abstract Chemotherapy was designed to target specific proteins by either upregulating or downregulating specific cellular pathways to induce apoptosis and stop cell proliferation of cancerous cells. However, a patient’s cancer cells are known to mutate and potentially develop resistance the cytotoxic mechanisms of these chemotherapy drugs. In addition, high dosages of chemotherapy drugs results in harmful side effects to the patients. As a result, researchers have been searching for ways to reduce drug dosages but maintain chemotherapeutic drugs killing efficiency. Bitter Melon (Momordica charantia) extract is considered a potential anti-cancer agent due to its antitumor and anti-inflammatory properties. The objective of this study is to examine the anti-cancer effects of bitter melon extract (BME) and to show an increased cytotoxicity of acute T-cell leukemia (Jurkat) treated with both cisplatin and BME. The results have shown that BME, when introduced at a 1% concentration, decreased the viability of Jurkat cells by an average of 12% (P-value 0.02). A high dosage treatment of Cisplatin (10μM) and a 1.5% concentration of BME decreased cell viability by 75% percent (P ≤ 0.05) when compared to the control group. At a low dose treatment of cisplatin (5μM), a 1.5% concentration of BME decreased the cell viability by 58.2% (P-value = 0.005). Our results indicate that a combination of these two compounds may help reduce to the need to use high dosages of cisplatin.

Relative dose intensity over the first four weeks of lenvatinib therapy is a factor of favorable response and overall survival in patients with unresectable hepatocellular carcinoma.

Lenvatinib is an approved first-line therapy for unresectable hepatocellular carcinoma (HCC), but the effect of dose modification on its efficacy is unclear. We analyzed the relationship between the relative dose intensity during the initial 4 weeks of therapy [4W-relative dose intensity (RDI)] and the efficacy of lenvatinib therapy in the real-world setting. A total of 48 consecutive patients with unresectable HCC who received lenvatinib therapy for more than 4 weeks were included. The 4W-RDI was calculated as the cumulative dose in the initial 4 weeks divided by the weight-based standard dose, and we evaluated its association with overall survival (OS) and best response by modified Response Evaluation Criteria in Solid Tumor (mRECIST). The baseline factors predicting high 4W-RDI were analyzed further. The median durations of follow-up and of therapy among the 48 participants were 7.6 and 6.6 months, respectively. The median OS was not reached. Drug interruption and/or dose reduction were necessary in 30 patients (62.5%) and the median 4W-RDI was 70% (range 22%–100%). Patients with 4W-RDI ≥70% had longer OS [hazard ratio (HR) 0.28, 95% confidential interval (CI):0.09–0.90, p = 0.03], and longer duration of lenvatinib therapy (HR 0.39, 95%CI:0.16–0.92, p = 0.03). Patients with 4W-RDI ≥70% showed higher disease control rate compared to those with 4W-RDI <70% (91.7% vs. 54.2%, p = 0.008). A baseline albumin level >3.4g/dL or ALBI score less than -2.171 were significantly associated with achieving 4W-RDI ≥70%. In conclusion, 4W-RDI of lenvatinib therapy is associated with favorable radiological response and longer OS.

An encyclopedic review on stereotactic hypofrac tionated radiotherapy, re-irradiation, and cancer genome research

Cancer is a disease that humans have been involved with, and scientists have done great efforts to treat it. But they have not had much success, On the other hand Nano science as a new scientific in various branches of science have been made many changes. Hence can be used to treat cancer of Nano science. Currently, cancer treatment is such that drugs used are not selectivity. The cancer cells are not specifically identified, it destroys healthy tissue and cause harm to the human body. So if we can reduce drug dose of the drug to the targeted tissue must be, we have partially solved the problem. With earlier studies, researchers in the field of folate and gold nanoclusters have done, specified in the detection and destruction of cancer cells are highly effective and very promising future. The gold nanoclusters were used because it has unique properties such as adsorption of heat for the destruction of cancer cells and is also well connected to the folate. the 4-aminothiophenol (4Atp) is one of the best linker for binding folate and gold Nano clusters. In this study we used computational method for computing stability of complex (folate and Nano clusters) and geometrical and physicochemical properties.Â

Heart rhythm and conduction disorders as manifestations of cardiotoxicity of anticancer treatment: myth or reality?

