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Progression‐free survival (PFS) is an important clinical metric for comparing and evaluating similar treatments for the same disease within oncology. After the completion of a clinical trial, a descriptive analysis of the patients' PFS is often performed post hoc using the Kaplan–Meier estimator. However, to perform predictions, more sophisticated quantitative methods are needed. Tumor growth inhibition models are commonly used to describe and predict the dynamics of preclinical and clinical tumor size data. Moreover, frameworks also exist for describing the probability of different types of events, such as tumor metastasis or patient dropout. Combining these two types of models into a so‐called joint model enables model‐based prediction of PFS. In this paper, we have constructed a joint model from clinical data comparing the efficacy of FOLFOX against FOLFOX + panitumumab in patients with metastatic colorectal cancer. The nonlinear mixed effects framework was used to quantify interindividual variability (IIV). The model describes tumor size and PFS data well, and showed good predictive capabilities using truncated as well as external data. A machine‐learning guided analysis was performed to reduce unexplained IIV by incorporating patient covariates. The model‐based approach illustrated in this paper could be useful to help design clinical trials or to determine new promising drug candidates for combination therapy trials. [ABSTRACT FROM AUTHOR]

The combination of chemotherapy and photothermal therapy shows great potential in cancer treatment, and the carbon nanomaterials have been attracted great attention in biomedical technology. However, it is still a great challenge to design stimuli‐responsive nano‐carbon‐based drug release systems with integrated functions. In this paper, rod‐like carbon nanomaterials (RCNs) were prepared by the soft template hydrothermal method with glucose as raw materials, which were proved to have high photothermal efficiency (∼23.7%), as well as good biocompatibility and excellent drug‐loading capacity. After that, RCNs were used to load doxorubicin (DOX) as DOX@RCNs for integrated photothermal/chemotherapy towards cancer, which demonstrated 52.2% higher cancer cell killing efficiency than that of RCNs under near infrared (NIR) irradiation in vitro. The authors' approach provided a novel NIR‐responsive nano platform for combined photothermal/chemotherapy towards cancer, which was considered to be of great potential in anticancer applications. [ABSTRACT FROM AUTHOR]

Introduction: Osteosarcoma is the most common primary malignancy of the bone. There is a lack of effective treatments for patients who experience relapsed osteosarcoma. One treatment for relapsed patients is gemcitabine and docetaxel combination chemotherapy (GEMDOX). This systematic review aimed to establish the efficacy of this chemotherapy regimen, as well as identify the common severe toxicities that are associated with it. Resistant osteosarcoma cell lines developed from MG‐63 and HOS‐143B were used to represent relapsed osteosarcoma patients in a pre‐clinical study. Results: We identified 11 retrospective and Phase II studies that were suitable for inclusion in our review. 10.65% of patients had a response to gemcitabine and docetaxel combination therapy and the disease control rate was 35% (n = 197). 36%, 35.3% and 18.04% of patients experienced grade 3 or 4 neutropenia, thrombocytopenia and anaemia respectively (n = 133). Male patients (X2 = 9.14, p < 0.05) and those below the age of 18 (X2 = 10.94, p < 0.05) responded better to GEMDOX treatment than females and patients older than 18 years. The resistant osteosarcoma cell lines remained sensitive to either single‐agent gemcitabine, docetaxel, and the combination of both. Cisplatin‐resistant models (MG‐63/CISR8 & HOS‐143B/CISR8) were the most responsive to GEMDOX treatment compared to doxorubicin, methotrexate, and triple‐combination resistant models. Conclusion: GEMDOX treatment has potential efficacy in relapsed osteosarcoma patients especially those with cisplatin resistance. To directly compare the efficacy of GEMDOX therapy against other therapies randomised phase III clinical trials with adequate patient follow up must be performed to improve treatment options for osteosarcoma. [ABSTRACT FROM AUTHOR]

To undertake a literature search and critical appraisal of best available evidence to answer the clinical question: Does the addition of clonidine (I) to standard treatment with an opioid (C) improve outcomes (O) in infants with Neonatal Abstinence Syndrome? A search of both comprehensive (MedLine and Embase) and pre-filtered databases (Dynamed, UpToDate and TRIP), utilising Boolean Operators to combine search terms appropriately. Three relevant studies were identified. One paper describing the outcomes of a randomised controlled trial by Agthe et al. (2009) most accurately answered the clinical question posed. This paper was critically appraised, and evidence applied to the clinical scenario. The use of clonidine as an adjunct to opioid in the management of infants with NAS reduces the total number of treatment days and dose of opioid required to control symptoms. However, there is a higher risk of rebound in symptoms post-cessation of opioid and clinicians need to account for this in their discharge planning. More large scale, multi-centre high-quality research is needed to clarify the role of clonidine in the treatment of NAS: as monotherapy versus adjunct, the optimal dose and longer-term impact on neurodevelopment. [ABSTRACT FROM AUTHOR]

Focus question: What is the efficacy of a chlorhexidine (CHX) mouthwash (MW) containing sodium fluoride (NaF) compared to a CHX − MW alone on the parameters of plaque, gingivitis and discoloration? Material and Methods: MEDLINE‐PubMed, Cochrane‐CENTRAL, and EMBASE were searched for papers from inception to December 2017. The inclusion criteria were (randomized) controlled clinical trials conducted in human subjects with good general health and without removable prosthesis. Papers evaluating the effect of a MW containing CHX + NaF compared to a CHX alone were included. From the eligible studies, data were extracted, a descriptive analysis was performed and a meta‐analysis when feasible. Results: Independent screening of 412 unique papers resulted in 9 eligible publications presenting 10 clinical trials comparing the effect of CHX + NaF to CHX − MW and provided 13 comparisons. Five evaluated the MW as an adjunct to brushing and 8 were non‐brushing comparisons of which 4 used an experimental gingivitis model. No significant difference was observed for plaque score reduction in the brushing studies the end scores (diffM; −0.04, P = .36; 95%CI: [−0.13, 0.05]) nor the differences (diffM; 0.11, P = .33; 95%CI: [−0.12, 0.24]). In the descriptive analysis, none of the experiments demonstrated a statistical significant difference regarding Gingival Index (GI), Bleeding Score and Discoloration Scores. For the GI, a meta‐analysis of the difference of Means was not significant when included experimental gingivitis model studies end scores (0.01, P = .78; 95%CI: [−0.08, 0.11]) and the difference (0.01, P = .81; 9 5%CI: [−0.08, 0.10]) either for the end scores of brushing studies (diffM; −0.01, P = .82; 95%CI: [−0.10, 0.08]). Conclusion: From this study, it can be concluded that NaF and CHX may be present in the same MW without reducing CHX efficacy with respect to plaque and gingivitis scores. Moreover, no difference in the development of tooth discoloration was observed. [ABSTRACT FROM AUTHOR]

Combination therapies have become increasingly researched and used in the treatment and management of complex diseases due to their ability to increase the chances for better efficacy and decreased toxicity. To evaluate drug combinations in drug development, pharmacokinetic and pharmacodynamic interactions between drugs in combination can be quantified using mathematical models; however, it can be difficult to deduce which models to use and how to use them to aid in clinical trial simulations to simulate the effect of a drug combination. This review paper aims to provide an overview of the various methods used to evaluate combination drug interaction for use in clinical trial development and a practical guideline on how combination modeling can be used in the settings of clinical trials. [ABSTRACT FROM AUTHOR]

