Drug Dose Reduction Research Articles

Use of Immunosuppressants/Immunomodulators in Autoimmune/Inflammatory Dermatologic Diseases during COVID-19 Pandemic-General Recommendation Based on Available Evidence.

Use of Immunosuppressants/Immunomodulators in Autoimmune/Inflammatory Dermatologic Diseases during COVID-19 Pandemic-General Recommendation Based on Available Evidence.

Comorbidity and Personalized Treatment of Multiple Myeloma in Real Clinical Practice

Aim. To study incidence and structure of comorbidity in multiple myeloma (MM) patients depending on their age; to determine its effect on overall survival, efficacy, and safety of the first-line therapy in real clinical practice. Materials & Methods. Overall, 369 patients with newly diagnosed MM were enrolled in the trial from January 2012 to December 2017. Among them there were 134 men and 235 women hospitalized at the Unit of Hematology in the Novosibirsk Municipal Clinical Hospital No. 2. Median age of patients was 67 years (range 32-82 years). Results. The analyzed patients were divided into three age groups: the first group of young/middle age (32-59 years) (n = 105), the second group of elderly patients (6074 years) (n = 186), and the third group of old age (> 75 years) (n = 78). In each patient prior to chemotherapy the comorbidity spectrum was identified and CIRS-G, CCI, and MCI comorbidity scores were calculated. Patients with newly diagnosed MM in real clinical practice prove to have high and increasing with age comorbidity incidence (91 % in patients of young/middle age, 97,7 % and 100 % in patients of elderly and old age, respectively). Comorbidity significantly reduces overall survival (OS) of MM patients. Important OS predictors are rhythm and conduction disorder (odds ratio, OR, 2.762; p < 0.002), chronic pancreatitis (OR 1.864; p < 0.001), exogenous constitutive obesity (OR 1.948; p < 0.002), chronic obstructive pulmonary disease (OR 2.105; p < 0.021), chronic kidney disease, stage С4-С5 (OR 2.255; p < 0.003), and chronic heart failure, functional class II (OR 1.915; p < 0.002). Highest importance in predicting OS, efficacy, and tolerance to chemotherapy in MM patients is attached to MCI score (OR 3.771; p < 0.001). MM patients with high risk by MCI are characterized by lower rate and depth of response to the first-line therapy, shorter time before the first relapse, higher incidence of non-hematologic toxicity of grade > 3, and therapy withdrawal or drug dose reduction.

Enhanced activity of vancomycin by encapsulation in hybrid magnetic nanoparticles conjugated to a cell-penetrating peptide.

We describe a novel antibiotic delivery system based on magnetic nanoparticles (NPs) conjugated to a cell-penetrating peptide (CPP). Silica-coated iron oxide NPs were produced via a co-deposition method, and coated by a polyvinyl alcohol (PVA) polymeric network via physicochemical binding. Vancomycin (VAN) was then entrapped into this PVA network. A hexapeptide sequence Gly-Ala-Phe-Pro-His-Arg, was synthesized in the solid phase and then conjugated onto the surface of the magnetic NPs. The drug ratio incorporation into the carrier system and drug release were monitored through precise analysis. Confocal microscopy showed that the NPs could be internalized into Staphylococcus aureus and Escherichia coli bacterial cells. The antimicrobial effects of VAN were significantly enhanced by this system with a low dosage of VAN. Advantages include rapid targeted-drug delivery process, drug dose reduction, and equal effects on both Gram-positive and Gram-negative bacteria.

Comparative evaluation of 2% turmeric extract with nanocarrier and 1% chlorhexidine gel as an adjunct to scaling and root planing in patients with chronic periodontitis: A pilot randomized controlled clinical trial.

