Two-drug Combination Research Articles

Prescription patterns of Antibiotics in Acute tonsillitis: Hospital-based study

Introduction: Acute tonsillitis is caused by either viruses or bacteria and is characterized by a sore throat and painful swallowing. About 49% of cases are thought to be caused by Group A beta-hemolytic streptococci. Penicillin should be given empirically after the diagnosis of acute tonsillitis. This study was carried out to find out the prescription pattern of antibiotics among the admitted cases of acute tonsillitis.
 Materials and Methods: This study was conducted in the Department of Otorhinolaryngology and Head and Neck Surgery, Gandaki Medical College Teaching Hospital and Research Centre (GMCTH), Pokhara. All the patients who were admitted for acute tonsillitis in the ENT ward were enrolled in this study. Age, gender, the average number of drugs per prescription, and the most commonly prescribed drug was recorded.
 Results: There were 320 patients with acute tonsillitis and the mean age was 27.44 ± 11.1 years. Most of the cases were in their twenties. The average number of drugs per prescription was four while the total number of antibiotics used was 520. The single antibiotic was used in 170 (53%) cases and a two-drug combination was used in 91(28.4%) cases. Ceftriaxone was the most commonly prescribed drug. There were 78 (24.3%) cases under monotherapy and 69 (21%) in multitherapy.
 Conclusion: Among the various effective antimicrobials, ceftriaxone was the most commonly prescribed antimicrobial. The injectable route of antibiotics administration was a widely used method in hospitalized patients in our setting.

Optimal Use of FOLFOXIRI Plus Bevacizumab as First-Line Systemic Treatment in Metastatic Colorectal Cancer

Colorectal cancer is the second leading cause of cancer-related deaths in the USA with more than half of diagnosed patients developing metastatic disease. The mainstay of treatment for metastatic disease is chemotherapy, and upfront treatment has generally consisted of a two-drug chemotherapy combination (FOLFOX or FOLFIRI) plus a biologic agent. In this review, we explore the emerging role of the three-drug chemotherapy combination FOLFOXIRI plus bevacizumab as first-line treatment in metastatic colorectal cancer. Randomized trials evaluating the efficacy of FOLFOXIRI plus bevacizumab have shown improvement in objective response rate, overall survival, and resection rate when compared to previous standard therapy. However, this comes with added toxicity, which can be one of the main barriers to its widespread implementation. FOLFOXIRI plus bevacizumab is an effective therapy in carefully selected patients; however, more clinical trials investigating the regimen’s role in colorectal cancer remain a significant need.

Polygonogram and isobolographic analysis of interactions between various novel antiepileptic drugs in the 6-Hz corneal stimulation-induced seizure model in mice.

Pharmacotherapy with two antiepileptic drugs in combination is usually prescribed to epilepsy patients with refractory seizures. The choice of antiepileptic drugs in combination should be based on synergistic cooperation of the drugs with respect to suppression of seizures. The selection of synergistic interactions between antiepileptic drugs is challenging issue for physicians, especially, if 25 antiepileptic drugs are currently available and approved to treat epilepsy patients. The aim of this study was to determine all possible interactions among 5 second-generation antiepileptic drugs (gabapentin (GBP), lacosamide (LCM), levetiracetam (LEV), pregabalin (PGB) and retigabine (RTG)) in the 6-Hz corneal stimulation-induced seizure model in adult male albino Swiss mice. The anticonvulsant effects of 10 various two-drug combinations of antiepileptic drugs were evaluated with type I isobolographic analysis associated with graphical presentation of polygonogram to visualize the types of interactions. Isobolographic analysis revealed that 7 two-drug combinations of LEV+RTG, LEV+LCM, GBP+RTG, PGB+LEV, GBP+LEV, PGB+RTG, PGB+LCM were synergistic in the 6-Hz corneal stimulation-induced seizure model in mice. The additive interaction was observed for the combinations of GBP+LCM, GBP+PGB, and RTG+LCM in this seizure model in mice. The most beneficial combination, offering the highest level of synergistic suppression of seizures in mice was that of LEV+RTG, whereas the most additive combination that protected the animals from seizures was that reporting additivity for RTG+LCM. The strength of interaction for two-drug combinations can be arranged from the synergistic to the additive, as follows: LEV+RTG > LEV+LCM > GBP+RTG > PGB+LEV > GBP+LEV > PGB+RTG > PGB+LCM > GBP+LCM > GBP+PGB > RTG+LCM.