The incidence of cancer has been growing worldwide. Better survival rates following the administration of novel drugs and new combination therapies may concomitantly cause concern regarding the long‐term adverse effects of cancer therapy, for example, second primary malignancies. Moreover, overcoming tumour resistance to anticancer agents has been long considered as a critical challenge in cancer research. Some low toxic adjuvants such as herb‐derived molecules may be of interest for chemoprevention and overcoming the resistance of malignancies to cancer therapy. Apigenin is a plant‐derived molecule with attractive properties for chemoprevention, for instance, promising anti‐tumour effects, which may make it a desirable adjuvant to reduce genomic instability and the risks of second malignancies among normal tissues. Moreover, it may improve the efficiency of anticancer modalities. This paper aims to review various effects of apigenin in both normal tissues and malignancies. In addition, we explain how apigenin may have the ability to protect usual cells against the genotoxic repercussions following radiotherapy and chemotherapy. Furthermore, the inhibitory effects of apigenin on tumours will be discussed. [ABSTRACT FROM AUTHOR]

Objectives: The treatment goal for rheumatoid arthritis has undergone a dramatic change over recent years with the advent of biologic and targeted synthetic disease‐modifying antirheumatic drugs (b/tsDMARDs). This systematic review aims to discuss the comparative efficiency of new drugs versus the standard of care methotrexate. Methods: Pubmed, Google Scholar, and Science Direct were searched, and 7072 records were retrieved. Randomized controlled trials published in the last five years with full‐text papers, blinded studies, and studies with an open‐label extension were included. Studies with a high risk of bias as calculated by the Cochrane risk of bias (RoB2) tool were excluded. The last database search was conducted on 21 August 2021. Results: Fifteen studies were identified and analyzed by categorizing drugs into Janus kinase (JAK) inhibitors, tumour necrosis factor (TNF) inhibitors, and monoclonal antibodies with other targets (anti‐GM‐CSF receptor, anti‐IL6 receptor, anti‐IL‐17 monoclonal antibodies), with a total of 7963 participants. Data were synthesized with tables and the PRISMA flow diagram. Our analysis included baricitinib, filgotinib, peficitinib, infliximab, certolizumab, sarilumab, tocilizumab namilumab, mavrilimumab, golimumab, and CNT06785. Conclusions: These studies showed that except for CNT 06785 (anti‐Interleukin 17A monoclonal antibody), biologic and targeted synthetic disease‐modifying drugs combined with methotrexate or as monotherapy yield better clinical and radiographical outcomes. This systematic review does not discuss biosimilars and the adverse effects of biologic drugs in detail. Infections remain a significant adverse drug reaction of monoclonal antibodies. However, these drugs play a crucial role in adequately managing this disease for patients with severe arthritis. [ABSTRACT FROM AUTHOR]

In this paper, a metal–organic skeleton material MIL‐101‐NH2‐AL was prepared for loading the chemotherapeutic drug Oridonin (Ori) and photosensitizer Chlorin e6 (Ce6). A drug delivery system for synergistic chemotherapy and photodynamic therapy was constructed. At the same time, we evaluated MIL‐101‐NH2‐AL as a drug therapy carrier, including drug loading, cytotoxicity, and safety, verified the photodynamic efficiency of MIL‐101‐NH2‐AL@Ori@Ce6 in vitro, and studied the ability of MIL‐101‐NH2‐AL@Ori@Ce6 cancer cells to produce reactive oxygen species, cell uptake, cytotoxicity, and so on. Experiments have confirmed that MIL‐101‐NH2‐AL, as a nano‐carrier, encapsulated Oridonin and Ce6, the combination of PDT and chemotherapy showed enhanced tumor inhibition and high biosafety. The killing effect on cells was caused by reactive oxygen species produced by photosensitizers and apoptosis of tumor cells induced by Oridonin. The drug delivery system demonstrates enormous potential for synergistic anti‐tumor effects of photodynamic and chemotherapy. [ABSTRACT FROM AUTHOR]

In a network meta-analysis, comparators of interest are ideally connected either directly or via one or more common comparators. However, in some therapeutic areas, the evidence base can produce networks that are disconnected, in which there is neither direct evidence nor an indirect route for comparing certain treatments within the network. Disconnected networks may occur when there is no accepted standard of care, when there has been a major paradigm shift in treatment, when use of a standard of care or placebo is debated, when a product receives orphan drug designation, or when there is a large number of available treatments and many accepted standards of care. These networks pose a challenge to decision makers and clinicians who want to estimate the relative efficacy and safety of newly available agents against alternatives. A currently recommended approach is to insert a distribution for the unknown treatment effect(s) into a network meta-analysis model of treatment effect. In this paper, we describe this approach along with two alternative Bayesian models that can accommodate disconnected networks. Additionally, we present a theoretical framework to guide the choice between modeling approaches. This paper presents researchers with the tools and framework for selecting appropriate models for indirect comparison of treatment efficacies when challenged with a disconnected framework. [ABSTRACT FROM AUTHOR]

We analyze a mathematical model for the combination of chemotherapy with antiangiogenic treatment as a multi‐input optimal control problem. Assuming that the total amounts of both agents to be given have been determined a priori based on a medical assessment of side effects, we consider the problem to minimize a weighted average of tumor volume and the carrying capacity of the tumor vasculature. For medically realistic initial conditions and data, based on a thorough theoretical analysis of the necessary conditions for optimality given by the Pontryagin maximum principle, in this paper, the optimal administration regimen for the antiangiogenic agent is determined. [ABSTRACT FROM AUTHOR]

Essential oils have shown good experimental potential as novel veterinary ectoparasiticides. However, if they are to be used as veterinary products, they must be available in formulations that are suitable for practical application against specific ectoparasites. Here, the efficacies of formulations containing 5% (v/v) lavender or tea tree oil, in combination with two emulsifiers [a surfactant, 5% (w/v) N-lauroylsarcosine sodium salt ( SLS), and a soluble polymer, 5% (w/v) polyvinylpyrrolidone ( PVP)], with or without 10% coconut oil, were tested in contact bioassays against the donkey chewing louse Bovicola ocellatus (Piaget) (Phthiraptera: Trichodectidae). Residual activity was quantified in open and closed containers; ovicidal efficacy was also examined. Exposure to either of 5% (v/v) lavender or tea tree oils with SLS or PVP resulted in louse mortality of 100%, but when coconut oil was included as an excipient, significantly lower efficacy was recorded. However, the formulations became significantly less effective after 2 h in open containers and 40 h in closed containers. The results confirm that the residual activity of essential oils is relatively transitory and the addition of 10% coconut oil does not prolong the period of insecticidal activity by slowing essential oil evaporation. Too short a period of residual activity is likely to be a significant impediment to the effective practical use of essential oils. However, unlike many synthetic pediculicides, the essential oils tested here were highly ovicidal, which suggests that prolonged residual activity may not be essential to kill newly hatched nymphs after treatment. [ABSTRACT FROM AUTHOR]

The outcome of management of diabetic foot ulcers remains a challenge, and there remains continuing uncertainty concerning optimal approaches to management. It is for these reasons that in 2008 and 2012, the International Working Group of the Diabetic Foot (IWGDF) working group on wound healing published systematic reviews of the evidence to inform protocols for routine care and to highlight areas, which should be considered for further study. The same working group has now updated this review by considering papers on the interventions to improve the healing of chronic ulcers published between June 2010 and June 2014. Methodological quality of selected studies was independently assessed by two reviewers using Scottish Intercollegiate Guidelines Network criteria. Selected studies fell into the following ten categories: sharp debridement and wound bed preparation with larvae or hydrotherapy; wound bed preparation using antiseptics, applications and dressing products; resection of the chronic wound; oxygen and other gases, compression or negative pressure therapy; products designed to correct aspects of wound biochemistry and cell biology associated with impaired wound healing; application of cells, including platelets and stem cells; bioengineered skin and skin grafts; electrical, electromagnetic, lasers, shockwaves and ultrasound and other systemic therapies, which did not fit in the aforementioned categories. Heterogeneity of studies prevented pooled analysis of results. Of the 2161 papers identified, 30 were selected for grading following full text review. The present report is an update of the earlier IWGDF systematic reviews, and the conclusion is similar: that with the possible exception of negative pressure wound therapy in post-operative wounds, there is little published evidence to justify the use of newer therapies. Analysis of the evidence continues to present difficulties in this field as controlled studies remain few and the majority continue to be of poor methodological quality. [ABSTRACT FROM AUTHOR]

