Multidrug Treatment Research Articles

Renal denervation in patients with end-stage renal disease and resistant hypertension on long-term haemodialysis.

Recent randomized controlled trials have confirmed the ability of renal denervation to lower blood pressure (BP) in patients, resistant to the BP-lowering effect of multiple antihypertensive drug administration. Evidence is limited, however, in patients with end-stage renal disease (ESRD) and haemodialysis, a condition in which a persistent BP elevation, despite administration of many antihypertensive drugs, is common. Aim of the present study was to test the BP-lowering efficacy of renal denervation in patients with resistant hypertension and ESRD on haemodialysis. BP was measured repeatedly in the office and over the 24 h during 1-year follow-up. The study was conducted from February 2017 to January 2018 at the Policlinico of Monza, Monza, Italy. We included 24 men and women aged at least 20 years (mean 55 ± 16) who had ESRD, were on long-term haemodialysis and exhibited resistant hypertension, that is, elevated office and ambulatory BP values, despite multidrug antihypertensive treatment (n = 5.4 ± 1). We excluded patients with renal artery stenosis, malignancy, and a probable life expectancy less than 1 year. Twelve patients were included in the renal denervation and 12 in the medical treatment (control) group. All patients underwent office and 24 h ambulatory BP measurements at baseline and at 1, 6 and 12 months during the follow-up. In the renal denervation group, baseline office and 24 h mean SBP were 180 ± 112 and 175 ± 11 mmHg, respectively, the corresponding values in the control group being 181 ± 19 and 181 ± 20 mmHg. Most of the other baseline characteristics were also similar or only slightly different between groups, including the mean number of administered antihypertensive drugs at baseline. SBP showed an early and persistent reduction after renal denervation (office SBP: 165 ± 13; 150 ± 7 and 149 ± 11mmHg; 24 h SBP 163 ± 20, 148 ± 10 and 149 ± 17 mmHg after 1, 6 and 12 months, respectively). The BP-lowering effect was almost always present and statistically significant during both the day and night. DBP changes followed a similar pattern whereas heart rate never showed any significant change. No significant periprocedural complication of renal denervation was seen. The mean number of administered drugs did not show any significant BP change during the study. In ESRD patients under long-term haemodialysis in whom BP was markedly elevated despite administration of many antihypertensive drugs, renal denervation lowered both ambulatory and office BP. The reduction persisted over a 1-year follow-up.

Etiologies, Cerebral Vasomotion, and Endothelial Dysfunction in the Pathophysiology of Posterior Reversible Encephalopathy Syndrome in Pediatric Patients

AbstractThe posterior reversible encephalopathy syndrome was characterized by Hinchey and colleagues in the 1990s. The condition frequently afflicts patients suffering from hematologic and solid organ malignancy and individuals undergoing transplantation. Cases are more frequently described in the adult population compared with children. In the pediatric population, malignancy, transplantation, renal disease, and hypertension represent the most common etiologies. Theories on pathogenesis have centered upon cerebrovascular dysautoregulation with increases in blood–brain barrier permeability. This generates vasogenic edema of the cerebral parenchyma and consequent neurologic deficits. The parietal and occipital lobes are affected with greatest prevalence, though frontal and temporal lobe involvement is frequent, and that of the contents of the infratentorial posterior cranial fossa are occasionally described. The clinical presentation involves a characteristic constellation of neurologic signs and symptoms, most typically inclusive of headache, visual-field disturbances, abnormalities of visual acuity, and seizures. Supportive care, withdrawal of the offending agent, antihypertensive therapy, and prophylactic anticonvulsants affect convalescence in majority of cases. The principal challenge lies in identifying the responsible agent precipitating the condition in patients with malignancy and those having undergone transplantation and thus deciding which medication among a multidrug treatment regimen to withhold, the duration of drug cessation required to effect clinical resolution, and the safety of resuming treatment with the compound. We accordingly reviewed and evaluated the literature discussing the posterior reversible encephalopathy syndrome in children.