Efficacy of Three-Drug Induction Chemotherapy Followed by Preoperative Chemoradiation in Patients with Localized Gastric Adenocarcinoma

Background: Preoperative induction chemotherapy followed by chemoradiation yields better R0 resection rates, pathologic complete response (pCR) rates and improved survival for localized gastric adenocarcinoma (GAC). We report the effect of three-drug induction chemotherapy on a large cohort of localized GAC patients. Methods: We identified 97 patients with localized GAC who received three-drug induction chemotherapy followed by preoperative chemoradiation therapy. We assessed various endpoints (overall survival [OS], recurrence-free survival [RFS], R0 resection and pCR rate). Results: The median follow-up time was 3.5 years (range; 0.4–16.7). The induction chemotherapy regimen was a fluoropyrimidine and a platinum compound (cisplatin or oxaliplatin) with a taxane (docetaxel or paclitaxel) for 95% of patients. Seventy-three (75.3%) out of 97 patients underwent planned surgery. R0 resection and pCR rae were 93.2 and 20.6%, respectively. Pathologic partial response (<50% residual carcinoma) rate was 50.7%. The median OS was 6.4 years (95% Cl 3.3–12.4) for the entire cohort and 11.1 years (95% Cl 7.1-not estimable) for patients that underwent surgery. The estimated 2- and 5-year OS rates were 72.4% (95% CI 62.1–80.3) and 54.3% (95% CI 43.2–64.1) for the entire cohort and 83.2% (95% CI 72.3–-90.1) and 66% (95% CI 52.3–75.8) for patients that underwent surgery. Pathologic lesser stage (stage I/II vs. stage III/IV) (p = 0.001) and R0 resection (p = 0.02) were independently associated with longer RFS in the multivariate analysis. Conclusion: Our data shows that three-drug combination is feasible without providing substantial advantage compared with two-drug combination in this setting of preoperative induction chemotherapy followed by chemoradiation and surgery.

Therapy for Stage IV Non–Small-Cell Lung Cancer Without Driver Alterations: ASCO and OH (CCO) Joint Guideline Update

The aim of this work is to provide evidence-based recommendations updating the 2017 ASCO guideline on systemic therapy for patients with stage IV non-small-cell lung cancer (NSCLC) without driver alterations. A guideline update for patients with stage IV NSCLC with driver alterations will be published separately. The American Society of Clinical Oncology and Ontario Health (Cancer Care Ontario) NSCLC Expert Panel made updated recommendations based on a systematic review of randomized controlled trials from December 2015 to 2019. This guideline update reflects changes in evidence since the previous guideline update. Five randomized controlled trials provide the evidence base. Additional literature suggested by the Expert Panel is discussed. Recommendations apply to patients without driver alterations in epidermal growth factor receptor or ALK. For patients with high programmed death ligand 1 (PD-L1) expression (tumor proportion score [TPS] ≥ 50%) and non-squamous cell carcinoma (non-SCC), the Expert Panel recommends single-agent pembrolizumab. Additional treatment options include pembrolizumab/carboplatin/pemetrexed, atezolizumab/carboplatin/paclitaxel/bevacizumab, or atezolizumab/carboplatin/nab-paclitaxel. For most patients with non-SCC and either negative (0%) or low positive (1% to 49%) PD-L1, the Expert Panel recommends pembrolizumab/carboplatin/pemetrexed. Additional options are atezolizumab/carboplatin/nab-paclitaxel, atezolizumab/carboplatin/paclitaxel/bevacizumab, platinum-based two-drug combination chemotherapy, or non-platinum-based two-drug therapy. Single-agent pembrolizumab is an option for low positive PD-L1. For patients with high PD-L1 expression (TPS ≥ 50%) and SCC, the Expert Panel recommends single-agent pembrolizumab. An additional treatment option is pembrolizumab/carboplatin/(paclitaxel or nab-paclitaxel). For most patients with SCC and either negative (0%) or low positive PD-L1 (TPS 1% to 49%), the Expert Panel recommends pembrolizumab/carboplatin/(paclitaxel or nab-paclitaxel) or chemotherapy. Single-agent pembrolizumab is an option in select cases of low positive PD-L1. Recommendations are conditional on the basis of histology, PD-L1 status, and/or the presence or absence of contraindications. Additional information is available at www.asco.org/lung-cancer-guidelines.