Aims: Patients surviving an acute myocardial infarction (AMI) are at risk of developing symptomatic heart failure (HF) or premature death. We hypothesized that sacubitril/valsartan, effective in the treatment of chronic HF, prevents development of HF and reduces cardiovascular death following high-risk AMI compared to a proven angiotensin-converting enzyme (ACE) inhibitor. This paper describes the study design and baseline characteristics of patients enrolled in the Prospective ARNI vs. ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction (PARADISE-MI) trial.Methods and Results: PARADISE-MI, a multinational (41 countries), double-blind, active-controlled trial, randomized patients within 0.5-7 days of presentation with index AMI to sacubitril/valsartan or ramipril. Transient pulmonary congestion and/or left ventricular ejection fraction (LVEF) ≤40% and at least one additional factor augmenting risk of HF or death (age ≥70 years, estimated glomerular filtration rate <60 mL/min/1.73 m2 , diabetes, prior myocardial infarction, atrial fibrillation, LVEF <30%, Killip class ≥III, ST-elevation myocardial infarction without reperfusion) were required for inclusion. PARADISE-MI was event-driven targeting 708 primary endpoints (cardiovascular death, HF hospitalization or outpatient development of HF). Randomization of 5669 patients occurred 4.3 ± 1.8 days from presentation with index AMI. The mean age was 64 ± 12 years, 24% were women. The majority (76%) qualified with ST-segment elevation myocardial infarction; acute percutaneous coronary intervention was performed in 88% and thrombolysis in 6%. LVEF was 37 ± 9% and 58% were in Killip class ≥II.Conclusions: Baseline therapies in PARADISE-MI reflect advances in contemporary evidence-based care. With enrollment complete PARADISE-MI is poised to determine whether sacubitril/valsartan is more effective than a proven ACE inhibitor in preventing development of HF and cardiovascular death following AMI. [ABSTRACT FROM AUTHOR]

Summary: Based on promising results in older adults with acute myeloid leukaemia (AML), we treated patients with NPM1mut measurable residual disease (MRD) using off‐label venetoclax in combination with low‐dose cytarabine or azacitidine. Twelve consecutive patients were retrospectively identified, including five with molecular persistence and seven with molecular relapse/progression. All patients with molecular persistence achieved durable molecular complete remission (CRMRD‐) without transplantation. Six of seven patients with molecular relapse/progression achieved CRMRD‐ after 1–2 cycles of venetoclax. This paper highlights the promising efficacy of venetoclax‐based therapy to reduce the relapse risk in patients with persistent or rising NPM1mut MRD. [ABSTRACT FROM AUTHOR]

One type is the simple hyperplastic polyp, which is typically a common small lesion that is not believed to possess malignant potential (unlike other types of serrated polyps). Keywords: adenomatous polyps; colorectal cancer; colorectal polyps; gastroenterology; randomized clinical trial; retrospective analysis; serrated polyps; VITAL trial; vitamin D deficiency; vitamins EN adenomatous polyps colorectal cancer colorectal polyps gastroenterology randomized clinical trial retrospective analysis serrated polyps VITAL trial vitamin D deficiency vitamins 469 471 3 03/02/22 20220201 NES 220201 A low serum vitamin D level has been associated with a number of non-bone diseases in epidemiologic studies. Colorectal cancer, gastroenterology, randomized clinical trial, vitamin D deficiency, vitamins, adenomatous polyps, colorectal polyps, retrospective analysis, serrated polyps, VITAL trial In fact, they could not even be sure that the polyps that were identified did not exist prior to the trial beginning, because both adenomas and serrated polyps are almost always asymptomatic and can exist for many years. [Extracted from the article]

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AGO‐OVAR 12 investigated the effect of adding the oral triple angiokinase inhibitor nintedanib to standard front‐line chemotherapy for advanced ovarian cancer. At the primary analysis, nintedanib demonstrated significantly improved progression‐free survival (PFS; primary endpoint) compared with placebo. We report final results, including overall survival (OS). Patients with primary debulked International Federation of Gynaecology and Obstetrics (FIGO) stage IIB–IV newly diagnosed ovarian cancer were randomised 2:1 to receive carboplatin (area under the curve 5 or 6) plus paclitaxel (175 mg/m2) on day 1 every 3 weeks for six cycles combined with either nintedanib 200 mg or placebo twice daily on days 2–21 every 3 weeks for up to 120 weeks. Between December 2009 and July 2011, 1,366 patients were randomised (911 to nintedanib, 455 to placebo). Disease was considered as high risk (FIGO stage III with >1 cm residuum, or any stage IV) in 39%. At the final analysis, 605 patients (44%) had died. There was no difference in OS (hazard ratio 0.99, 95% confidence interval [CI] 0.83–1.17, p = 0.86; median 62.0 months with nintedanib vs. 62.8 months with placebo). Subgroup analyses according to stratification factors, clinical characteristics and risk status showed no OS difference between treatments. The previously reported PFS improvement seen with nintedanib did not translate into an OS benefit in the nonhigh‐risk subgroup. Updated PFS results were consistent with the primary analysis (hazard ratio 0.86, 95% CI 0.75–0.98; p = 0.029) favouring nintedanib. The safety profile was consistent with previous reports. What's new? Primary results from the randomised phase III AGO‐OVAR 12 trial comparing nintedanib (a triple angiokinase inhibitor) with placebo given in combination with chemotherapy and then continued as maintenance therapy in patients with newly diagnosed advanced ovarian carcinoma demonstrated a significant improvement in progression‐free survival with nintedanib. However, as reported in this paper, final overall survival (OS) results showed that the addition of nintedanib had no impact on OS. These results do not, therefore, support use of nintedanib in ovarian cancer. [ABSTRACT FROM AUTHOR]

Background: Polycystic ovary syndrome (PCOS) is complex with reproductive, metabolic and psychological features. Infertility is a prevalent presenting feature of PCOS with approximately 75% of these women suffering infertility due to anovulation, making PCOS by far the most common cause of anovulatory infertility. Previous guidelines either lacked rigorous evidence‐based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated. Aims: This review paper aims to provide a brief update on the best available and most current research evidence supporting the treatment of PCOS which informed the recommendations in the assessment and treatment of infertility section of the international evidence‐based guideline on PCOS 2018. Materials and Methods: International evidence‐based guideline development engaged professional societies and consumer organisations with multidisciplinary experts and women with PCOS directly involved at all stages. Results: Lifestyle change alone is considered the first‐line treatment for the management of infertile anovulatory PCOS women who are overweight or obese. Letrozole should now be considered first‐line pharmacological treatment for ovulation induction to improve fertility outcomes. Clomiphene citrate alone and metformin alone could also be used as first‐line pharmacological therapy, although both are less effective than letrozole and metformin is less effective than clomiphene citrate in obese women. Gonadotrophins or laparoscopic ovarian surgery are usually second‐line ovulation induction therapies. In the absence of an absolute indication for in vitro fertilisation (IVF) / intracytoplasmic sperm injection, women with PCOS and anovulatory infertility could be offered IVF as third‐line therapy where first‐ or second‐line ovulation induction therapies have failed. Conclusion: This review provides the best available evidence informing recommendations (along with clinical expertise and consumer preference) which provide clinicians with clear advice on best practice for the management of infertile women with PCOS. [ABSTRACT FROM AUTHOR]