Oncologic diseases are currently one of the leading causes of death. Modern anticancer therapy allows preserving life and social adaptation of cancer patients for many years. However, the use of anticancer drugs is limited due to their adverse and, in some cases, severe cardiotoxic effects such as coronary artery disease, toxic cardiomyopathy, chronic heart failure, arterial hypertension, and others. Heart rhythm and conduction disorders occur, on average, in 16–36% chemotherapy patients and atrial fibrillation is one of the most common arrhythmogenic manifestations of cardiotoxicity. Anthracyclines, alkylating agents, and monoclonal antibodies disrupt the ion pumps function, contribute to the excess release of calcium from the sarcoplasmic reticulum, cause more rapid development of spontaneous diastolic depolarization, and ultimately provoke the occurrence of atrial fibrillation. Some chemotherapy drugs, in particular, anthracyclines, tyrosine kinase inhibitors, and histone deacetylases disrupt the functioning of potassium channels, which leads to an increase in the action potential and prolongation of QT interval. Data on the effects of other classes of chemotherapy drugs on the heart conduction system are scarce and contradictory. Heart rhythm and conduction disorders caused by chemotherapy can lead to a dose reduction or discontinuation of anticancer drugs and require careful monitoring and a joint approach by doctors of several specialties in the management of these patients.

A clinical study of effects of clonidine as adjuvant with ropivacaine in ultrasound guided axillary brachial plexus block

Background: Axillary Brachial plexus block is the distal block performed on the brachial plexus. With the advent of ultrasound guidance establishing the blockade has been easier with reduced drug dosage and less complications. Objective: To evaluate and compare the effects of addition of clonidine with ropivacaine for axillary block with reference to a) onset of sensory blockade b) onset of motor blockade c) duration of analgesia. Methods: 60 patients of ASA class 1& 2 for upper limb surgical procedures were randomly allocated into two groups of 30 each, Group P will receive ropivacaine 0.75% 20ml + NaCl 0.9% (0.5ml) Group D will receive ropivacaine 0.75% 20ml + clonidine 75µg (0.5ml). With ultrasound guidance axillary brachial plexus block was administered. Testing for onset of sensory blockade was done using pin prick method, Motor block was assessed using modified Bromage scale, Post operatively patients would be assessed for the duration of sensory and motor blockade. Results: The present study shows that 20 ml of 0.75% Ropivacaine with clonidine 75 mcg prolonged the duration of motor, sensory block and duration of analgesia when compared with 20 ml of 0.75% Ropivacaine with NaCl 0.9% .The onset of sensory, motor blocks was significantly faster with 0.75% Ropivacaine with clonidine 75 mcg group (Group D) when compared with 0.75% Ropivacaine with NaCl 0.9% group (Group P). Conclusion: Clonidine 75 µg as an adjuvant to 0.75% ropivacaine produces satisfactory onset of sensory and motor blockade, with increased duration of analgesia when used for axillary brachial plexus block under ultrasound guidance without any adverse effects.

Bilosomes nanocarriers for improved oral bioavailability of acyclovir: A complete characterization through in vitro, ex-vivo and in vivo assessment

Acyclovir (ACV) is an antiviral drug given as tablet that has variable and incomplete absorption from the gastrointestinal tract. Also the absorption is saturated with multi-dose regime leading to only 10-20% bioavailability. Since the drug absorption site is the upper segment of the small intestine so we hypothesised that absorption of acyclovir would increase through novel carriers such as bilosomes which are resistant to digestive enzymes disruption and offer greater drug absorption owing to higher tissue penetration. Also, reduction in drug dose would be possible through bilosomes oral delivery. To prove our hypothesis, ACV loaded bilosomes were prepared by thin film hydration technique and optimized by Box–Behnken statistical design. The mean vesicle size, polydispersity index and entrapment efficiency (%) of optimized bilosome formulation was observed to be 121.2 ± 3.21 nm, 0.261 ± 0.023 and 83.32 ± 5.46% respectively. In vitro release of ACV bilosomes at pH 6.8 was significantly higher (95.1 ± 7.27%) compared to ACV suspension and marketed formulation 40.23 ± 5.32% and 52.74 ± 5.84 respectively. Ex vivo gut permeation study revealed a good enhancement in penetration of bilosomes compared to ACV solution and marketed formulation which was further confirmed by confocal laser scanning microscopy which showed high penetration of bilosomes owing to vesicle stability against intestinal bile salts. Pharmacokinetic study in Wistar rats showed 4.36 and 2.5 fold increase in relative bioavailability with bilosomes (p<0.05) at a dose of 5mg/Kg body weight compared to ACV suspension and its marketed formulation respectively. Bilosomes treated tissue sections of the kidney, liver and intestine showed normal histology at the tested dose for a period of 24 h. Therefore, it is concluded that bilosomes are the safe carriers for improved absorption and bioavailability of acyclovir.