Combinational treatment of 5-fluorouracil and casticin induces apoptosis in mouse leukemia WEHI-3 cells in vitro.

Leukemia is one of the major diseases causing cancer-related deaths in the young population, and its cure rate is unsatisfying with side effects on patients. Fluorouracil (5-FU) is currently used as an anticancer drug for leukemia patients. Casticin, a natural polymethoxyflavone, exerts anticancer activity against many human cancer cell lines in vitro, but no other reports show 5-FU combined with casticin increased the mouse leukemia cell apoptosis in vitro. Herein, the antileukemia activity of 5-FU combined with casticin in WEHI-3 mouse leukemia cells was investigated in vitro. Treatment of two-drug combination had a higher decrease in cell viability and a higher increase in apoptotic cell death, the level of DNA condensation, and the length of comet tail than that of 5-FU or casticin treatment alone in WEHI-3 cells. In addition, the two-drug combination has a greater production rate of reactive oxygen species but a lower level of Ca2+ release and mitochondrial membrane potential (ΔΨm ) than that of 5-FU alone. Combined drugs also induced higher caspase-3 and caspase-8 activities than that of casticin alone and higher caspase-9 activity than that of 5-FU or casticin alone at 48 hours treatment. Furthermore, 5-FU combined with casticin has a higher expression of Cu/Zn superoxide dismutase (SOD [Cu/Zn]) and lower catalase than that of 5-FU or casticin treatment alone. The combined treatment has higher levels of Bax, Endo G, and cytochrome C of proapoptotic proteins than that of casticin alone and induced lower levels of B-cell lymphoma 2 (BCL-2) and BCL-X of antiapoptotic proteins than that of 5-FU or casticin only. Furthermore, the combined treatment had a higher expression of cleaved poly (ADP-ribose) polymerase (PARP) than that of casticin only. Based on these findings, we may suggest that 5-FU combined with casticin treatment increased apoptotic cell death in WEHI-3 mouse leukemia cells that may undergo mitochondria and caspases signaling pathways in vitro.

Drug antagonism and single-agent dominance result from differences in death kinetics.

Cancer treatment generally involves drugs used in combinations. Most prior work has focused on identifying and understanding synergistic drug-drug interactions; however, understanding antagonistic interactions remains an important and understudied issue. To enrich for antagonism and reveal common features of these combinations, we screened all pairwise combinations of drugs characterized as activators regulated cell death. This network is strongly enriched for antagonism, particularly a form of antagonism that we call “single agent dominance”. Single agent dominance refers to antagonisms in which a two-drug combination phenocopies one of the two agents. Dominance results from differences in death onset time, with dominant drugs acting earlier than their suppressed counterparts. We explored mechanisms by which parthanatotic agents dominate apoptotic agents, finding dominance in this scenario caused by mutually exclusive and conflicting use of PARP1. Taken together, our study reveals death kinetics as a predictive feature of antagonism, due to inhibitory crosstalk between death pathways.

A pharmacodynamic model of clinical synergy in multiple myeloma.

BackgroundMultiagent therapies, due to their ability to delay or overcome resistance, are a hallmark of treatment in multiple myeloma (MM). The growing number of therapeutic options in MM requires high-throughput combination screening tools to better allocate treatment, and facilitate personalized therapy.MethodsA second-order drug response model was employed to fit patient-specific ex vivo responses of 203 MM patients to single-agent models. A novel pharmacodynamic model, developed to account for two-way combination effects, was tested with 130 two-drug combinations. We have demonstrated that this model is sufficiently parameterized by single-agent and fixed-ratio combination responses, by validating model estimates with ex vivo combination responses for different concentration ratios, using a checkerboard assay. This new model reconciles ex vivo observations from both Loewe and BLISS synergy models, by accounting for the dimension of time, as opposed to focusing on arbitrary time-points or drug effect. Clinical outcomes of patients were simulated by coupling patient-specific drug combination models with pharmacokinetic data.FindingsCombination screening showed 1 in 5 combinations (21.43% by LD50, 18.42% by AUC) were synergistic ex vivo with statistical significance (P < 0.05), but clinical synergy was predicted for only 1 in 10 combinations (8.69%), which was attributed to the role of pharmacokinetics and dosing schedules.InterpretationThe proposed framework can inform clinical decisions from ex vivo observations, thus providing a path toward personalized therapy using combination regimens.FundingThis research was funded by the H. Lee Moffitt Cancer Center Physical Sciences in Oncology (PSOC) Grant (1U54CA193489-01A1) and by H. Lee Moffitt Cancer Center's Team Science Grant. This work has been supported in part by the PSOC Pilot Project Award (5U54CA193489-04), the Translational Research Core Facility at the H. Lee Moffitt Cancer Center & Research Institute, an NCI-designated Comprehensive Cancer Center (P30-CA076292), the Pentecost Family Foundation, and Miles for Moffitt Foundation.