Background: Behavioural emergencies (BEs) are complex situations in the emergency department (ED) setting. Treatment decisions always must be made within a limited time and are based on incomplete patient data. As a result of the urgency and complexity, patients often are exposed to increased risk of harm. Aim: The aim of this paper is to describe the prescribing patterns and adverse events (AEs) associated with parenteral sedation for the management of BEs in Australian EDs. Methods: Ten Australian EDs enrolled a convenience sample of adult patients (aged ≥18 years) requiring parenteral sedative medication for BEs. Data were collected prospectively between March 2015 and April 2017 using a designated case report form. Results: In all, 564 cases were enrolled in this study. Incomplete cases (n = 17; 3%) were excluded. Of the 547 remaining cases, 63% were male and the median age was 34 years (range 18–95 years). Approximately half the patients (n = 230; 42.1%) required mechanical restraint and parenteral sedation to manage their BEs. Intramuscular monotherapy was administered in most cases (n = 390; 71.3%). The main sedative medications used as monotherapy were droperidol (n = 381; 69.7%), midazolam (n = 54; 9.9%) and olanzapine (n = 26; 4.8%). The most common combination therapy was midazolam + droperidol (n = 36; 6.6%). The incidence of AEs from sedative administration was 13.5%. No deaths or irreversible AEs were reported. Conclusions: Overall, the participating EDs provided safe pharmacological management for BEs. AEs following parenteral sedation are common, although serious AEs are rare. Because all patients receiving parenteral sedation for BEs are at risk of AEs, ongoing monitoring of vital signs after parenteral sedation should be a standard protocol in all EDs. [ABSTRACT FROM AUTHOR]

Intravaginal rings (IVRs) are an established option for continuous administration of drugs in women. The combination of anastrozole (ATZ) and levonorgestrel (LNG) in an IVR with an intended 4‐week wearing period has been considered for long‐term treatment of endometriosis‐associated pelvic pain. A randomized, parallel‐group, multicenter phase 2b study to assess the efficacy and safety of different dose combinations in women with symptomatic endometriosis has recently been performed. This paper will focus on the investigation of pharmacokinetic (PK) effects of ATZ on LNG using data collected from this study. Two hundred sixteen patients were randomized to the treatment group with IVRs releasing LNG 40 μg/day alone or in combination with ATZ 300 μg/day, 600 μg/day, or 1050 μg/day for 12 weeks. PK blood samples were taken before dosing and before IVR replacement or removal (days 28, 56, and 84). The primary PK parameter was the plasma concentration in apparent steady state of ATZ and LNG at the end of each IVR wearing period. Results of PK analysis demonstrate that ATZ concentrations increased proportionally with increasing dose (geometric mean values of 7.85, 15.48, and 22.61 μg/L at 300, 600, and 1050 μg/day nominal release, respectively). All point estimates for LNG concentration in apparent steady state ratios between the mono and combination IVR groups were close to 1, and the 90% confidence interval limits were in the 0.80 to 1.25 range (1.01 [0.85‐1.19], 1.03 [0.88‐1.20], 0.94 [0.80‐1.10]). In conclusion, our data indicate there is no evidence of drug‐drug interaction of ATZ on LNG. [ABSTRACT FROM AUTHOR]

Immune-deficient patients depend on the antibodies in pooled human immunoglobulin G (IgG) preparations to remain free from serious infections. The potency of IgG preparations is therefore an ongoing concern. The use of pooled IgG to prevent infection is based on the concept that healthy adults have recovered from infections earlier in life and maintain relatively high antibody titers. In general, vaccine-induced immunity is less robust or long-lasting than immunity after natural infection, and many infectious diseases which were formerly widely prevalent have become much less common due to improved hygiene and vaccines. This raises questions as to the adequacy of protective antibodies in current IgG preparations. This paper reviews available data on antibodies against selected bacterial and virus vaccine antigens in current IgG products. Most products contain sufficient antibody to yield levels above minimal protective concentrations to a broad range of pathogens and toxins. Illustrative examples of effects of vaccines on antibody content of IgG products are also discussed: antibody titers to hepatitis A virus in donor plasma pools in both the US and EU are dropping due to decreased natural infection, but they are still sufficient to provide robust protection. Increasing seroprevalence of hepatitis B virus as a result of immunization suggests that antibody titers against this virus may actually be increasing. Finally, serial studies suggest that pooled IgG provides protection against seasonal influenza viruses despite year-to-year antigenic drift, and is also likely to provide at least some protective antibody against potentially pandemic strains. [ABSTRACT FROM AUTHOR]

Linked Content This article is linked to Majumdar et al paper. To view this article visit https://doi.org/10.1111/apt.13633. [ABSTRACT FROM AUTHOR]

SUMMARY In this paper, a mathematical model for the scheduling of angiogenic inhibitors with a killing agent is used to derive a robust state feedback control for the combined therapy of cancer. Robustness is considered against parameter uncertainties through the solution of the associated Hamilton-Jacobi-Isaacs (HJI) partial differential equation. Unlike open-loop optimal control paradigm, solving the HJI equation provides a guaranteed-cost feedback control and a whole visibility of the achievable performance for any possible initial state within the region of interest and for any predefined level of parameter uncertainties. Numerical investigation is proposed using an existing model that has been partially validated using human data. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: There is considerable public and political interest in the use of cannabis products for medical purposes.Methods: The task force of the European Pain Federation (EFIC) conducted a survey with its national chapters representatives on the status of approval of all types of cannabis-based medicines, the covering of costs and the availability of a position paper of a national medical association on the use of medical cannabis for chronic pain and for symptom control in palliative/supportive care.Results: Thirty-one out of 37 contacted councillors responded. Plant-derived tetrahydrocannabinol/cannabidiol (THC/CBD) oromucosal spray is approved for spasticity in multiple sclerosis refractory to conventional treatment in 21 EFIC chapters. Plant-derived THC (dronabinol) is approved for some palliative care conditions in four EFIC chapters. Synthetic THC analogue (nabilone) is approved for chemotherapy-associated nausea and vomiting refractory to conventional treatment in four EFIC chapters'. Eight EFIC chapters' countries have an exceptional and six chapters an expanded access programme for medical cannabis. German and Israeli pain societies recommend the use of cannabis-based medicines as third-line drug therapies for chronic pain within a multicomponent approach. Conversely, the German medical association and a team of finish experts and officials do not recommend the prescription of medical cannabis due to the lack of high-quality evidence of efficacy and the potential harms.Conclusions: There are marked differences between the countries represented in EFIC in the approval and availability of cannabis-based products for medical use. EFIC countries are encouraged to collaborate with the European Medicines Agency to publish a common document on cannabis-based medicines.Significance: There are striking differences between European countries in the availability of plant-derived and synthetic cannabinoids and of medical cannabis for pain management and for symptom control in palliative care and in the covering of costs by health insurance companies or state social security systems. [ABSTRACT FROM AUTHOR]

Drug-drug interactions (DDIs) are a common cause of adverse drug events (ADEs). The electronic medical record (EMR) database and the FDA's adverse event reporting system (FAERS) database are the major data sources for mining and testing the ADE associated DDI signals. Most DDI data mining methods focus on pair-wise drug interactions, and methods to detect high-dimensional DDIs in medical databases are lacking. In this paper, we propose 2 novel mixture drug-count response models for detecting high-dimensional drug combinations that induce myopathy. The "count" indicates the number of drugs in a combination. One model is called fixed probability mixture drug-count response model with a maximum risk threshold (FMDRM-MRT). The other model is called count-dependent probability mixture drug-count response model with a maximum risk threshold (CMDRM-MRT), in which the mixture probability is count dependent. Compared with the previous mixture drug-count response model (MDRM) developed by our group, these 2 new models show a better likelihood in detecting high-dimensional drug combinatory effects on myopathy. CMDRM-MRT identified and validated (54; 374; 637; 442; 131) 2-way to 6-way drug interactions, respectively, which induce myopathy in both EMR and FAERS databases. We further demonstrate FAERS data capture much higher maximum myopathy risk than EMR data do. The consistency of 2 mixture models' parameters and local false discovery rate estimates are evaluated through statistical simulation studies. [ABSTRACT FROM AUTHOR]

