Beneficial Effects of Bioactive Compounds in Mulberry Fruits against Cisplatin-Induced Nephrotoxicity.

Int J Mol Sci. 2018 Apr 09;19(4):

Authors: Lee D, Yu JS, Lee SR, Hwang GS, Kang KS, Park JG, Kim HY, Kim KH, Yamabe N

Abstract
Mulberry, the fruit of white mulberry tree (Morus alba L., Moraceae), is commonly used in traditional Chinese medicines as a sedative, tonic, laxative, and emetic. In our continuing research of the bioactive metabolites from mulberry, chemical analysis of the fruits led to the isolation of five compounds, 1-5. The compounds were identified as butyl pyroglutamate (1), quercetin 3-O-β-d-glucoside (2), kaempferol 3-O-β-d-rutinoside (3), rutin (4), and 2-phenylethyl d-rutinoside (5) by spectroscopic data analysis, comparing their nuclear magnetic resonance (NMR) data with those in published literature, and liquid chromatography-mass spectrometry analysis. The isolated compounds 1-5 were evaluated for their effects on anticancer drug-induced side effects by cell-based assays. Compound 1 exerted the highest protective effect against cisplatin-induced kidney cell damage. This effect was found to be mediated through the attenuation of phosphorylation of c-Jun N-terminal kinase, extracellular signal-regulated kinase, p38, mitogen-activated protein kinase, and caspase-3 in cisplatin-induced kidney cell damage.

PMID: 29642519 [PubMed - in process]

Utility of spherical human liver microtissues for prediction of clinical drug-induced liver injury.

Arch Toxicol. 2017 Aug;91(8):2849-2863

Authors: Proctor WR, Foster AJ, Vogt J, Summers C, Middleton B, Pilling MA, Shienson D, Kijanska M, Ströbel S, Kelm JM, Morgan P, Messner S, Williams D

Abstract
Drug-induced liver injury (DILI) continues to be a major source of clinical attrition, precautionary warnings, and post-market withdrawal of drugs. Accordingly, there is a need for more predictive tools to assess hepatotoxicity risk in drug discovery. Three-dimensional (3D) spheroid hepatic cultures have emerged as promising tools to assess mechanisms of hepatotoxicity, as they demonstrate enhanced liver phenotype, metabolic activity, and stability in culture not attainable with conventional two-dimensional hepatic models. Increased sensitivity of these models to drug-induced cytotoxicity has been demonstrated with relatively small panels of hepatotoxicants. However, a comprehensive evaluation of these models is lacking. Here, the predictive value of 3D human liver microtissues (hLiMT) to identify known hepatotoxicants using a panel of 110 drugs with and without clinical DILI has been assessed in comparison to plated two-dimensional primary human hepatocytes (PHH). Compounds were treated long-term (14 days) in hLiMT and acutely (2 days) in PHH to assess drug-induced cytotoxicity over an 8-point concentration range to generate IC50 values. Regardless of comparing IC50 values or exposure-corrected margin of safety values, hLiMT demonstrated increased sensitivity in identifying known hepatotoxicants than PHH, while specificity was consistent across both assays. In addition, hLiMT out performed PHH in correctly classifying hepatotoxicants from different pharmacological classes of molecules. The hLiMT demonstrated sufficient capability to warrant exploratory liver injury biomarker investigation (miR-122, HMGB1, α-GST) in the cell-culture media. Taken together, this study represents the most comprehensive evaluation of 3D spheroid hepatic cultures up to now and supports their utility for hepatotoxicity risk assessment in drug discovery.

PMID: 28612260 [PubMed - indexed for MEDLINE]

Editorial.

Rev Med Brux. 2016;37(6):459

Authors: Berghmans T

PMID: 28525172 [PubMed - indexed for MEDLINE]

Treatment of giant-cell arteritis, a literature review.