Context:Nanoparticles, owing to their smaller size, penetrate regions inaccessible to other delivery systems, such as periodontal pockets. Thus, the present study aimed to comparatively evaluate efficacy of 2% curcumin with nanocarrier and 1% chlorhexidine gel as a local drug delivery (LDD) in the treatment of periodontal pockets.Materials and Methods:Forty-five chronic periodontitis patients with pocket depth 5–7 mm in two or more teeth were selected. Full-mouth scaling and root planing (SRP) was done for all patients followed by random allocation to the three treatment groups, namely SRP group (Group 1), 2% curcumin with nanogel (Group 2), and 1% chlorhexidine gel (Group 3). Clinical parameter assessment and microbiological analysis of subgingival plaque samples for Aggregatibacter actinomycetemcomitans (Aa), Porphyromonas gingivalis (Pg), and Tannerella forsythia (Tf) was done at baseline, 21st day, and 45th day.Results:The results showed that when the two LDD agents were used as an adjunct to SRP in chronic periodontitis, there was an improvement in all clinical parameters. Evaluation of microbiological parameters also showed a significant reduction in Aa, Pg, and Tf levels. Comparison of 2% turmeric extract with a nanocarrier system with 1% chlorhexidine gel showed that both the agents had a comparable antibacterial effect on the three selected periodontopathic bacteria.Conclusion:The present study showed that both the LDD agents showed an effective improvement of clinical and microbiologic parameters. 2% curcumin delivered with a nanocarrier system showed results comparable to chlorhexidine gel and hence shows promising future as an LDD agent in the treatment of periodontal pockets.

Prevention and Treatment of Cancer Therapeutics-related Cardiac Dysfunction

Cancer therapeutics-related cardiac dysfunction(CTRCD)is receiving more attention.Risk factors assessment before cancer therapy,cardiac function monitoring during and after cancer therapy,and early detection and treatment of myocardial injury are key to preventing clinical heart failure.The incidence and severity of cardiotoxicity can be reduced by measures such as reducing drug dose,adjusting administration route,and using low toxic drugs.Cardioprotective agents including anti-heart failure drugs and dexrazoxane are important for the prevention and treatment of CTRCD.Patients with advanced heart failure may also benefit from mechanical treatments including cardiac resynchronization therapy and mechanically-assisted ventricular devices.This article reviews the recent advances in the prevention and treatment of CTRCD.

In vitro interactions of ambroxol hydrochloride or amlodipine in combination with antibacterial agents against carbapenem-resistant Acinetobacter baumannii.

The aim of this study was to investigate the in vitro interactions of ambroxol hydrochloride (ABH) or amlodipine (AML) with commonly used antibacterial agents, including meropenem, imipenem-cilastatin sodium, biapenem, cefoperazone-sulbactam, polymyxin B, and tigecycline, against six carbapenem-resistant Acinetobacter baumannii (CRAB) clinical isolates. Drug interactions were interpreted using two models, that is, the fractional inhibitory concentration index (FICI) model and the percentage of growth difference (ΔE) model. The results show that a majority of the combination groups exhibited partial synergy and additive interactions, such as the combinations of carbapenems and cefoperazone-sulbactam (SCF) with ABH or AML. While the combination of PB/AML exhibited synergistic interactions against all tested isolates, and PB/ABH exhibited synergistic interactions against two isolates. The FICI and ΔE model correlated very well for the combinations of PBABH and PB/AML against AB2. The combinations of TGC with ABH or AML mainly exhibited additive and indifferent interactions. There were no antagonistic interactions observed in any of the combinations. In conclusion, this study revealed that the non-antibacterial agents ABH or AML can work synergistically or partial synergistically with antibacterial agents against CRAB. This finding is crucial for overcoming the carbapenem resistance of A. baumannii. SIGNIFICANCE AND IMPACT OF THE STUDY: Drug combination is an effective approach for the treatment of resistant bacterial infection. The significance of using drug combination is that it can reduce drug dosage requirements, reduce the toxic effects of agents and prevent or delay the emergence of drug resistance. This study measured the in vitro interactions between non-antimicrobial agents and antibacterial agents against carbapenem-resistant Acinetobacter baumannii and the results of this study provide new insight to find strategies to overcome the carbapenem resistance in A. baumannii.

Implementation of a standardised pharmacist check of medical orders prior to preparation of anticancer drugs to reduce drug wastage.