Multifunctional Antimicrobial Biometallohydrogels Based on Amino Acid Coordinated Self-Assembly.

There is a real need for new antibiotics against self-evolving bacteria. One option is to use biofriendly broad-spectrum and mechanically tunable antimicrobial hydrogels that can combat multidrug-resistant microbes. Whilst appealing, there are currently limited options. Herein, broad-spectrum antimicrobial biometallohydrogels based on the self-assembly and local mineralization of Ag+ -coordinated Fmoc-amino acids are reported. Such biometallohydrogels have the advantages of localized delivery and sustained release, reduced drug dosage and toxicity yet improved bioavailability, prolonged drug effect, and tunable mechanical strength. Furthermore, they can directly interact with the cell walls and membrane, resulting in the detachment of the plasma membrane and leakage of the cytoplasm. This leads to cell death, triggering a significant antibacterial effect against both Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) bacteria in cells and mice. This study paves the way for developing a multifunctional integration platform based on simple biomolecules coordinated self-assembly toward a broad range of biomedical applications.

P830 Genotype-based treatment with thiopurine reduces incidence of myelosuppression in patients with inflammatory bowel diseases

Abstract Background Thiopurine-related myelosuppression (most frequently leukopenia) interferes with thiopurine therapy for patients with inflammatory bowel diseases (IBD). We investigated whether pre-treatment analyses genetic variants associated with thiopurine-induced leukopenia could be used to effectively identify patients who required dose adjustments. Methods We performed a multicentre, prospective study of patients with IBD at 5 tertiary medical centres in Korea, from January 2016 through September 2018. Seventy-two patients were randomly assigned to a group that underwent genotype analysis for the NUDT15 variant (rs116855232) and FTO variant (rs79206939) and 3 common TPMT variants (rs1800460, rs1800462, rs1142345) associated with myelosuppression and 92 patients were assigned to a group that did not undergo genotype analysis (non-genotyping group). Patients heterozygous for any variant received 50 mg azathioprine equivalents, whereas those who were homozygous for any variant received alternative drugs. Patients who did not carry any of the genetic variants and patients in the non-genotyping group received 50 mg azathioprine equivalents followed by dose escalation up to 2–2.5 mg/kg. Myelosuppression was defined as white blood cell counts below 3000/μL, levels of haemoglobin 10 g/dl, or platelet counts below 100 K/μl. Results Twelve patients (16.7%) in the genotype analysis group and 33 patients (35.9%) in the non-genotyping group developed myelosuppression (p = .005). A multivariate analysis revealed that body mass indices above 21 kg/m2 (hazard ratio [HR], 0.43; 95% CI, 0.22–0.81; p = 0.009), pre-treatment genotype analysis (HR, 0.37; 95% CI, 0.18–0.77; p = 0.008), and the maximum dose of thiopurines (HR, 0.34; 95% CI, 0.19–0.59; p &amp;lt; 0.001) independently decreased risk of myelosuppression. Pre-treatment genotype analysis reduced numbers of outpatient clinic visit and numbers of patients with drug discontinuation or dose reductions. Conclusion In a randomised controlled study of patients undergoing thiopurine therapy for IBD, we found that selection of therapy based on genetic variants associated with thiopurine-induced leucopoenia significantly reduced the proportion of patients with myelosuppression during treatment.