Mod Rheumatol. 2017 Sep;27(5):747-754

Authors: Watelet B, Samson M, de Boysson H, Bienvenu B

Abstract
Giant-cell arteritis (GCA) is the most common vasculitis in people aged more than 50 years. Despite the frequency of this disease, there is currently no international consensus on its therapeutic modalities. The aim of this study was to conduct a review on an international literature about the treatment of GCA, whatever the clinical pattern might be. Oral corticosteroids remain the cornerstone treatment, possibly preceded by intravenous bolus in complicated forms. In cases of glucocorticoid (GC) dependence or GC-related side effects, a GC-sparing agent may be necessary. Methotrexate is one of the most used treatments despite its low level of evidence and mild efficacy. Cyclophosphamide and tocilizumab look promising but require validation in further studies. The results for TNF-α blockers and azathioprine are disappointing. Preventing complications of prolonged corticosteroid therapy is a world challenge and the management of GC-induced osteoporosis is not the same from one country to another. There is a significant risk of arterial thrombosis, mainly at treatment onset, which may encourage to associate an antiplatelet therapy, especially in patients with other cardiovascular risk factors. Place of statins in the treatment of the disease is uncertain.

PMID: 27919193 [PubMed - indexed for MEDLINE]

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2018/04/11

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

13 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2018/04/10

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2018/04/10

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

DPD functional tests in plasma, fresh saliva and dried saliva samples as predictors of 5-fluorouracil exposure and occurrence of drug-related severe toxicity.

Clin Biochem. 2018 Apr 03;:

Authors: Neto OV, Raymundo S, Franzoi MA, do Carmo Artmann A, Tegner M, Müller VV, Hahn RZ, Alves GV, Schwartsmann G, Linden R, Antunes MV

Abstract
OBJECTIVE: to evaluate plasma and salivary uracil (U) to dihydrouracil (UH2) ratios as tools for predicting 5-fluorouracil systemic exposure and drug-related severe toxicity, and clinically validate the use of dried saliva spots (DSS) as an alternative sampling strategy for dihydropyrimidine dehydrogenase (DPD) deficiency assessment.
METHODS: Pre-chemotherapy plasma, fresh saliva and DSS samples were obtained from gastrointestinal patients (N = 40) for measurement of endogenous U and UH2 concentrations by LC-MS/MS. A second plasma sample collected during 5FU infusion was used for 5FU area under the curve (AUC) determination by HPLC-DAD. Data on toxicity was reported according to CTCAE.
RESULTS: 15% of the patients developed severe 5FU-related toxicity, with neutropenia accounting for 67% of the cases. U, UH2 and [UH2,]/[U] were highly correlated between fresh and dried saliva samples (rs = 0.960; rs = 0.828; rs = 0.910, respectively). 5FU AUC ranged from 11.3 to 37.31 mg h L-1, with 46.2% of under-dosed and 10.3% over-dosed patients. The [UH2]/[U] ratios in plasma, fresh saliva and dried saliva samples were moderately correlated with 5FU AUC and adverse events grade, indicating a partial contribution of the variables to drug exposure (r = -0.412, rs = -0.373, rs = 0.377) and toxicity (r = -0.363, rs = -0.523, rs = 0.542). Metabolic ratios were lower in patients with severe toxicity (P < .01 salivary ratios, and P < .5 plasma ratios), and 5FU AUC were in average 47% higher in this group than in moderate toxicity. The diagnostic performance of [UH2]/[U] ratios in fresh saliva and DSS for the identification of patients with severe toxicity were comparable.
CONCLUSIONS: The [UH2]/[U] metabolic ratios in plasma, fresh saliva and DSS were significantly associated with 5FU systemic exposure and toxicity degree. This study also demonstrated the applicability of DSS as alternative sampling for evaluating DPD activity.

PMID: 29625079 [PubMed - as supplied by publisher]

Trabectedin plus pegylated liposomal doxorubicin (PLD) for patients with platinum-sensitive recurrent ovarian cancer: a prospective, observational, multicenter study.