The increasing cost of anticancer drugs is now being recognised as a global problem, and measures against drug wastage are among the most important cost containment strategies for anticancer drugs. When blood examination results or changes to a patient's condition necessitate dose reduction or discontinuation of anticancer drugs after their preparation, the compounded anticancer drugs are discarded. To reduce anticancer drug wastage after preparation, we developed a protocol that set the eligibility, start of treatment, dose reduction and discontinuation criteria for injectable anticancer drugs and assessed the effect of pharmacists' checks of these criteria based on the present protocol prior to preparation of injectable anticancer drugs. Observations before and after introduction of the protocol were conducted at Gifu University Hospital. We recorded the number, type and cost of anticancer drugs discarded after preparation and the reason for discarding these drugs in our dedicated database. Checking the criteria for anticancer drug administration before preparation significantly reduced the rate at which anticancer drugs within a chemotherapy cycle were discarded after preparation compared with that prior to the protocol's introduction (0.367% [18/4909] vs 0.032% [2/6248], P<.001). Additionally, the total cost of anticancer drugs discarded after preparation was reduced from JPY 2041786 (USD 18562) to JPY 398414 (USD 3622). Pharmacists' checks of the eligibility, start of treatment, dose reduction and discontinuation criteria for anticancer drugs based on the present protocol prior to preparation of injectable anticancer drugs was useful for reducing drug wastage after preparation.

E-Jet 3D-Printed Scaffolds as Sustained Multi-Drug Delivery Vehicles in Breast Cancer Therapy.

Combination chemotherapy is gradually receiving more attention because of its potential synergistic effect and reduced drug doses in clinical application. However, how to precisely control drug release dose and time using vehicles remains a challenge. This work developed an efficient drug delivery system to combat breast cancer, which can enhance drug effects despite reducing its concentration. Controlled-release poly-lactic-co-glycolic acid (PLGA) scaffolds were fabricated by E-jet 3D printing to deliver doxorubicin (DOX) and cisplatin (CDDP) simultaneously. This drug delivery system allowed the use of a reduced drug dosage resulting in a better effect on the human breast cancer cell apoptosis and inhibiting tumor growth, compared with the effect of each drug and the two drugs administrated without PLGA scaffolds. Our study suggested that DOX-CDDP-PLGA scaffolds could efficiently destroy MDA-MB-231 cells and restrain tumor growth. The 3D printed PLGA scaffolds with their time-programmed drug release might be useful as a new multi-drug delivery vehicle in cancer therapy, which has a potential advantage in a long term tumor cure and prevention of tumor recurrence.

In Systemic Masocytosis, Midostaurin Targets Both Kit and Aurora Kinase a Reverting H3K36Me3 Deficiency and Synergizes with Second-Generation Tyrosine Kinase Inhibitors

H3K36 tri-methylation by SETD2 has been linked to a plethora of pathways critical for the regulation of a multitude of cellular processes, including transcription, DNA replication and DNA repair after damage, yet the functional implications of perturbed H3K36 tri-methylation by SETD2 mutations or non-genomic loss of function in leukemia are still unclear. We have previously reported that the HMC-1.1 and -1.2 mast cell leukemia (MCL) cell lines and many patients (pts) with advanced systemic mastocytosis (advSM) display H3K36Me3 deficiency as a result of non-genomic loss of function of SETD2. Proteasome inhibition restored SETD2 protein expression and H3K36me3, suggesting that a functional protein is produced but rapidly degraded. To understand the mechanisms underlying this phenomenon, we used an in silico approach to identify candidate SETD2-interacting proteins, followed by experimental confirmation by co-immunoprecipitation. We found that, after proteasomal inhibition, SETD2 co-immunoprecipitates with Aurora Kinase A (AKA). We also found that AKA was overexpressed and hyper-activated in pts with advSM compared to ISM pts and to a pool of healthy donors, and that AKA can phosphorylate SETD2. Both pharmacological inhibition by Danusertib and siRNA-mediated knock-down of AKA rescued SETD2 expression and activity, raising the hypothesis that phosphorylation by AKA might be implicated in proteasome-mediated degradation of SETD2. The new standard of therapy in advSM is midostaurin, that inhibits the activity of both wild‐type and D816V mutant KIT, as well as of various other kinases including AKA. Therefore we investigated if midostaurin effects may be addressed to AKA inhibition and consequent SETD2/H3K36me3 rescue. To this purpose, HMC-1 cells were treated with 5 µM midostaurin for 24 h and AKA, SETD2 and H3K36me3 expression were evaluated by western blotting. Treatment with midostaurin was able to inhibit AKA activity by about 60%, partially restoring SETD2 expression and H3K36Me3. Moreover, midostaurin treatment of HMC-1 cells at micromolar doses induced cytostatic but not cytotoxic effects as shown by cell growth curves performed in liquid medium and as confirmed by annexin V/PI staining and subsequent cytofluorimetric analysis of apoptotic cell death. Our observations in cell lines were confirmed in neoplastic mast cells collected from six patients with advSM before and after three months of midostaurin treatment. Western blotting showed that midostaurin treatment in vivo indeed results in a rescue of SEDT2 expression and activity, associated with a partial de-phosphorylation of AKA. Our subsequent experimental step was therefore to hypothesize and test the possibility of a combined treatment between midostaurin and second generation TKIs to induce not only a cytostatic but also a cytotoxic effect both in our in vitro models and in primary cells obtained from bone marrow samples of advSM patients. We performed growth curves in liquid medium and clonogenic assays to evaluate the therapeutic potential of pharmacological combination of midostaurin with Nilotinib and Dasatinib in HMC-1 cells and in neoplastic mast cells from 3 patients with advSM and we observed in all cases synergistic effects at nanomolar doses. Moreover, cytofluorimetric analysis of apoptotic cell death in HMC-1 cells showed an important advantage in using the combination of the two drugs, compared to single agents, underlined by the significant reduction of drug doses used to obtain cytotoxic effects (Figure 1). Our results suggest that AKA-mediated post-translational modifications contribute to SETD2 non-genomic loss of function in advSM. Inhibiting AKA and c-Kit activity by midostaurin in combination with a second generation TKI is a promising therapeutic strategy in patients with SETD2/H3K36Me3 deficiency. Acknowledgments: study supported by AIRC (project code 16996) and AIL (Associazione Italiana contro le Leucemia, Linfomi e Mieloma). Disclosures Papayannidis: Incyte: Honoraria; Shire: Honoraria; Novartis: Honoraria; Teva: Honoraria; Amgen: Honoraria; Pfizer: Honoraria. Bonifacio:Pfizer: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Incyte: Honoraria; BMS: Honoraria. Albano:Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Elena:Novartis: Consultancy; Pfizer: Consultancy. Valent:Deciphera: Honoraria, Research Funding; Blueprint: Research Funding; Pfizer: Honoraria; Celgene: Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Cavo:celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Soverini:Incyte: Consultancy.