Background: Despite advances in the treatment of cancer, pancreatic ductal adenocarcinoma (PDAC) remains highly lethal due to the lack of effective therapies. Our previous study showed that Luteolin (Lut), a flavonoid, suppressed pancreatocarcinogenesis and reduced the expression of dihydropyrimidine dehydrogenase (DPYD), an enzyme that degrades pyrimidines such as 5‐fluorouracil (5‐FU), in PDACs. In this study, we investigated the role of DPYD and evaluated the therapeutic potential of combining 5‐FU with Lut in PDACs. Methods and Results: PDAC cells overexpressing DPYD showed increased proliferation, and invasiveness, adding to the resistance to 5‐FU. The xenograft tumors of DPYD‐overexpressing PDAC cells also exhibit enhanced growth and invasion compared to the control xenograft tumors. RNA‐seq analysis of the DPYD‐overexpressing PDAC xenograft tumors revealed an upregulation of genes associated with metallopeptidase activity—MMP9 and MEP1A. Furthermore, the overexpression of MEP1A in PDAC was associated with invasion. Next, we investigated the combined effects of Lut, a DPYD suppressor, and 5‐FU on DPYD‐overexpressing xenograft tumors and PDAC of Pdx1‐Cre; LSL‐KrasG12D/+; Trp53flox/flox(KPPC) mice. Neither single administration of 5‐FU nor Lut showed significant inhibitory effects; however, the combined administration of 5‐FU and Lut exhibited a significant tumor‐suppressive effect in both the xenograft tumors and KPPC models. Conclusion: We have elucidated that DPYD expression contributes to proliferation, invasiveness, and 5‐FU resistance, in PDACs. The combination therapy of Lut and 5‐FU holds the potential for enhanced efficacy against PDACs. [ABSTRACT FROM AUTHOR]

Background: Small cell lung cancer (SCLC) is a highly aggressive tumor with limited effectiveness in its standard chemotherapy treatment. Targeted antiangiogenic therapy and immune checkpoint inhibitors (ICIs) have demonstrated potential as alternative treatments for extensive‐stage SCLC (ES‐SCLC). However, there is insufficient comparative evidence available to determine the optimal first‐line treatment option between ICIs plus chemotherapy and targeted antiangiogenic therapy plus chemotherapy. Objective: This study is aimed at analyzing clinical data from ES‐SCLC patients treated at the First Affiliated Hospital of Bengbu Medical College between June 2021 and June 2023. The study compared the efficacy and safety of three first‐line treatment regimens: standard chemotherapy, antiangiogenic therapy combined with chemotherapy, and immune combination therapy. Methods: Patients who met the inclusion criteria were divided into three groups: chemotherapy, immune combination therapy, and antiangiogenic therapy combined with chemotherapy. The study collected data on clinical characteristics, treatment regimens, and adverse reactions. The analysis included objective response rate (ORR), duration of response (DoR), disease control rate (DCR), progression‐free survival (PFS), and treatment safety. Results: A total of 101 patients were included in the study, with 49 receiving chemotherapy alone, 19 receiving antiangiogenic therapy, and 33 receiving immune combination therapy. The ORRs were 78.9% for antiangiogenic therapy, 72.7% for immune combination therapy, and 42.9% for chemotherapy alone. The median PFS was 8.0 months for antiangiogenic therapy, 7.8 months for immune combination therapy, and 5.2 months for chemotherapy alone. Both combination therapy groups demonstrated superior efficacy compared to chemotherapy alone. Conclusion: Targeted combined chemotherapy and immune combination chemotherapy showed superior efficacy as first‐line treatments for ES‐SCLC compared to chemotherapy alone, with manageable adverse reactions. [ABSTRACT FROM AUTHOR]

Patients with chronic lymphocytic leukaemia (CLL) are generally older, with many considered 'unfit' for fludarabine-cyclophosphamide-rituximab therapy. In these patients, the combination of obinutuzumab-chlorambucil may be an appropriate therapeutic choice. Obinutuzumab-chlorambucil has been demonstrated to improve overall survival rates compared to chlorambucil alone and to improve progression-free survival and overall response rates compared to rituximab-chlorambucil. This combination can lead to certain toxicities that need to be addressed through appropriate patient selection, pre-medication and management. In this paper, we discuss evidence-based and author-recommended practical management of first-line CLL patients receiving obinutuzumab-chlorambucil. [ABSTRACT FROM AUTHOR]

Mike Kirby, GP and Visiting Professor to the University of Hertfordshire and The Prostate Centre, London, picks some interesting recent papers and highlights the 'take-home' message. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate whether a combination of platelet‐rich plasma (PRP) and decalcified freeze‐dried bone allograft (DFDBA) offers advantages over DFDBA and saline in infrabony defects. The objectives were to primarily evaluate changes in clinical attachment level (CAL) and secondarily changes in pocket depth (PD). A search was performed of electronic databases (Medline, PubMed, Embase, The Cochrane Central Register of Controlled Trials, and Web of Science), as well as hand searching and reference list searching. Only randomized, controlled trials published up until 30 March 2018 were included that had a follow‐up period of at least 6 months. Four papers met the eligibility criteria and were critically appraised using the Consolidated Standards of Reporting Trials statement and put through the Cochrane Collaboration's tool for assessing risk of bias. In three of the four studies, clinically and significantly greater CAL gains and PD reductions were observed in patients who received PRP and DFDBA in comparison to those who received DFDBA and saline (P < 0.05). Methodological heterogeneity existed among the studies, especially in the preparation of PRP and the type of infrabony defect. This made it difficult to draw clear conclusions, but despite this, the studies could still be regarded, as significant as they showed a low risk of bias. [ABSTRACT FROM AUTHOR]

In this meta‐analysis, we reviewed the findings and definitive findings of a new study that assessed the impact of bevacizumab on wound healing following combined chemotherapy for ovarian cancer (OC). The results of a controlled study that assessed the efficacy of bevacizumab in the treatment of ovarian cancer were retrieved from 4 databases, such as the Web of Science and EMBASE. The results of the adverse event associated with wound healing were determined by comparison of the controlled studies of bevacizumab plus chemotherapy in the treatment of ovarian cancer. A meta‐analysis was conducted with either a randomized or a fixed‐effect model in order to establish an odds ratio for time to event variables and for a binary outcome. In the research literature, 830 trials have been identified and seven have been chosen to be included in a definitive analysis of the trial. Among the 4134 cases who received chemotherapy after operation, 2098 received standard chemotherapy and 2036 received the addition of bevacizumab. A total of 7 trials have shown that the use of bevacizumab in the treatment of ovarian cancer patients has reduced wound healing (OR, 0.55; 95% CI: 0.37, 0.80, p = 0.002). Four trials demonstrated that there was no change in the incidence of haemorrhage in patients with ovarian cancer when administered with or without bevacizumab (OR, 0.48; 95% CI, 0.10, 2.34, p = 0.37). The combined use of bevacizumab and chemotherapy may have a negative effect on the healing of wound. [ABSTRACT FROM AUTHOR]

We evaluated the primary application of crushed prednisolone combined with hydrocolloid powder for clinically diagnosed peristomal pyoderma gangrenosum (PPG). We present our data on this cohort and follow‐up of our previous patients. Of the 23 patients who were commenced on this regime, 18 healed (78%). Twenty‐two patients commenced on this regime as the primary treatment for their PPG, and for one, it was a rescue remedy after failed conventional therapy. Four patients with significant medical comorbidities failed to heal and one had their stomal reversal surgery before being fully healed. The proposed treatment regime for PPG is demonstrated to be effective, inexpensive and able to be managed in the patient's usual home environment. In vitro drug release analysis was undertaken, and data are presented to provide further insights into the efficacy of this regime. [ABSTRACT FROM AUTHOR]