Involvement of Transcription Elongation Factor GreA in Mycobacterium Viability, Antibiotic Susceptibility, and Intracellular Fitness.

There is growing evidence that GreA aids adaptation to stressful environments in various bacteria. However, the functions of GreA among mycobacteria remain obscure. Here, we report on cellular consequences following deletion of greA gene in Mycobacterium spp. The greA mutant strain (ΔgreA) was generated in Mycobacterium smegmatis, Mycobacterium tuberculosis (MTB) H37Ra, and M. tuberculosis H37Rv. Deletion of greA results in growth retardation and poor survival in response to adverse stress, besides rendering M. tuberculosis more susceptible to vancomycin and rifampicin. By using RNA-seq, we observe that disrupting greA results in the differential regulation of 195 genes in M. smegmatis with 167 being negatively regulated. Among these, KEGG pathways significantly enriched for differentially regulated genes included tryptophan metabolism, starch and sucrose metabolism, and carotenoid biosynthesis, supporting a role of GreA in the metabolic regulation of mycobacteria. Moreover, like Escherichia coli GreA, M. smegmatis GreA exhibits a series of conservative features, and the anti-backtracking activity of C-terminal domain is indispensable for the expression of glgX, a gene was down-regulated in the RNA-seq data. Interestingly, the decrease in the expression of glgX by CRISPR interference, resulted in reduced growth. Finally, intracellular fitness significantly declines due to loss of greA. Our data indicates that GreA is an important factor for the survival and resistance establishment in Mycobacterium spp. This study provides new insight into GreA as a potential target in multi-drug resistant TB treatment.

Surveillance for multi-drug and rifampicin resistant tuberculosis and treatment outcomes among previously treated persons with tuberculosis in the era of GeneXpert in rural eastern Uganda

RationalePreviously treated persons with bacteriologically confirmed pulmonary tuberculosis (BC-PTB) have increased risk of developing multi-drug resistant or rifampicin resistant tuberculosis (MDR/RR-TB). Surveillance for resistance is critical to identify and treat MDR/RR-TB to ensure cure and prevent transmission. There are limited studies conducted on this subject. ObjectivesWe examined the frequency and factors associated with MDR/RR-TB surveillance among previously treated persons with BC-PTB, and described their treatment outcomes in rural eastern Uganda. MethodsWe reviewed treatment records for BC-PTB between January 2015 and June 2018 at 10 clinics in eastern Uganda. We collected data on demographics, surveillance for MDR/RR, use of GeneXpert and treatment outcomes. We performed bivariate and multivariate analyses. For multivariate analysis, we used the modified Poisson regression analysis with robust standard errors and stated the results as adjusted risk ratio (aRR) with 95% confidence intervals (CI). All analyses were conducted in R version 3.5.2. Measurements and main resultsWe obtained records for 135 previously treated persons with BC-PTB and of these, 41 (30.4%) had undergone surveillance for MDR/RR-TB. Treatment failures were less likely to have surveillance compared to relapses (aRR, 0.28; 95% CI, 0.08–0.95), and there was an increasing trend in the likelihood for surveillance between 2015 and 2018 (aRR, 1.77; 95% CI, 1.39–2.25). There was no difference in MDR/RR-TB surveillance rate between health facilities with and without GeneXpert on-site (aRR, 1.52; 95% CI, 0.81–2.86) and between male and female patients (aRR, 0.54; 95% CI, 0.21–1.37). Overall, 92 (68.1%) previously treated persons with BC-PTB were successfully treated for tuberculosis. ConclusionsMDR/RR-TB surveillance and treatment success rates among previously treated persons with BC-PTB in rural eastern Uganda are low. Tuberculosis programs should strengthen MDR/RR-TB surveillance and especially target those with treatment failure.

Acinetobacter baumannii Efflux Pumps and Antibiotic Resistance.