In Vitro Evaluation of Antifungal Drug Combinations against Multidrug-Resistant Candida auris Isolates from New York Outbreak.

Since 2016, New York hospitals and health care facilities have faced an unprecedented outbreak of the pathogenic yeast Candida auris We tested over 1,000 C. auris isolates from affected facilities and found high resistance to fluconazole (MIC > 256 mg/liter) and variable resistance to other antifungal drugs. Therefore, we tested if two-drug combinations are effective in vitro against multidrug-resistant C. auris Broth microdilution antifungal combination plates were custom manufactured by TREK Diagnostic System. We used 100% inhibition endpoints for the drug combination as reported earlier for the intra- and interlaboratory agreements against Candida species. The results were derived from 12,960 readings, for 15 C. auris isolates tested against 864 two-drug antifungal combinations for nine antifungal drugs. Flucytosine (5FC) at 1.0 mg/liter potentiated the most combinations. For nine C. auris isolates resistant to amphotericin B (AMB; MIC ≥ 2.0 mg/liter), AMB-5FC (0.25/1.0 mg/liter) yielded 100% inhibition. Six C. auris isolates resistant to three echinocandins (anidulafungin [AFG], MIC ≥ 4.0 mg/liter; caspofungin [CAS], MIC ≥ 2.0 mg/liter; and micafungin [MFG], MIC ≥ 4.0 mg/liter) were 100% inhibited by AFG-5FC and CAS-5FC (0.0078/1 mg/liter) and MFG-5FC (0.12/1 mg/liter). None of the combinations were effective for C. auris 18-1 and 18-13 (fluconazole [FLC] > 256 mg/liter, 5FC > 32 mg/liter) except MFG-5FC (0.1/0.06 mg/liter). Thirteen isolates with a high voriconazole (VRC) MIC (>2 mg/liter) were 100% inhibited by the VRC-5FC (0.015/1 mg/liter). The simplified two-drug combination susceptibility test format would permit laboratories to provide clinicians and public health experts with additional data to manage multidrug-resistant C. auris.

Olaparib Combined with an ATR or Chk1 Inhibitor as a Treatment Strategy for Acquired Olaparib-Resistant BRCA1 Mutant Ovarian Cells.

Objective: Despite the promise of PARP inhibitors (PARPi) for treating BRCA1/2 mutated ovarian cancer (OC), drug resistance invariably develops. We hypothesized rationale drug combinations, targeting key molecules in DNA repair pathways and the cell cycle may be synergistic and overcome acquired PARPi resistance. Methods: Drug sensitivity to PARPi alone and in combination with inhibitors of key DNA repair and cell cycle proteins, including ATR (VE-821), Chk1 (MK-8776), Wee1 (MK-1775), RAD51 (RI-1) was assessed in PARPi-sensitive (UWB1) and -resistant (UWB1-R) gBRCA1 mutant OC cell lines using a cell proliferation assay. The Bliss synergy model was used to estimate the two-drug combination effect and pharmacologic synergy (Bliss score ≥ 0) or antagonistic (Bliss score ≥ 0) response of the PARPi in combination with the inhibitors. Results: IC50 for olaparib alone was 1.6 ± 0.9 µM compared to 3.4 ± 0.6 µM (p = 0.05) for UWB1 and UWB1-R cells, respectively. UWB1-R demonstrated increased sensitivity to ATRi (p = 0.04) compared to UWB1. Olaparib (0.3–1.25 µM) and ATRi (0.8–2.5 µM) were synergistic with Bliss scores of 17.2 ± 0.2, 11.9 ± 0.6 for UWB1 and UWB1-R cells, respectively. Olaparib (0.3–1.25 µM) and Chk1i(0.05–1.25 µM) were synergistic with Bliss scores of 8.3 ± 1.6, 5.7 ± 2.9 for UWB1 and UWB1-R cells, respectively. Conclusions: Combining an ATRi or Chk1i with olaparib is synergistic in both PARPi-sensitive and -resistant BRCA1 mutated OC cell models, and are rationale combinations for further clinical development.