J Cancer Res Clin Oncol. 2018 Apr 06;:

Authors: Runnebaum IB, Reichert D, Ringsdorf U, Kuther M, Hesse T, Sehouli J, Wimberger P

Abstract
PURPOSE: The OVA-YOND study is the first prospective, non-interventional trial designed to evaluate trabectedin (1.1 mg/m2) plus PLD (30 mg/m2) in patients with platinum-sensitive recurrent ovarian cancer (ROC), given according to the marketing authorization in real-life clinical practice across Germany.
METHODS: Eligible patients were adults with platinum-sensitive ROC, pretreated with ≥ 1 platinum-containing regimen/s. The primary endpoint was to assess safety/tolerability of the combination.
RESULTS: Seventy-seven patients with platinum-sensitive relapse from 31 sites were evaluated. Patients received a median of 6 cycles (range 1-21) with 39 patients (50.6%) receiving ≥ 6 cycles. Median treatment duration was 4.2 months (range 0.7-18.8), mostly on an outpatient basis (88.3% of patients). Most common grade 3/4 trabectedin-related adverse events (AEs) were leukopenia (18.2%), neutropenia (15.6%), thrombocytopenia (9.1%), alanine (7.8%) and aspartate aminotransferase (6.5%) increase, and nausea/vomiting (5.2% each). Neutropenia (18.2%), leukopenia (15.6%), thrombocytopenia (10.4%), and nausea/vomiting (5.2% each) were the most frequent grade 3/4 PLD-related AEs. No deaths attributed to drug-related AEs or unexpected AEs occurred. Five patients (6.5%) had a complete response and 19 patients (24.7%) achieved a partial response for an objective response rate of 31.2% with median response duration of 6.25 months. Sixteen patients (20.8%) had disease stabilization for a disease control rate of 51.9%. Median progression-free survival was 6.3 months and median overall survival was 16.4 months.
CONCLUSION: Trabectedin plus PLD confer clinically meaningful benefit to pre-treated patients with platinum-sensitive ROC, being comparable to those previously observed in selected populations from clinical trials and with a manageable safety profile.

PMID: 29623421 [PubMed - as supplied by publisher]

Does high-dose benzodiazepine abuse really produce liver toxicity? Results from a series of 201 benzodiazepine monoabusers.

Expert Opin Drug Saf. 2018 Apr 06;:1-6

Authors: Lugoboni F, Mirijello A, Morbioli L, Arzenton E, Leone R, Faccini M, Casari R, De Cosmo S, Gasbarrini A, Addolorato G

Abstract
BACKGROUND: Several side-effects related to prolonged benzodiazepines (BZD) use have been reported. Given the primary role of liver in BZD metabolism, toxicity related to prolonged high-dose BZD use could be conceivable. No data are available on the long-term impact of high-dose BZD use on liver.
RESEARCH DESIGN AND METHODS: A total of 201 BZD mono-abusers admitted to an Addiction Unit for detoxification were evaluated. Liver enzymes were evaluated at admission, before starting any treatment. An elevation of more than five times the upper limit of normal range (ULN) in serum ALT or conjugated bilirubin, or a combined elevation of AST, alkaline phosphatase and total bilirubin, one of which exceeding >2 the ULN, was considered diagnostic for drug-induced liver injury.
RESULTS: None of the evaluated subjects showed significant alterations of liver enzymes. Those with the highest transaminase levels were showing high body mass index. Twenty patients (10%) showed elevated gamma-glutamyl-transferase. No alteration of alkaline phosphatase, nor bilirubin was found in any patient. The average dosage of BZD was 307 mg of diazepam-equivalents for 7 years.
CONCLUSIONS: Present data suggest that prolonged use of high-dose BZD, although very dangerous for several reasons, does not seem to produce a significant drug-induced liver injury.

PMID: 29621907 [PubMed - as supplied by publisher]

Managing Cancer Pain in Older Adults.

Cancer J. 2017 Jul/Aug;23(4):242-245

Authors: Guerard EJ, Cleary JF

Abstract
Managing cancer pain in older adults can be complex and challenging. Understanding the unique needs of older patients with cancer is important to safe and effective pain management. The goals of this review are to discuss the assessment of older adults with cancer-related pain, treatment of cancer pain, and adverse effects or potential risks from treatment that are unique to older patients. A detailed pain assessment and when possible utilizing the geriatric assessment are vital to developing a cancer pain management plan. The geriatric assessment can help clinicians uncover problems not routinely assessed in the standard oncologic evaluation. Opioid pain medications are safe and effective for older adults with cancer pain as long as these medications are closely monitored and titrated slowly. In addition to the well-known adverse effects of opioid medications, clinicians need to be aware of the unique risks in older adults, which could include delirium, polypharmacy, and falls.