Deprescribing as a Clinical Improvement Focus

ObjectivesPolypharmacy is a concern in the practice of geriatrics because of consequences such as adverse drug events and poorer quality of life. Deprescribing, a response to polypharmacy, refers to the systematic, programmed, and appropriate reduction in drug number and dose. Although now broadly recognized, challenges exist in practice for effective implementation. This study was conducted to determine the deprescribing success rate and relate it to drug classes and clinical settings, and to identify factors that influence the deprescribing process. DesignAs a performance improvement (PI) project, fellows in geriatric medicine, under supervision of faculty geriatricians, attempted deprescribing during at least 1 encounter daily at 2 long-term care (LTC) facilities and an outpatient geriatrics clinic (C) in Bronx, New York, from August 2018 to January 2019. Deprescribing was initiated following discussion and consent from patient or caregiver. Following the data collection, involved fellows and faculty physicians participated in a survey to identify factors that influenced the process. ResultsOut of 449 encounters, 383 encounters were included for analysis. Average patient age was 78.2 years (LTC: 77.9, C: 79.1). Average patient comorbidities was 6.5 (LTC: 6.7, C: 5.8). Deprescribing was successful in 90.1% of encounters (LTC: 96.9%, C: 67.4%). On average, 1.3 medications were deprescribed per encounter (LTC: 1.4, C: 1.0). Analgesics (32.2%), multivitamin-minerals supplements (29.7%), lipid-lowering agents (22.9%), antihistamines (46.7%), and acid blockers (26.2%) had highest success. Conclusions and ImplicationsDeprescribing is possible in practice in both LTC and community settings at each encounter, until it is no longer applicable. Factors that contribute to successful deprescribing primarily include meaningful and earnest provider effort, ideally in collaboration with interdisciplinary team members (nurses, pharmacists, social worker, and others), besides interactions with consultants for the patient. Certain medication classes such as vitamins, minerals, analgesics, and proton pump inhibitors can be deprescribed with high success, as noted in our study, whereas antipsychotic agents, antidepressants, and ophthalmic preparations, prescribed by specialists, proved harder to deprescribe. An understanding of barriers to deprescribing (outlined in the article) and addressing them are crucial in enabling success. The study demonstrates that as a performance improvement project in collaborative effort with multiple disciplines, deprescribing is possible in health care. Factors promoting success and barriers to deprescribing are detailed. Appropriate deprescribing has the potential to help lower adverse drug events, costs of care, and possibly improve quality of life.