Phase I/II trial of enzalutamide (Enz) plus mifepristone (Mif) for metastatic castration-resistant prostate cancer (mCRPC).

91 Background: Resistance to androgen receptor (AR) targeted therapies is common in mCRPC. Glucocorticoid receptor (GR) expression increases with AR inhibition in patients (pts) and blockade of GR signaling inhibits CRPC growth in preclinical models when combined with AR blockade. We thus conducted a phase I/II open label trial of Enz combined with Mif, a GR, AR, and progesterone receptor antagonist for pts with mCRPC to assess the feasibility and impact on disease progression with dual AR/GR antagonism. Methods: The phase I dose escalation portion assessed the safety of the two-drug combination and a recommended phase II dose (R2PD) was determined based on safety, pharmacokinetic and endocrine assessments. In the phase II portion, patients (pts) received 12 weeks of Enz (160mg/day) followed by randomization to Enz alone or Enz plus Mif with PSA-progression free survival (PFS) as the primary endpoint. 42 pts were to randomize to each arm to provide 80% power to detect a hazard ratio of 0.6, with a one-sided alpha of 0.1; there was a planned interim futility analysis after 50% of progression events. Results: 106 pts (18 phase I/88 phase II) were enrolled. Pts had a median age of 70 (range 53-89) and baseline PSA of 12.8 (range 0.1-755). 34% of pts received prior docetaxel. The RP2D was 120mg/day Enz and 300mg/day Mif. In phase II, 33 patients were randomized to each arm, with well-balanced baseline demographics. 22 pts were not randomized (15 due to disease progression, 2 due to toxicity, and 5 due to the interim study analysis). The interim analysis showed no difference between arms in PSA-PFS (hazard ratio = 1.34, p=0.395), 12-month PSA-PFS of 31% in both arms, and per-protocol, the trial was stopped. Toxicities were similar in the arms, e.g. fatigue (12% vs. 14%), hot flashes (6% vs. 5%), and pain (4% vs. 4%). Conclusions: The addition of Mif to Enz following a 12-week Enz lead-in did not delay time to PSA progression. Further analyses of secondary endpoints, including translational biomarkers such as hormone levels, GR/AR-v7 expression in circulating tumor cells and cell free DNA analyses are ongoing. Clinical trial information: NCT02012296.

Eslicarbazepine acetate interacts in a beneficial manner with standard and alternative analgesics to reduce trigeminal nociception.

Acute pain states in the trigeminal region (headaches, dental pain) fall into the most prevalent painful conditions. Standard analgesics (paracetamol/NSAIDs) represent the cornerstone of their treatment, whereas triptans are primarily used in migraine attacks. Due to limited efficacy and/or side effects of current treatments, identifying favorable combinations of available drugs is justified. Eslicarbazepine acetate (ESL) is a novel antiepileptic drug whose effectiveness against trigeminal pain was recently demonstrated. Here, we examined the interactions between ESL and several standard/alternative analgesics (paracetamol, propyphenazone, naproxen, zolmitriptan, and metoclopramide) in a model of trigeminal pain. The antinociceptive effects of orally administered ESL, standard/alternative analgesics, and two-drug ESL-analgesic combinations were examined in the orofacial formalin test in mice. The type of interaction between drugs was determined by isobolographic analysis. ESL, analgesics, and two-drug ESL-analgesic combinations significantly and dose-dependently reduced nociceptive behaviour in the second, inflammatory phase of the test. Isobolographic analysis revealed that ESL interacted additively with paracetamol/propyphenazone/zolmitriptan and synergistically with naproxen/metoclopramide (with about a 4-fold and 3-fold reduction of doses in the ESL-naproxen and ESL-metoclopramide combination, respectively). ESL interacted in a beneficial manner with several analgesics that are used for trigeminal pain treatment, producing synergistic interactions with naproxen/metoclopramide and additive interactions with paracetamol/propyphenazone/zolmitriptan. Our results suggest that combining ESL with analgesics could theoretically enable the use of lower doses of individual drugs for achieving pain relief.