Background A short-term course of pegylated-interferon (Peg- IFN), or a long-term treatment with a third generation nucleot(s)ide analogue ( NUC), of chronic hepatitis B (CHB) infection achieves viral suppression and may prevent disease progression. Owing to different mechanisms of action of the two regimens, a Peg- IFN and NUC combination treatment may be an attractive approach to enhance the off-treatment rates of virological and serological response. Aim To review the literature on combinations of Peg- IFN plus NUC, including the simultaneous initiation of Peg- IFN and NUC in naïve patients; an 'add-on' combination, where Peg- IFN is started at variable times after the beginning of NUC; or a 'switch-to' strategy usually from NUC to Peg- IFN. Methods We performed a PubMed literature search using the following terms individually or in combination: NUC, hepatitis B virus, chronic hepatitis, interferon, pegylated-interferon, nucleos(t)ide analogues, entecavir, tenofovir. English-language articles published up to December 2015, as well as conference proceedings from international meetings were reviewed. References from selected papers were reviewed and used if relevant. Results While combination and NUC pre-treatment failed to increase HBsAg clearance rates, more promising results were achieved in patients under long-term effective NUC therapy. Conclusion While Peg- IFN and nucleos(t)ide analogue combination therapy should not be recommended currently, the addition of or the switch to Peg- IFN in nucleos(t)ide analogue-treated patients with chronic hepatitis B infection may be useful option. [ABSTRACT FROM AUTHOR]

Background and aims Codeine is the most commonly used opioid in the world, and is available over the counter (OTC) in many countries, including Australia. Several countries are reconsidering codeine's OTC status due to concerns over addiction and misuse, with serious morbidity and mortality being reported. Australia's Therapeutic Goods Administration restricted codeine containing analgesics to 'Pharmacist Only' in 2010, and has recently been considering further up-scheduling to make codeine 'Prescription Only'. This paper estimated Australian trends of codeine misuse over the past 12 years, and examined whether trends changed following previous rescheduling efforts in 2010. Design A retrospective review of calls regarding codeine misuse made to the New South Wales Poisons Information Centre (NSWPIC, Australia's largest poisons centre), 2004-15. Joinpoint software was used to quantify the average annual change in calls, and whether there was a significant change in trend at any time, including following rescheduling. Setting Australia. Participants Four hundred patients about whom a call was made to the NSWPIC. Measures Calls per year, patient age, gender, tablets taken per day, formulation used, symptom disposition. Findings The NSWPIC database contained 400 cases of codeine combination analgesic misuse from 2004 to 2015. Joinpoint analysis showed that the frequency of cases increased significantly from 2004 to 2015, with an average annual percentage change (AAPC) of 19.5% [95% confidence interval (CI) = 13.8-25.5% P < 0.0001] for paracetamol/codeine and 17.9% (95% CI = 7.9-28.9%, P < 0.01) for ibuprofen/codeine. No significant change in trend was seen at any time, including following 2010 rescheduling. The median age of patients was 34 and 27 years for paracetamol/codeine and ibuprofen/codeine cases, respectively. Gender distribution was approximately equal. Clinical features reported were consistent with codeine, paracetamol and ibuprofen toxicity. Conclusions Misuse of codeine combination products appears to be increasing in Australia. Limited rescheduling in 2010 failed to curb this increase. [ABSTRACT FROM AUTHOR]

The progressive nature of Type 2 diabetes necessitates treatment intensification over time in order to maintain glycaemic control, with many patients ultimately requiring insulin therapy. While insulin has unlimited potential efficacy, its initiation is often delayed and improvements in glycaemic control are typically accompanied by weight gain and an increased risk of hypoglycaemia, particularly as HbA1c approaches and falls below target levels. This may account for the sub-optimal control often achieved after insulin initiation. Combining insulin with antihyperglycaemic therapies that have a low risk of hypoglycaemia and are weight-neutral or result in weight loss is a therapeutic strategy with the potential to improve Type 2 diabetes management. Although the effects differ with each individual class of therapy, clinical trials have shown that adding a glucagon-like peptide-1 receptor agonist, dipeptidyl peptidase-4 inhibitor or sodium-glucose co-transporter-2 inhibitor to insulin regimens can offer a significant reduction in HbA1c without substantially increasing hypoglycaemia risk, or weight. The evidence and merit of each approach are reviewed in this paper. Once-daily co-formulations of a basal insulin and a glucagon-like peptide-1 receptor agonist have been developed (insulin degludec/liraglutide) or are under development (lixisenatide/insulin glargine). Insulin degludec/liraglutide phase III trials and a lixisenatide/insulin glargine phase II trial have shown robust HbA1c reductions, with weight loss and a low risk of hypoglycaemia. With insulin degludec/liraglutide now approved in Europe, an important consideration will be the types of patients who may benefit most from a fixed-ratio combination; this is discussed in the present review, and we also take a look toward future developments in the field. [ABSTRACT FROM AUTHOR]

In current industry practice, it is difficult to assess QT effects at potential therapeutic doses based on Phase I dose-escalation trials in oncology due to data scarcity, particularly in combinations trials. In this paper, we propose to use dose-concentration and concentration-QT models jointly to model the exposures and effects of multiple drugs in combination. The fitted models then can be used to make early predictions for QT prolongation to aid choosing recommended dose combinations for further investigation. The models consider potential correlation between concentrations of test drugs and potential drug-drug interactions at PK and QT levels. In addition, this approach allows for the assessment of the probability of QT prolongation exceeding given thresholds of clinical significance. The performance of this approach was examined via simulation under practical scenarios for dose-escalation trials for a combination of two drugs. The simulation results show that invaluable information of QT effects at therapeutic dose combinations can be gained by the proposed approaches. Early detection of dose combinations with substantial QT prolongation is evaluated effectively through the CIs of the predicted peak QT prolongation at each dose combination. Furthermore, the probability of QT prolongation exceeding a certain threshold is also computed to support early detection of safety signals while accounting for uncertainty associated with data from Phase I studies. While the prediction of QT effects is sensitive to the dose escalation process, the sensitivity and limited sample size should be considered when providing support to the decision-making process for further developing certain dose combinations. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Tubulin-binding agents are potent cytotoxic drugs that are largely used to treat haematological malignancies and solid tumours. In this issue of British Journal of Pharmacology, doxorubicin was shown to decrease the activity of vincristine when administered simultaneously, unless cell cycle arrest mechanisms were disrupted. This observation emphasizes the need to better explore schedule-dependent antagonist effects in anticancer drug combination therapies. Linked Article This article is a commentary on the research paper by Ehrhardt et al., pp. 1558-1569 of this issue. To view this paper visit http://dx.doi.org/10.1111/bph.12068 [ABSTRACT FROM AUTHOR]

Introduction: Towards the end of the twentieth century, significant success was achieved in reducing incidence in several global HIV epidemics through ongoing prevention strategies. However, further progress in risk reduction was uncertain. For one thing, it was clear that social vulnerability had to be addressed, through research on interventions addressing health systems and other structural barriers. As soon as antiretroviral treatment became available, researchers started to conceive that antiretrovirals might play a role in decreasing either susceptibility in uninfected people or infectiousness among people living with HIV. In this paper we focus on the origin, present status, and potential contribution of pre-exposure prophylaxis (PrEP) within the combination HIV prevention framework. Discussion: After a phase of controversy, PrEP efficacy trials took off. By 2015, daily oral PrEP, using tenofovir alone or in combination with emtricitabine, has been proven efficacious, though efficacy seems heavily contingent upon adherence to pill uptake. Initial demonstration projects after release of efficacy results have shown that PrEP can be implemented in real settings and adherence can be high, leading to high effectiveness. Despite its substantial potential, beliefs persist about unfeasibility in reallife settings due to stigma, cost, adherence, and potential risk compensation barriers. Conclusions: The strategic synergy of behavioural change communication, biomedical strategies (including PrEP), and structural programmes is providing the basis for the combination HIV prevention framework. If PrEP is to ever become a key component of that framework, several negative beliefs must be confronted based on emerging evidence; moreover, research gaps regarding PrEP implementation must be filled, and appropriate prioritization strategies must be set up. Those challenges are significant, proportional to the impact that PrEP implementation may have in the global response to HIV. [ABSTRACT FROM AUTHOR]