Acinetobacter baumannii is a nosocomial pathogen and gram-negative coccobacillus that is responsible for opportunistic infections, pneumonia, and infections of the urinary tract, bloodstream, skin, and soft tissue. This bacterium poses a major public health problem due to inducing resistance to several drugs, isolates, multidrug treatment, and occasionally pan drugs. Drug resistance is not only a major concern caused by A. baumannii but also is considered as the main challenge in many other pathogens. Several factors such as the efflux pump are associated with antibiotic resistance, biofilm production, and genetic mutations. In this review, A. baumannii is introduced in then some of the practical works conducted on the existing efflux pump are reviewed. The importance of the efflux pump is considered in this paper in relation to the antibiotic resistance and mechanisms developed for the inhibition of these pumps as well.

Efficacy of Topical Insulin Therapy for Chronic Trophic Ulcers in Patients with Leprosy: A Randomized Interventional Pilot Study.

Chronic trophic ulcers (CTUs), especially those located over the plantar region, are a leading cause of deformity and disability in patients with leprosy. Despite the various treatment modalities available, CTUs can be chronic and refractory to treatment. The successful use of topical insulin in various types of wounds led researchers to evaluate its safety and efficacy in the treatment of plantar CTUs. Forty-two patients who had completed a multidrug treatment for leprosy were recruited and randomized into two groups. In the test group, 23 patients received 10 units (0.1 mL) of topical insulin (Actrapid) in 1 mL of normal saline twice daily over treated areas. The placebo group (n = 19) received topical normal saline only. The primary end point was the proportion of patients with complete wound closure by 12 weeks. Secondary end points included time to healing, wound area reduction, Physician Global Assessment of Efficacy scores, and Dermatology Life Quality Index scores at the end of 12 weeks. The majority of CTUs (80%) were situated over the forefoot; the metatarsal head of the hallux was the most common site (86%). Wound healing was faster (0.61 ± 0.31 vs 0.14 ± 0.42 cm per week, P < .0001), and the number of days to complete healing was significantly shorter in the test group compared with the placebo group (31.5 ± 17.6 vs 44.3 ± 16.2 days, P = .02). The only observed adverse effect in the test group was white granular deposits over the CTU (n = 10). Topical insulin therapy may be a safe, efficacious, cheap, and easily available treatment option in CTUs among patients with leprosy.

Demographics of new diagnoses of leprosy in the UK over 23 years: a retrospective study of cases at the Hospital for Tropical Diseases, London

BACKGROUND: Leprosy is rare in the UK, but migration from endemic countries results in new diagnoses annually. Early recognition, diagnosis and treatment can prevent harmful stigma and disability. METHODS: We conducted retrospective analysis from a database of new cases of leprosy seen at the Hospital for Tropical Diseases, London from 1995 to 2018. We aimed to identify typical demographics of patients presenting with leprosy and identify causes and consequences of delayed diagnosis. RESULTS: 157 cases were included. A large proportion were male (67.5%) with a median age of 34 years. Most were non-UK born and migrated in adulthood. 41.3% of cases were acquired in India, Sri Lanka or Bangladesh. Borderline tuberculoid (43.9%) was the most common type, followed by lepromatous leprosy (33.8%). The mean time between arrival in the UK and symptom onset was 5.87 years (SD 10.33). It took over 5 years for 12.8% of patients to be diagnosed. 93.6% of patients completed multidrug treatment following diagnosis. CONCLUSION: Male predominance and age at diagnosis reflects global epidemiology of leprosy. Patterns of acquisition reflect trends in UK migration from endemic countries. The typical patient presenting to the clinician is a young male who has migrated as an adult and developed symptoms in the years surrounding migration. Many patients may have developed disability before treatment commences as the time to diagnosis can be prolonged. Once diagnosed in the UK, treatment is of high quality, readily available, and effective: earlier recognition by clinicians can prevent disability and reduce the risk of transmission.