Identification of synergistic drug combinations using breast cancer patient-derived xenografts

Compared with other breast cancer subtypes, triple-negative breast cancer (TNBC) is associated with relatively poor outcomes due to its metastatic propensity, frequent failure to respond to chemotherapy, and lack of alternative, targeted treatment options, despite decades of major research efforts. Our studies sought to identify promising targeted therapeutic candidates for TNBC through in vitro screening of 1,363 drugs in patient-derived xenograft (PDX) models. Using this approach, we generated a dataset that can be used to assess and compare responses of various breast cancer PDXs to many different drugs. Through a series of further drug screening assays and two-drug combination testing, we identified that the combination of afatinib (epidermal growth factor receptor (EGFR) inhibitor) and YM155 (inhibitor of baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5; survivin) expression) is synergistically cytotoxic across multiple models of basal-like TNBC and reduces PDX mammary tumor growth in vivo. We found that YM155 reduces EGFR expression in TNBC cells, shedding light on its potential mechanism of synergism with afatinib. Both EGFR and BIRC5 are highly expressed in basal-like PDXs, cell lines, and patients, and high expression of both genes reduces metastasis-free survival, suggesting that co-targeting of these proteins holds promise for potential clinical success in TNBC.

Differential detection of M184V/I between plasma historical HIV genotypes and HIV proviral DNA from PBMCs.

The M184V/I reverse transcriptase mutation, which confers major resistance to lamivudine and emtricitabine, is still quite frequent in people living with HIV. The underlying presence of the M184V/I mutation may undermine virological outcomes of ART, particularly in the context of proposed treatment with two-drug combinations that include drugs affected by M184V, such as lamivudine. In suppressed patients for whom historical data are seldom available, resistance assays evaluating integrated viral DNA can help select a fully active switch regimen. To compare detectability of M184V/I in historical HIV-1 RNA analyses versus HIV-1 DNA sequencing. We analysed the detection of the M184V/I mutation in a prospective study and compared HIV historical genotypes (plasma) versus integrated HIV DNA (PBMCs) obtained via a validated commercial proviral HIV DNA assay. Eligible participants had HIV-1 RNA <50 copies/mL for ≥6 consecutive months prior to screening. A plasma historical genotypic report (HGR) showing the presence of M184V/I was required for all participants and proviral HIV DNA analysis was conducted prior to enrolment. All 84 participants had evidence of M184V or M184I in their HGR (100%), whereas the mutation was detected in only 40/84 participants by proviral HIV DNA sequencing analysis (48%). Differential detection of M184V/I was not associated with timing differences between the HGR and proviral HIV DNA sampling, the overall duration of ART, or CD4 cell counts and HIV-1 viral load at baseline. Our results suggest that undetected M184V/I should be considered when switching virologically suppressed patients to new regimens, particularly two-drug lamivudine- or emtricitabine-containing combinations.

Combinational treatment of all-trans retinoic acid (ATRA) and bisdemethoxycurcumin (BDMC)-induced apoptosis in liver cancer Hep3B cells.

The effects of two-drug combination, all-trans retinoic acid (ATRA) and bisdemethoxycurcumin (BDMC), on apoptosis induction of liver cancer cells were investigated in human liver Hep 3B cells. Two-drug combination caused a more effective decrease in cell viability and in induction of S phase arrest, DNA damage, and cell apoptosis than that of ATRA or BDMC only. Also, the two-drug combination caused more cells to undergo significantly increased ROS productions when compared to that of ATRA or BDMC only. Results of Western blotting demonstrated that two-drug combination increased expressions of Fas, pro-apoptotic proteins, and active form of caspase-3 and -9, but decreased that of anti-apoptotic proteins and XIAP than that of ATRA or BDMC only in Hep 3B cells. In conclusion, ATRA combined with BDMC enhance cell apoptosis and associated protein expression in Hep 3B cells. PRACTICAL APPLICATIONS: Bisdemethoxycurcumin (BDMC) derived from natural plants, turmeric (Curcuma longa), which had been used for Asia food for thousands of years. All-trans retinoid acid (ATRA) is currently used as a primary treatment for patients with acute promyelocytic leukemia. In previous study, ATRA and BDMC were reported to have anti-inflammatory and anticancer effects. Our results showed that treatment of ATRA combined with BDMC showed more effectively apoptosis than that of ATRA or BDMC only in Hep 3B cells. The findings also provided possible pathways concerning the induction of liver cancer cell apoptosis. We conclude that ATRA combined with BDMC may be potent anticancer agents or adjuvants for liver cancer therapy in the future.