This study is to compare the effectiveness of combinational use of bupivacaine with fentanyl (BUPI-FEN) and sufentanil (BUPI-SUF) in epidural/intrathecal analgesia for labor. Electronic databases were searched for relevant research papers published between 1985 and 2014. Meta-analyses of mean differences or odds ratios were performed and statistical heterogeneity between the studies tested by I2 index. Ten studies recruiting a total of 728 women in labor were selected. Concentrations of the anesthetics used as mean ± sd were bupivacaine 0.115 ± 0.056%, fentanyl 0.0007 ± 0.001%, and sufentanil 0.00017 ± 0.00022%. Duration of analgesia was not significantly different between BUPI-SUF and BUPI-FEN administered mothers (mean difference [95%CI] of −33.55 [−74.94, 7.83] minutes; P = .11) under random effects. The onset of analgesia was also not significantly different between both groups (mean difference [95%CI] of −0.61 [−1.38, 0.16] minutes; P = .12). The number of neonates with Apgar score < 7 was significantly lower in BUPI-FEN group (odd ratio [95%CI] of 0.31 [0.10, 0.95]; P < .05). Pruritus incidence was similar. In conclusion, BUPI-FEN combination exhibits significantly better tolerability at an approximate ratio of 6 FEN:1 SUF, albeit, both fentanyl and sufentanil in combination with bupivacaine provide similar analgesic properties via the epidural or intrathecal routes for labor pain relief. [ABSTRACT FROM AUTHOR]

Chronic prostatitis, which frequently manifests with perineal or urethral ulcers, can have substantial impact on the quality of life experienced by affected individuals. Present treatment approaches primarily target the alleviation of symptoms and control of complications. In patients with chronic prostatitis, this investigation examined the potential synergistic effects of tamsulosin and levofloxacin on urinary function and urethral and perineal wounds healing. This cross‐sectional observational study was carried out at Chongqing Western Hospital, China, from February to November 2023. The participants comprised 88 males aged 40–75 years who had been clinically diagnosed with chronic prostatitis and complications that accompany the wound healing process. The participants were equally distributed into two groups: one assigned to the treatment group, which received a daily combination of levofloxacin (500 mg) and tamsulosin (0.4 mg) and other to receive conventional care. The wound healing rate and improvement in urinary function were the primary outcomes evaluated monthly for 9 months. Patient satisfaction and symptom amelioration were secondary outcomes, in addition to the surveillance of adverse effects. In comparison to the control, treatment group exhibited significantly higher rate of wound closure (78.08% at 1 month and 79.38% at 9 months) and urinary function improvement (66.69% at 1 month and 67.95% at 9 months). In addition, the treatment group exhibited a greater degree of symptom amelioration; however, a rise in adverse effects was observed. In every domain, patient satisfaction scores were significantly higher in the treatment group. Thus the combination of tamsulosin and levofloxacin improved urinary function and wound repair in patients with chronic prostatitis, while also exhibiting tolerable profile of adverse effects. [ABSTRACT FROM AUTHOR]

Multidrug antibiotic resistance is an urgent public health concern. Multiple strategies have been suggested to alleviate this problem, including the use of antibiotic combinations and cyclic therapies. We examine how adaptation to (1) combinations of drugs affects resistance to individual drugs, and to (2) individual drugs alters responses to drug combinations. To evaluate this, we evolved multiple strains of drug resistant Staphylococcus epidermidis in the lab. We show that evolving resistance to four highly synergistic combinations does not result in cross‐resistance to all of their components. Likewise, prior resistance to one antibiotic in a combination does not guarantee survival when exposed to the combination. We also identify four 3‐step and four 2‐step treatments that inhibit bacterial growth and confer collateral sensitivity with each step, impeding the development of multidrug resistance. This study highlights the importance of considering higher‐order drug combinations in sequential therapies and how antibiotic interactions can influence the evolutionary trajectory of bacterial populations. [ABSTRACT FROM AUTHOR]

Objective This pilot study explored the potential for 2 recognized acute migraine medications, 85 mg of sumatriptan plus 500 mg of naproxen sodium in a combination tablet ( SumaRT/ Nap) and 500 mg of naproxen sodium, to treat and modify the disease progression of migraine. In other words, can these medications both abort an acute attack of migraine and reduce the number of future migraine attacks? Background Patients suffering with moderate to severe attacks of migraine desire acute treatment. As migraine frequency increases, so does the need for more frequent relief of acute attacks. This may lead to medication overuse and potentially medication overuse headache ( MOH). Ideally, acute medication would have the ability to abort an attack of migraine and reduce the likelihood of future attacks. Study Design The primary endpoint of this study was a reduction in migraine headache days from baseline through month 3 of the study. Subjects were randomized 1:1 to treat 14 or fewer migraines per month with SumaRT/ Nap (Group A) or naproxen sodium (Group B) for 3 months. Subjects in group A utilized SumaRT/ Nap were encouraged, but not required, to treat migraine headache within 1 hour of onset of headache when the pain was mild. They could re-treat if needed after 2 hours. Subjects in group B utilized the same treatment strategy with 500 mg of naproxen sodium. Tablets of study medication were identical for both groups. Subjects recorded headache days, migraine attacks, duration of attacks, treatment, and treatment results daily on paper diaries. Subjects took the Migraine Disability Assessment Test ( MIDAS) at randomization and 3 months later at the end of study. Results Naproxen sodium was associated with a statistically significant reduction in migraine headache days at month 3 compared to baseline ( P = .0002). SumaRT/ Nap was also associated with a reduction of migraine headache days, but this decrease did not reach statistical significance ( P = .2). In addition, subjects in the naproxen sodium group had a statistically significant reduction of migraine attacks in all 3 months of the study compared to baseline. A greater than 50% reduction in the number of migraine headache days at month 3 occurred in 43% (6/14) of subjects in group B compared to 17% (3/18) of subjects in group A. Consistent with large regulatory studies comparing the efficacy of SumaRT/ Nap with naproxen sodium, SumaRT/ Nap in this study was statistically superior to naproxen sodium at 2 hours in reducing headache severity during months 2 and 3. There was a reduction of acute medication used from baseline to month 3 and improvement in MIDAS scores for both groups. Conclusion Naproxen sodium, when used as a sole acute treatment early in attacks, appears to reduce the frequency of headache days and migraine attacks for a select number of subjects over a 3-month period. SumaRT/ Nap is more effective at 2-hour headache reduction than naproxen sodium alone, but has less impact on reducing attack frequency or the number of headache days. Both treatments were well tolerated, and there was no convincing evidence that either medication led to MOH. [ABSTRACT FROM AUTHOR]

Use of the immunomodulators thiopurines and methotrexate (MTX) in the treatment of inflammatory bowel disease (IBD), i.e., Crohn's disease and ulcerative colitis (UC), is considered to be good clinical practice. However, despite being administered to a considerable number of IBD patients over the years, questions remain about the most rational treatment regimens of azathioprine (AZA), 6-mercaptopurine (6-MP), and MTX, and results from a range of recent studies necessitate increased attention to how to optimize the use of these immunomodulators. First and foremost, it is of utmost importance to define the subgroup of IBD patients in need of immunomodulators, including those in need of combination therapy with biologic agents, especially because some side effects may be rather severe. Second, colorectal cancer is observed more often in IBD patients than in the background population. However, a recent nationwide Dutch study pointed to a preventive effect of thiopurines. Finally, the need for an appropriate approach to the discontinuation of immunomodulators is emphasized. Since controversy continues regarding the most appropriate use of immunomodulators, this paper is focusing on pharmacokinetics, pharmacogenetics, and therapeutic blood testing, as well as the occurrence of adverse events, when using AZA, 6-MP, and MTX in an attempt to determine a more up-to-date and rational treatment regimen in IBD. [ABSTRACT FROM AUTHOR]