A Randomized Trial of Alerting to Hypocholesterolemia Results of the Low Indexes of Metabolism Intervention Trial-C (LIMIT-C)

ObjectivesThe benefit of alerting clinical staff to drug-induced hypocholesterolemia in patients aged 75 years and older remains uncertain. Design, setting, and participantsThe study included 1791 patients with serum cholesterol <160 mg/dL and on cholesterol-lowering drugs who were assigned to have an e-mail alert sent to their physician, and 1804 patients who were assigned to receive usual clinical care (control group). The primary outcome of the trial was annual death rate. Secondary outcomes included cholesterol-lowering drug dose reduction and emergency department (ED) visits. ResultsAt 1 year, 58 patients (3.2%) in the intervention group and 61 (3.4%) in the control group had died [relative risk 0.94, 95% confidence interval (CI) 0.66-1.34; P = .74]. Quarter-averaged cholesterol-lowering drug defined daily doses were reduced by −13.5 ± 47.0 (−17% ± 60%) in the intervention group and by −5.1 ± 42.2 (−6%±54%) in the control group (difference −8.5 ± 1.5, 95% CI –5.5 to −11.4; P < .0001). Annual ED visit rates per 1000 patients were 291 in the intervention group and 336 in the control group (45 fewer visits per 1000 patients in the intervention group, 95% CI –1 to −89; P = .04). Conclusions and implicationsIn this trial, alerting clinical staff to hypocholesterolemia in patients aged 75 years and older being treated with cholesterol-lowering drugs was associated with mildly reduced cholesterol-lowering drugs doses and marginally reduced ED visit rates. This e-mail alert intervention was not associated with a significant difference in 1-year survival rate compared with usual clinical care.

A Randomized Trial of Alerting to Low Glycated Hemoglobin Level in Older Adults: Results of the Low Indexes of Metabolism Intervention Trial B (LIMIT-B)

ObjectivesThe benefit of alerting clinical staff to low plasma glycated hemoglobin (HbA1c) in patients aged 75 years and older who receive antidiabetic drugs remains uncertain. Design, Setting, and ParticipantsIn a randomized controlled trial, 1684 patients with HbA1c ≤ 6.5% who received antidiabetic drugs were assigned to have an e-mail alert sent to their physician, and 1643 were assigned to have no such alert (control group). The primary outcome of the trial was annual death. Secondary outcomes included antidiabetic drug dose reduction and HbA1c change. ResultsIn the first quarter, antidiabetic drug-defined daily doses were reduced on average by 10.4 ± 35.8 (16% ± 55%) in the intervention group and by 6.4 ± 36.1 (10% ± 56%) in the control group (difference −4.1 ± 1.2, 95% confidence interval [CI] −6.5 to −1.6; P = .001). Measured HbA1c levels were raised by a mean (± standard deviation) of 0.28 ± 0.77 in the intervention group and by 0.18 ± 0.57 in the control group (difference 0.10 ± 0.02, 95% CI –0.15 to −0.059, P < .001). One year after the alerts, 121 patients (7.2%) died in the intervention group and 107 patients (6.5%) died in the control group (relative risk 1.1, 95% CI 0.86-1.42; P = .44). Conclusions and ImplicationsIn this trial, alerting clinical staff to low HbA1c in patients aged 75 years and older treated with antidiabetic medicines was associated with mildly reduced antidiabetic doses and increased HbA1c but was not associated with a significant difference in survival rate compared with usual clinical care.

Inflammatory side effects of BRAF and MEK inhibitors.

The aim of this study was to describe inflammatory side effects in patients treated with BRAF and MEK inhibitors at a single tertiary care institution. This was a retrospective chart review of patients prescribed single-agent or combination BRAF and MEK inhibitors from January 2010 until May 2015. The primary outcome was the presence of inflammatory side effects. Among 124 patients, 56.4% were male, the median age was 59 years, and most (91.1%) were treated for metastatic melanoma. Most patients (74.2%) developed inflammatory side effects, some with multiple occurrences, for a total of 211 occurrences. The overall prevalence of inflammatory side effects did not differ across therapies. In a subanalysis, patients treated with both single-agent and combination therapies were more likely to experience an inflammatory side effect on single-agent therapy (P = 0.0126 for BRAF inhibitor, P = 0.0833 for MEK inhibitor). The most common inflammatory side effects for the entire cohort included arthralgias/myalgias (32.9%), nonacneiform rash (28.0%), pyrexia (25.5%), and erythema nodosum (11.2%), although side effects differed across the class of therapy. Corticosteroids were initiated in 73 side effect instances among 47 patients. Drug interruption or dose reduction was reported in 78 side effect instances in 50 patients. Fifteen side effect instances led to treatment termination. There is a high prevalence of inflammatory side effects encompassing all organ systems in patients treated with BRAF and MEK inhibitors. There is no significant difference in the prevalence of inflammatory side effects in patients treated with single-agent versus combination therapies, however, side effect profile differs across agents.