Multivariate curve resolution-alternating least squares to study the simultaneous release of Sumatriptan and Naproxen from the polymeric substrate

The use of the efficient drug delivery systems in combinatorial or multi-drug treatment of complicated diseases for effective and target-specific delivery of therapeutic agents necessitates the use of the fast and reliable analytical techniques to reveal the true release profiles of the investigated drugs. The knowledge about the release kinetics of the drugs from different substrates and the effective parameters on this process can be obtained by mathematical modeling of release profiles which is a difficult and cost-effective task in multi-drug delivery processes because of the difficulty in the simultaneous determination of multiple release profiles. In this study, a kinetic-spectrophotometric analytical methodology has been proposed for the simultaneous determination of release profiles of Sumatriptan and Naproxen, two widely used drugs in migraine treatment which use MCR-ALS for the decomposition of the release data matrices. The obtained release profiles have been subjected to mathematical modeling for further determination of release mechanisms. It has been shown that the MCR-ALS effectively decomposes the data matrices (more than 97% of explained variance) and Korsmeyer–Peppas and Ritger–Peppas models can well describe the release behavior of drugs from the investigated substrate (R2 > 0.99 for both compounds and acceptable low SSE values).

Homology Modeling and Molecular Docking of hABCC3/MRP3 with Chemotherapeutic Agents in Acute Leukemia

Background: Human ABCC3 (hABCC3) or multidrug resistance protein 3 (MRP3), third member of the subfamily C of the ABC proteins, is associated with multidrug resistance and treatment failure in acute leukemia. Hence, targeting this protein might be a useful approach to provide more effective drugs to overcome cancer drug resistance. Objectives: The present study aimed at predicting the possible ligand binding sites (PBSs) on hABCC3 and examining the possible binding of different chemotherapeutic drugs to this protein. Methods: To predict the PBSs on the hABCC3 transporter, a three-dimensional homology model of hABCC3 was generated in the current study based on bovine ABCC1 (bABCC1) using SWISS-MODEL and MODELLER programs, and then a molecular docking was qualified. Finally, binding affinities of 14 ligands including chemotherapeutic and immunosuppressive drugs, in addition to hABCC3 inhibitors, for hABCC3 were evaluated using binding free energies and the corresponding scores. Molecular docking was performed using AutoDock. Furthermore, Chimera, LigPlot, and Swiss PDB viewer (SPDBV) were used for interactive visualization and analysis of molecular structures. Results: The two PBSs on hABCC3 were predicted using the blind docking method. Docking results in both PBSs showed that vincristine, doxorubicin, and daunorubicin had the highest binding affinities, respectively, with vincristine having the highest docking score. Conclusions: In the current study, three drugs with the highest affinity for hABCC3 were introduced in order to take a step toward the possible hABCC3 targeting in drug-resistant acute leukemia. Furthermore, the application of in-silico methods in targeted cancer therapy, especially leukemia treatment, was highlighted.

Novel Antibacterial Strategies for Combating Bacterial Multidrug Resistance.

Antibacterial multidrug resistance has emerged as one of the foremost global problems affecting human health. The emergence of resistant infections with the increasing number of multidrug-resistant pathogens has posed a serious problem, which required innovative collaborations across multiple disciplines to address this issue. In this review, we will explain the mechanisms of bacterial multidrug resistance and discuss different strategies for combating it, including combination therapy, the use of novel natural antibiotics, and the use of nanotechnology in the development of efflux pump inhibitors. While combination therapy will remain the mainstay of bacterial multi-drug resistance treatment, nanotechnology will play critical roles in the development of novel treatments in the coming years. Nanotechnology provides an encouraging platform for the development of clinically relevant and practical strategies to overcome drug resistance in the future.