Objective This paper presents the final analysis of once-daily darunavir/ritonavir ( DRV/r) vs. lopinavir/ritonavir ( LPV/r) in treatment-naïve HIV-1-infected adults. Methods ARTEMIS ( AntiRetroviral Therapy with TMC114 ExaMined In naïve Subjects; NCT00258557) was a randomized, open-label, phase- III, 192-week trial. Patients were stratified by baseline HIV-1 RNA and CD4 count, and randomized to once-daily DRV/r 800/100 mg or LPV/r 800/200 mg total daily dose (either once or twice daily) plus tenofovir/emtricitabine. Results Of 689 randomized patients receiving treatment ( DRV/r: 343; LPV/r: 346), 85 and 114 patients in the DRV/r and LPV/r arms, respectively, had discontinued by week 192. Noninferiority was shown in the primary endpoint of virological response ( HIV-1 RNA < 50 copies/ mL) [ DRV/r: 68.8%; LPV/r: 57.2%; P < 0.001; intent to treat ( ITT)/time to loss of virological response; estimated difference in response 11.6% (95% confidence interval 4.4-18.8%)]. Statistical superiority in virological response of DRV/r over LPV/r was demonstrated for the primary endpoint ( P = 0.002) and for the ITT non-virological-failure-censored analysis (87.4% vs. 80.8%, respectively; P = 0.040). No protease inhibitor ( PI) primary mutations developed and only low levels of nucleoside reverse transcriptase inhibitor ( NRTI) resistance developed in virological failures in both groups. Significantly fewer discontinuations because of adverse events were observed with DRV/r (4.7%) than with LPV/r (12.7%; P = 0.005). Grade 2-4 treatment-related diarrhoea was significantly less frequent with DRV/r than with LPV/r (5.0% vs. 11.3%, respectively; P = 0.003). DRV/r was associated with smaller median increases in total cholesterol and triglyceride levels than LPV/r. Changes in low- and high-density lipoprotein cholesterol were similar between groups. Similar increases in aspartate aminotransferase and alanine aminotransferase for DRV/r and LPV/r were observed. Conclusion Over 192 weeks, once-daily DRV/r was noninferior and statistically superior in virological response to LPV/r, with a more favourable gastrointestinal profile, demonstrating its suitability for long-term use in treatment-naïve patients. [ABSTRACT FROM AUTHOR]

Acute ischemic stroke develops from an interruption in focal cerebral blood flow. In many cases, it is caused by an acute thromboembolism. Although systemic fibrinolytic therapy for acute ischemic stroke has been a significant breakthrough in the management of this disease, additional agents and methods that could improve or restore cerebral flow are necessary. Similarly to findings in acute myocardial infarction, combination pharmacotherapy has the potential to improve current thrombolytic treatment in acute ischemic stroke. In recent years, research efforts were directed toward various combination therapy with pharmacological and nonpharmacological methods. Several trials tested tissue plasminogen activator (t-PA) in combination with antiplateletes and anticoagulants. Combination of t-PA with nonpharmacological agents included sonothrombolysis (amplifying the thrombolytic effect), laser (neuro-recovery), hypothermia (cytoprotection and decreasing brain swelling), and blood flow augmentation (increasing residual flow and recruitment of collateral vessels). This paper will review ongoing clinical trials and safety of these promising combinatory treatments. [ABSTRACT FROM AUTHOR]

Abstract: With the event of new Molecular targets, clinical trial design requirements to perform these trials are changing. This paper discusses some of the considerations that need to be taken into account when designing a trial, including those trials that assess combinations of targets. [Copyright &y& Elsevier]

Please cite this paper as: Adams G, Zekri J, Wong H, Walking J, Green J. Platinum-based adjuvant chemotherapy for early-stage epithelial ovarian cancer: single or combination chemotherapy? BJOG 2010;117:1459-1467. Objective To evaluate the clinical benefit and toxicity of two regimens; single agent carboplatin (C) and a carboplatin/paclitaxel (CP) combination in early epithelial ovarian cancer. Design A retrospective review. Setting Single cancer centre serving a population of 2.1 million in the northwest of England. Population All women treated with adjuvant chemotherapy for International Federation of Obstetrics and Gynecology stage Ia-IIc ovarian cancer between 2002 and 2005. Methods Case and operation notes were reviewed. Details of the surgery performed, performance status (PS), tumour histology, stage, grade, intended chemotherapy, chemotherapy received, acute and late toxicity, relapse and death were all recorded. Main outcome measures Overall survival (OS), relapse-free survival (RFS), acute and late toxicity. Results Sixty women received CP and 35 received C. Younger women ( P < 0.0001) and those with a better performance status ( P = 0.045) were more likely to receive CP. Median follow up was 38 months (range 0-70). Five-year OS was 62% (95% CI 44-81%) for C and 73% (95% CI 61-85%) for CP P = 0.316. For the subgroup with stage I disease and good PS (0/1) 5-year OS was 80% (59-100%) for C and 79% (63-95%) for CP; P = 1.0. For those with stage 2 disease, 5-year OS was 29% (95% CI 0-62%) for C and 63% (95% CI 44-82%) for CP; P = 0.025. Subgroup analyses by grade or histology showed no difference in OS. P was discontinued prematurely in nine (15%) women on account of toxicity, whereas C was not stopped early. P-related neuropathy (G1/2) was reported in ten (17%) women at 6 months and in two (3%) at 1 year. Conclusions Combination therapy is administered more often than carboplatin; especially in those with younger age, better PS and nonmucinous histology. Recurrence and death rates were similar with both treatments. Well-designed trials are needed to identify the optimum chemotherapy regimen in this group. [ABSTRACT FROM AUTHOR]

Two different combinations of anaesthetics were evaluated and compared in a prospective randomised crossover experimental study in pigs. One of the two combinations was administered intramuscularly to each of six Landrace x Yorkshire mixed-breed pigs. The combinations were: 2.2 mg/kg xylazine and 4.4 mg/kg tiletamine/zolazepam (2.2 mg/kg tiletamine plus 2.2 mg/kg zolazepam) (XTZ); and 0.04 mg/kg medetomidine and 4.4 mg/kg tiletamine/zolazepam (MTZ). The anaesthesia and recovery times, score for anaesthetic effect and cardiopulmonary parameters were recorded for each pig. Anaesthesia was successfully induced in all of the pigs. Both drug combinations provided smooth induction and good immobilisation, and their anaesthetic effects were similar. In both treatment groups, the mean heart rate decreased significantly five minutes after the drugs were administered and remained consistent for 70 minutes, with no significant difference between the XTZ and MTZ groups. However, there were differences in cardiopulmonary effects between the groups. The arterial pressure was significantly higher in the MTZ group than in the XTZ group. The initial hypertension associated with medetomidine was more marked than the initial hypertension associated with xylazine. Arterial oxygen partial pressure and arterial oxygen saturation decreased significantly from baseline in both groups. The respiratory rates and levels of blood gases were similar in both groups. Hypoventilation and hypoxaemia were observed in both groups. The scores for anaesthetic effect, induction time, anaesthesia time and recovery times were similar in the two groups. [ABSTRACT FROM AUTHOR]

A conference paper about the use of radioimmunotherapy combined with antibodies such as rituximab on the extended mortality of patients with non-Hodgkin lymphoma (NHL) is presented. It discusses the use of radiolabeled antibody therapy on the improvement of the overall survival of patients. It examines the effectiveness of radioimmunoconjugates on newly diagnosed patients along with the administration of combined methods of chemotherapy and monoclonal antibodies.