A 4-D approach for amelioration of periodontitis

Global prevalence of the severe periodontitis is at the alarming stage and its association with the systemic complications is highly evident which cannot be neglected. An insight into the pathophysiology of the periodontitis reveals that the promising amelioration could only be envisaged with the 4-D/multi-pronged approach of combining antibiotic along with the host modulating agents. The complications of the disease itself suggest that the use of antibiotic alone is not able to cater the symptoms completely. There is a need of other host modulatory agents too, such as Cyclo-oxygenase –II (COX II) enzyme inhibitors, Matrix metalloproteinase’s (MMPs) inhibitors and osteo-integrating agents. Also, there is an unmet need of singular treatment modality through which all these agents can be sequentially and directly delivered into the periodontal cavity. The current hypothesis takes it a step forward wherein an antibiotic is combined with other three host modulatory agents in a singular drug delivery system. The encapsulation of multiple therapeutic agents with controlled release would therefore allow for reduced drug dose thus minimizing side effects; contributing to enhanced patient compliance and treatment efficacy. Hence this approach can be presented as a 4-D/multi-pronged approach for circumvention of periodontitis.

Variable impact of three different antiangiogenic drugs alone or in combination with chemotherapy on multiple bone marrow-derived cell populations involved in angiogenesis and immunity.

In contrast to VEGF pathway-targeting antibodies, antiangiogenic tyrosine kinase inhibitors (TKIs) have failed to meet primary endpoints in almost all phase III clinical trials when combined with conventional chemotherapy. One exception is the combination of nintedanib and docetaxel as a second-line therapy for rapidly progressing advanced NSCLC. In addition to increased toxicity caused by this type of combination, thus necessitating drug dose reductions or treatment breaks, such phase III trial failures may also be related to the differential impact of host-mediated responses involving mobilization and tumor infiltration of bone marrow-derived cell populations (BMDCs), comprising both pro-angiogenic as well as immune effector cells. Herein, we evaluated two different antiangiogenic TKIs (sunitinib or nintedanib) and a VEGFR-2 antibody (DC101) either alone or combined with maximum tolerated dose paclitaxel for their differential impact on the BMDC host response, evaluating four different cell types. TKIs (in particular sunitinib) induced myelosuppression similar to paclitaxel, whereas DC101 had no such effect. Sunitinib also significantly decreased the number of tumor-infiltrating CD8 + T and B cells, MDSCs, and macrophages. In contrast, the effect of nintedanib on these BMDC populations was less marked, behaving closer to the VEGFR-2 antibody effects than sunitinib. The results raise the possibility that differences observed between antiangiogenic antibodies and TKIs in increasing chemotherapy efficacy could be related, at least in part, to differential effects on cells associated with local immunity within the tumor microenvironment.

Prediction of Synergistic Drug Combinations by Learning from Deep Representations of Multiple Networks.

Drug combination therapy can improve drug efficacy, reduce drug dosage, and overcome drug resistance. Many studies have focused on predicting synergistic drug combinations. However, existing methods fail to consider the heterogeneous characteristics of drugs fully, and it is difficult to identify effective drug combinations. Therefore, we propose a new integrated prediction model based on deep representations by integrating information from multiple domains to accurately and effectively predict drug combinations.