Isolated versus Drug Combined Vestibular Rehabilitation for the Treatment of Metabolic Dizziness

Introduction: Systemic processes and inappropriate use of medications may affect vestibular adaptation. Objectives: To assess the efficacy of isolated and combined drug therapy for treating metabolic dizziness and to determine the effect of multidrug treatment. Methodology: We analyzed 100 questionnaires of patients diagnosed with dizziness of metabolic origin. Results: The group treated with vestibular rehabilitation alone showed improvement with 9 months of therapy (p = 0.01). The group treated with vestibular rehabilitation and medication showed improvement with 45 days of therapy (p = 0.01). The group treated with a single type of drug did not show significant improvement. The group treated with several drugs showed improvement with 45 days of therapy (p = 0.03). Conclusion: Combined vestibular rehabilitation resulted in immediate improvement of symptoms without contributing to long-term compensation. Vestibular rehabilitation alone resulted in improve- ment of symptoms over time. Multidrug treatment was beneficial for immediate relief of dizziness.

Identification of Anti-COVID-19 Agents, Cepharanthine and Nelfinavir, and Their Potential Usage for Combination Treatment

Antiviral treatments targeting the coronavirus disease 2019 (COVID-19) are urgently required. We screened a panel of already-approved drugs in a cell culture model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and identified two new agents having higher antiviral potentials than the drug candidates such as remdesivir and chroloquine: the anti-inflammatory drug Cepharanthine and HIV protease inhibitor Nelfinavir. Cepharanthine inhibited SARS-CoV-2 entry into cells, whilst Nelfinavir inhibited the catalytic activity of viral main protease to suppress viral replication. Consistent with their different modes of action, in vitro assays highlight a synergistic effect of this combined treatment to limit SARS-CoV-2 proliferation. Mathematical modeling in vitro antiviral activity coupled with the known pharmacokinetics for these drugs predicts that Nelfinavir will shorten the period until viral clearance by 5.5-days and the combining Cepharanthine/Nelfinavir enhanced their predicted efficacy to control viral proliferation. In summary, this study identifies a new multidrug combination treatment for COVID-19.Funding: This work was supported by The Agency for Medical Research and Development (AMED) emerging/re-emerging infectious diseases project (JP19fk0108111, JP19fk0108110, JP20fk0108104); the AMED Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS, JP19am0101114, JP19am0101069, JP19am0101111) program; The Japan Society for the Promotion of Science 260 KAKENHI (JP17H04085, JP20H03499, JP15H05707, 19H04839); The JST MIRAI program; and Wellcome Trust funded Investigator award (200838/Z/16/Z). Conflict of Interest: None.

Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19).

The SARS-CoV-2 virus spreading across the world has led to surges of COVID-19 illness, hospitalizations, and death. The complex and multifaceted pathophysiology of life-threatening COVID-19 illness including viral mediated organ damage, cytokine storm, and thrombosis warrants early interventions to address all components of the devastating illness. In countries where therapeutic nihilism is prevalent, patients endure escalating symptoms and without early treatment can succumb to delayed in-hospital care and death. Prompt early initiation of sequenced multidrug therapy (SMDT) is a widely and currently available solution to stem the tide of hospitalizations and death. A multipronged therapeutic approach includes 1) adjuvant nutraceuticals, 2) combination intracellular anti-infective therapy, 3) inhaled/oral corticosteroids, 4) antiplatelet agents/anticoagulants, 5) supportive care including supplemental oxygen, monitoring, and telemedicine. Randomized trials of individual, novel oral therapies have not delivered tools for physicians to combat the pandemic in practice. No single therapeutic option thus far has been entirely effective and therefore a combination is required at this time. An urgent immediate pivot from single drug to SMDT regimens should be employed as a critical strategy to deal with the large numbers of acute COVID-19 patients with the aim of reducing the intensity and duration of symptoms and avoiding hospitalization and death.

Drug–drug cocrystals of anticancer drugs erlotinib–furosemide and gefitinib–mefenamic acid for alternative multi-drug treatment

Drug–drug cocrystals of anticancer drugs erlotinib and gefitinib with furosemide and mefenamic acid, respectively, have been synthesized, characterized and their solubilities and dissolution rates were correlated with crystal structures.