Utilization of antihypertensive drugs among chronic kidney disease patients: Results from the Chinese cohort study of chronic kidney disease (C-STRIDE).

The utilization of antihypertensive drugs plays an important role in blood pressure control among chronic kidney disease (CKD) patients. Limited information was available on how antihypertensive drugs were used among Chinese CKD patients. In the present study, the utilization of antihypertensive drugs among a subgroup of hypertensive participants with a complete record of antihypertensive drug information from the Chinese Cohort Study of Chronic Kidney Disease was analyzed. Among 2213 subjects, 61.7% and 26.5% had their blood pressure controlled to <140/90mmHg and <130/80mmHg, respectively. In total, 38.5% were on monotherapy. Of those patients who received combination therapy, 57.8% were treated with a two-drug combination. Renin-angiotensin system inhibitors (RASIs) were the most commonly prescribed drugs (71.2%). Only 10.2% of the patients were prescribed diuretics. After multivariable adjustment, participants taking RASI were more likely to have their blood pressure controlled to <140/90mmHg (prevalence ratio (PR) 1.153, 95% confidence interval (CI): 1.071-1.240). CKD stage 4 (PR 0.548, 95% CI: 0.434-0.692) was associated with RASIs treatment. Additionally, diabetes (PR 1.498, 95% CI: 1.120-2.004), albumin/creatinine ratio ≥300mg/g (PR 1.547, 95% CI: 1.020-2.344), and CKD stage 4 (PR 2.022, 95% CI: 1.223-3.343) were associated with diuretic use. The results suggested that combination therapy, diuretics use in general, and utilization of RASIs in advanced CKD stage were insufficient in the current treatment of Chinese hypertensive CKD patients.

Database of adverse events associated with drugs and drug combinations

Due to the aging world population and increasing trend in clinical practice to treat patients with multiple drugs, adverse events (AEs) are becoming a major challenge in drug discovery and public health. In particular, identifying AEs caused by drug combinations remains a challenging task. Clinical trials typically focus on individual drugs rather than drug combinations and animal models are unreliable. An added difficulty is the combinatorial explosion in the number of possible combinations that can be made using the increasingly large set of FDA approved chemicals. We present a statistical and computational technique for identifying AEs caused by two-drug combinations. Taking advantage of the large and increasing data deposited in FDA’s postmarketing reports, we demonstrate that the task of predicting AEs for 2-drug combinations is amenable to the Likelihood Ratio Test (LRT). Our pAERS database constructed with LRT contains almost 77 thousand associations between pairs of drugs and corresponding AEs caused solely by drug-drug interactions (DDIs). The DDIs stored in pAERS complement the existing data sets. Due to our stringent statistical test, we expect many of the associations in pAERS to be unrecorded or poorly documented in the literature.

1579. Multidrug-Resistant Candida auris Isolates From New York Hospitals and Healthcare Facilities Are Susceptible to Antifungal Combinations

Background Candida auris outbreak continues unabated in New York with the current case counts exceeding 300 patients. We used a modification of standard CLSI broth microdilution method (BMD) if two-drug combinations are efficacious against C. auris isolates with high-resistance to fluconazole (FZ, MIC50 >256 mg/L), and variable resistance to other broad-spectrum antifungal drugs.MethodsBMD plates were custom-designed and quality controlled by TREK Diagnostic System. The combination tests of 15 drug-resistant C. auris involved microtiter wells with the initial 144 two-drug combinations and their two-fold dilutions (1/2–1/32) to get 864 two-drug combinations finally. We utilized MIC100 endpoints for the drug combination readings as reported earlier for the intra- and inter-laboratory agreements obtained against Candida species and Aspergillus fumigatus (Antimicrob Agents Chemother. 2015. 59:1759–1766). We also tested minimum fungicidal concentrations (MFC).ResultsWe tested all possible 864 two-drug antifungal combinations for nine antifungal drugs in use to yield 12,960 MIC100 readings, and MFC readings for 15 C. auris isolates. Flucytosine (FLC) at 2.0 mg/L potentiated most successful combinations with other drugs. Micafungin (MFG), Anidulafungin (AFG), Caspofungin (CAS) at individual concentrations of 0.25 mg/L combined well with FLC (2.0 mg/L) to yield MIC100 for 14, 13, and 12 of 15 C. auris isolates tested, respectively. MFG/FLC combination was also fungicidal for 4 of 15 isolates. AMB / FLC (0.25/1.0 mg/L) yielded MIC100 for 13 isolates and MFC for three test isolates. Posaconazole (POS), and Isavuconazole (ISA) and Voriconazole (VRC) also combined well with FLC (0.25/2.0 mg/L) to yield MIC100 for 12, 13, and 13 isolates, respectively. POS/FLC combination was fungicidal for three isolates.ConclusionWe identified seven two drug-combinations of antifungals efficacious against drug-resistant C. auris strains. The modified BMD combination susceptibility testing could be used by the clinical laboratories to assist providers with the selection of optimal treatment for C. auris candidemia. Disclosures All authors: No reported disclosures.