Genotype-based Treatment With Thiopurine Reduces Incidence of Myelosuppression in Patients With Inflammatory Bowel Diseases

Thiopurine-related myelosuppression (most frequently leukopenia) interferes with thiopurine therapy for patients with inflammatory bowel diseases (IBD). We investigated whether pretreatment analyses genetic variants associated with thiopurine-induced leukopenia could be used to effectively identify patients who required dose adjustments. We performed a multicenter, prospective study of patients with IBD at 5 tertiary medical centers 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 hemoglobin 10 g/dL, or platelet counts below 100 K/μL. 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= .009), pretreatment genotype analysis (HR, 0.37; 95% CI, 0.18-0.77; P= .008), and the maximum dose of thiopurines (HR, 0.34; 95% CI, 0.19-0.59; P < .001) independently decreased risk of myelosuppression. Pretreatment genotype analysis reduced numbers of outpatient clinic visit and numbers of patients with drug discontinuation or dose reductions. In a randomized controlled study of patients undergoing thiopurine therapy for IBD, we found that selection of therapy based on genetic variants associated with thiopurine-induced leukopenia significantly reduced the proportion of patients with myelosuppression during treatment. ClinicalTrials.gov no: NCT03719118.

INSIGHTS INTO FORMULATION TECHNOLOGIES AND NOVEL STRATEGIES FOR THE DESIGN OF ORALLY DISINTEGRATING DOSAGE FORMS: A COMPREHENSIVE INDUSTRIAL REVIEW

Among the various routes of administration, the oral route remains the most convenient and commonly employed route for drug delivery. The oral conventional drug delivery systems have some drawbacks, such as possibility of gastrointestinal destruction of labile molecules, low absorption of macromolecules, slow onset of action, and unavoidable fluctuation in the concentration of drugs which can either lead to under- or over medication with concomitant adverse effects, especially for drugs with small therapeutic index. Therefore, it became essential to design novel oral drug delivery systems to achieve quick dissolution, absorption, rapid onset of action and reduction of drug dose. Among those novel drug delivery systems are oral disintegrating tablets (ODTs). The purpose of this review article is to report the recent advances in ODT systems with emphasis on their preparations, characterizations and applications.

Synergistic Effects of Anionic/Cationic Dendrimers and Levofloxacin on Antibacterial Activities.

Despite the numerous studies on dendrimers for biomedical applications, the antibacterial activity of anionic phosphorus dendrimers has not been explored. In our research, we evaluated the antibacterial activity of modified polycationic and polyanionic dendrimers in combination with levofloxacin (LVFX) against Gram-negative (Escherichia coli ATCC 25922, Proteus hauseri ATCC 15442) and Gram-positive (Staphylococcus aureus ATCC 6538) bacteria. In the case of Gram-negative bacteria, we concluded that a combination of dendrimers and antibiotic gave satisfactory results due to a synergistic effect. The use of fluoroquinolone antibiotics, such as LVFX, not only caused resistance in disease-causing microorganisms but also increased environmental pollution. Therefore, reduction of drug dosage is of general interest.

Interim results of a real-world observational study of eribulin in soft tissue sarcoma including rare subtypes.

Although eribulin is used to treat soft tissue sarcomas (STSs), treatment data for rare subtypes are limited. We conducted a post-marketing surveillance study to assess safety and efficacy of eribulin in STS patients stratified by subtype. Japanese patients (n = 256) with advanced or metastatic STS receiving eribulin treatment were monitored for treatment status, adverse events, diagnostic imaging, and clinical outcomes at 3 months and 1 year. Interim analysis was performed. Patients will be monitored up to 2 years. Interim analysis included 3-month (n = 255), imaging (n = 226), and 1-year (n = 105) data. STS subtype distribution was normal. Median number of eribulin cycles was 3.0 (range: 1-17 cycles). Among patients with imaging data, best overall tumor response (12 weeks) was partial response, 7.5% (n = 17); stable disease, 34.5% (n = 78); and stable disease ≥11 weeks, 10.2% (n = 23). Overall response rate (ORR), disease control rate (DCR), and clinical benefit rate (CBR) for all patients were 7.5%, 42.0% and 17.7%, respectively. ORR, DCR, and CBR were 10.3%, 32.0% and 16.5%, respectively, for patients with STS subtypes other than liposarcoma and leiomyosarcoma and included responses from patients with rare STS subtypes. Adverse drug reactions (ADRs) occurred in 211 (82.7%) patients (42 [16.5%] patients had serious ADRs), and none led to death. ADRs leading to drug withdrawal and dose reduction occurred in 27 (10.6%) and 55 (21.6%) patients, respectively. Eribulin was generally well tolerated and showed antitumor activity against STSs, including rare subtypes that currently have few treatment options. NCT03058406 (ClinicalTrials.gov).