Effects of cinnamon extract on complications of treatment and eradication of Helicobacter pylori in infected people

Introduction: Treatment of Helicobacter pylori has various side effects like antibiotic resistance. The purpose of this study was to evaluate the effects of cinnamon extract on complications of treatment and eradication of H. pylori in infected people. Methods: In this randomized clinical trial, a total of 98 eligible healthy and H. pylori-infected patients approved by esophageal endoscopy were selected. The cinnamon group received multi-drug treatment including clarithromycin, amoxicillin and pantoprazole as well as a cinnamon extract capsule. The control group received multi-drug treatment and a 40 mg starch capsule. In order to analyze the cinnamon extract efficacy, the urea breath test (UBT) was performed 3 months after the start of treatment. Clinical symptoms were evaluated by a questionnaire at the beginning (day of 0), 7 days and 14 days after starting treatment. Results: The clinical symptoms such as nausea, vomiting, diarrhea, constipation, blurred vision, headache, metallic flavor, epigastric pain, burp, and appetite were significantly reduced in the cinnamon group (P &lt; 0.05). The odds ratio exhibited a higher eradication rate of H. pylori in the cinnamon group (73.47% in the cinnamon group compared to 53.06% in the control group) (P = 0.036). Conclusion: Cinnamon as assisted therapy is able to alleviate the disease and reduce the complications of H. pylori treatment.

Diagnosis and treatment of children with purpura nephritis

Henoch-Schonlein purpura nephritis is the most common secondary renal disease in children, which is caused by immune complex mediated glomerular injury.Most children show mild symptoms, only presenting as microscopic hematuria or microalbuminuria, and a few children show renal insufficiency.The diagnosis of purpura nephritis is clear at home and abroad.Both clinical classification and pathological grading have consensus, but there is no unified treatment on the international at present.Early diagnosis and treatment have a profound effect on prognosis.Especially for the continuous proteinuria, multi-drug treatment should be taken to reduce the probability of progression to chronic renal insufficiency. Key words: Children; Purpura nephritis; Diagnosis; Treatment

Blood pressure control in chronic kidney disease according to underlying renal disease: the Fukushima CKD cohort.

Inadequate blood pressure control is one of the important causes of chronic kidney disease (CKD), but only a limited number of reports have examined blood pressure control in Japanese patients with pre-dialysis CKD. Differences in blood pressure control due to underlying renal disease in pre-dialysis patients with CKD were investigated in the present study using the baseline data of the Fukushima CKD cohort study. The study involved 1351 CKD patients, classified by underlying disease of primary renal disease, hypertensive nephropathy, diabetic nephropathy, other nephropathies, or unknown. Target blood pressure of CKD patients was defined as < 130/80mmHg in patients under 75years old with diabetes and/or proteinuria, and < 140/90mmHg in other patients. The achievement rate of target systolic blood pressure was lower in the diabetic and hypertensive nephropathy groups than in the primary renal disease group (33.3%, 46.0% vs. 68.1%, p < 0.001). However, the number of antihypertensive medications increased in the diabetic and hypertensive nephropathy groups compared to the primary renal disease group (2.16, 2.04 vs. 1.55, p < 0.001). Inadequate blood pressure control was independently related to the underlying renal disease, with a significant difference between diabetic nephropathy and primary renal disease (odds ratio 3.19; 95% confidence interval, 2.16-4.69; p < 0.001). This study showed that blood pressure control differs by the underlying renal disease. Blood pressure control was poor especially in diabetic nephropathy despite multidrug combination antihypertensive treatment. It is necessary to verify whether strict blood pressure control improves patients' prognosis in diabetic nephropathy.

DDIGIP: predicting drug-drug interactions based on Gaussian interaction profile kernels