Cost effectiveness analysis of anti-hypertensive drugs used for chronic kidney disease patients

Cost effectiveness analysis branch of pharmacoeconomics is a technique used to aid in decision making between alternatives. A prospective observational study would be conducted in the nephrology department at O.P, Patients with CKD with hypertension, with or deprived of diabetes are included in the study. Patients with drug-induced renal disease or unknown cause. Pregnant women with chronic kidney disease are excluded from the study. The research was conducted in150 patients in which common are men. The mean age of the research people was found to be 51.2 ±7. 02. .It was observed that calcium channel blockers 127 (84.6%), diuretics 51 (34%), α agonists 33 (22%), β blockers 21 (14%), α blockers 17 (11.3%), α+β blockers 10 (6.6%), Angiotensin receptor blockers 3 (2%) and angiotensin-converting enzyme inhibitors 1 (0.6%) were the numerous antihypertensive drugs given to the study people. Incremental Cost-Effectiveness Ratio was assessed, and it was observed that Rs.31.80 was extra required while using diuretics than Calcium Channel Blockers for achieving respective maintenance value. The major classes of antihypertensive drugs prescribed in all of them are CCB+α agonist was found most effective CCB+ Diuretics were the second most effective. Incremental Cost-Effectiveness Ratio was calculated, and it was found that Rs.4.40 was Extra needed to attaining essential upkeep of blood pressure. Pharmacoeconomic study shows that Calcium channel blockers were the utmost cost-effective antihypertensive in CKD patients when linked to other antihypertensive drugs. In two-drug combination therapy, CCB+α agonist was found most effective.

The Potential Role of Sulbactam and Cephalosporins Plus Daptomycin Against Daptomycin-Nonsusceptible VISA and H-VISA Isolates: An in Vitro Study.

This study assesses the synergistic effect of the combination of cephalosporins and sulbactam with daptomycin against daptomycin-nonsusceptible, vancomycin-intermediate resistant Staphylococcus aureus (VISA) or heterogeneous vancomycin-intermediate S. aureus (h-VISA) isolates. The in vitro activity of daptomycin against daptomycin-nonsusceptible VISA/h-VISA isolates after adding cephalosporins with or without sulbactam was evaluated. The MIC of daptomycin against the VISA/h-VISA isolates was reduced after adding cephalosporins to daptomycin. Except for one VISA and two h-VISA isolates, the other VISA/h-VISA isolates became daptomycin-susceptible (MICs ≤ 1 mg/L). After adding sulbactam to each daptomycin/cephalosporin combination, the MIC of daptomycin against the VISA/h-VISA isolates decreased for 5 (33.3%), 6 (40.0%), 6 (40.0%), and 6 (40.0%) isolates with the cefazolin, cefmetazole, cefotaxime, and cefepime combinations, respectively. Synergism using the checkerboard method was noted in 100% of cefazolin and cefotaxime combinations and 87% and 80% of cefmetazole and cefepime combinations for all the VISA and h-VISA isolates. With the addition of sulbactam, synergism was noted in 100% of cefazolin, cefmetazole, and cefotaxime combinations and 93% of the cefepime combinations for all the VISA and h-VISA isolates. Almost all the FICs for the three-drug combinations were lower than those for the two-drug combinations. Using time-killing methods, a synergistic effect against five h-VISA isolates was observed. A synergistic effect of daptomycin, sulbactam, and each cephalosporin was observed for all VISA isolates. In conclusion, the activity of daptomycin against daptomycin-nonsusceptible VISA/h-VISA isolates can be enhanced by adding cephalosporins, and partially further promoted by sulbactam.