BackgroundA drug-drug interaction (DDI) is defined as a drug effect modified by another drug, which is very common in treating complex diseases such as cancer. Many studies have evidenced that some DDIs could be an increase or a decrease of the drug effect. However, the adverse DDIs maybe result in severe morbidity and even morality of patients, which also cause some drugs to withdraw from the market. As the multi-drug treatment becomes more and more common, identifying the potential DDIs has become the key issue in drug development and disease treatment. However, traditional biological experimental methods, including in vitro and vivo, are very time-consuming and expensive to validate new DDIs. With the development of high-throughput sequencing technology, many pharmaceutical studies and various bioinformatics data provide unprecedented opportunities to study DDIs.ResultIn this study, we propose a method to predict new DDIs, namely DDIGIP, which is based on Gaussian Interaction Profile (GIP) kernel on the drug-drug interaction profiles and the Regularized Least Squares (RLS) classifier. In addition, we also use the k-nearest neighbors (KNN) to calculate the initial relational score in the presence of new drugs via the chemical, biological, phenotypic data of drugs. We compare the prediction performance of DDIGIP with other competing methods via the 5-fold cross validation, 10-cross validation and de novo drug validation.ConlusionIn 5-fold cross validation and 10-cross validation, DDRGIP method achieves the area under the ROC curve (AUC) of 0.9600 and 0.9636 which are better than state-of-the-art method (L1 Classifier ensemble method) of 0.9570 and 0.9599. Furthermore, for new drugs, the AUC value of DDIGIP in de novo drug validation reaches 0.9262 which also outperforms the other state-of-the-art method (Weighted average ensemble method) of 0.9073. Case studies and these results demonstrate that DDRGIP is an effective method to predict DDIs while being beneficial to drug development and disease treatment.

Intermittent treatment interruption and its effect on multidrug resistant tuberculosis treatment outcome in Ethiopia

Treatment interruption is one of the main risk factors of poor treatment outcome and occurrence of additional drug resistant tuberculosis. This study is a national retrospective cohort study with 10 years follow up period in MDR-TB patients in Ethiopia. We included 204 patients who had missed the treatment at least for one day over the course of the treatment (exposed group) and 203 patients who had never interrupted the treatment (unexposed group). We categorized treatment outcome into successful (cured or completed) and unsuccessful (lost to follow up, failed or died). We described treatment interruption by the length of time between interruptions, time to first interruption, total number of interruption episodes and percent of missed doses. We used Poisson regression model with robust standard error to determine the association between treatment interruption and outcome. 82% of the patients interrupted the treatment in the first six month of treatment period, and considerable proportion of patients demonstrated long intervals between two consecutive interruptions. Treatment interruption was significantly associated with unsuccessful treatment outcome (Adjusted Risk Ratio (ARR) = 1.9; 95% CI (1.4–2.6)). Early identification of patients at high risk of interruption is vital in improving successful treatment outcome.

Dissecting the Anticancer Mechanism of Trifluoperazine on Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with almost no curative chemotherapeutic treatment. Besides the development of new compounds, repurposing of approved drugs to treat cancer, alone or in combination, has become an attractive strategy, showing many therapeutic and economic advantages. However, it is necessary to improve our knowledge about the mechanism of cell death elicited by approved drugs itself, but also to rationally develop more powerful multidrug treatments. In this work, we focus our attention on determining the mechanism promoting cell death following trifluoperazine (TFP) treatment, which is an antipsychotic drug with strong anticancer activity in PDAC. We demonstrate that TFP induces cell death by apoptosis and necroptosis, which can be partially inhibited by Z-VAD-FMK as well as necrostatin-1, respectively. This cell death promotion is triggered by a poor ATP content, observed in TFP-treated cells as a consequence of a dramatic decrease in OXPHOS metabolism due to mitochondrial stress. Remarkably, mitochondrial homeostasis was seriously affected, and a loss of mitochondrial membrane potential and ROS overproduction was observed. Moreover, this mitochondrial stress was coupled with an ER stress and the activation of the endoplasmic-reticulum-associated protein degradation (ERAD) and the unf olded protein response (UPR) pathways. We took advantage of this information and inhibited this process by using the proteasome inhibitors MG-132 or bortezomib compounds in combination with TFP and found a significant improvement of the anticancer effect of the TFP on primary PDAC-derived cells. In conclusion, this study not only uncovers the molecular mechanisms that are triggered upon TFP-treatment but also its possible combination with bortezomib for the future development of therapies for pancreatic cancer.