PMID: 28731948 [PubMed - indexed for MEDLINE]

The Impact of Polypharmacy on Patient Outcomes in Older Adults With Cancer.

Cancer J. 2017 Jul/Aug;23(4):211-218

Authors: Nightingale G, Skonecki E, Boparai MK

Abstract
Polypharmacy is prevalent in older adults with cancer and may be advantageous for the management of certain chronic disease states, but uncertainty exists regarding potential hazards and consequences. Cancer-related therapy adds to the prevalence of polypharmacy, which can lead to compromised cancer management plans (i.e., postoperative complications, treatment delays, and/or premature treatment discontinuation). Polypharmacy has been identified as one of the domains commonly included in the Comprehensive Geriatric Assessment likely because of the potential influence on health outcomes. This review summarizes existing evidence regarding health outcomes associated with polypharmacy in older adults with cancer. Preliminary evidence demonstrated that relationships exist between polypharmacy and health outcomes including adverse drug events, falls, frailty, hospitalization, postoperative complications, and mortality. This research is limited by study confounders, inconsistent definitions for polypharmacy, heterogeneous cancer types and stages, and the complex relationship between medication regimens and outcomes. Additional studies are needed to enhance the accuracy and replicability of this research.

PMID: 28731943 [PubMed - indexed for MEDLINE]

Points to Consider in Designing and Conducting Juvenile Toxicology Studies.

Int J Toxicol. 2017 Jul/Aug;36(4):325-339

Authors: Kim NN, Parker RM, Weinbauer GF, Remick AK, Steinbach T

Abstract
In support of a clinical trial in the pediatric population, available nonclinical and clinical data provide input on the study design and safety monitoring considerations. When the existing data are lacking to support the safety of the planned pediatric clinical trial, a juvenile animal toxicity study is likely required. Usually a single relevant species, preferably a rodent, is chosen as the species of choice, while a nonrodent species can be appropriate when scientifically justified. Juvenile toxicology studies, in general, are complicated both conceptually and logistically. Development in young animals is a continuous process with different organs maturing at different rates and time. Structural and functional maturational differences have been shown to affect drug safety. Key points to consider in conducting a juvenile toxicology study include a comparative development of the organ systems, differences in the pharmacokinetics/absorption, distribution, metabolism, excretion (PK/ADME) profiles of the drug between young animal and child, and logistical requirement in the juvenile study design. The purpose of this publication is to note pertinent points to consider when designing and conducting juvenile toxicology studies and to aid in future modifications and enhancements of these studies to enable a superior predictability of safety of medicines in the pediatric population.

PMID: 28466670 [PubMed - indexed for MEDLINE]

Minocycline hepatotoxicity: Clinical characterization and identification of HLA-B∗35:02 as a risk factor.

J Hepatol. 2017 Jul;67(1):137-144

Authors: Urban TJ, Nicoletti P, Chalasani N, Serrano J, Stolz A, Daly AK, Aithal GP, Dillon J, Navarro V, Odin J, Barnhart H, Ostrov D, Long N, Cirulli ET, Watkins PB, Fontana RJ, Drug-Induced Liver Injury Network (DILIN), Pharmacogenetics of Drug-Induced Liver Injury group (DILIGEN), International Serious Adverse Events Consortium (iSAEC)

Abstract
BACKGROUND & AIMS: Minocycline hepatotoxicity can present with prominent autoimmune features in previously healthy individuals. The aim of this study was to identify genetic determinants of minocycline drug-induced liver injury (DILI) in a well-phenotyped cohort of patients.
METHODS: Caucasian patients with minocycline DILI underwent genome-wide genotyping and were compared to unexposed population controls. Human leukocyte antigen (HLA) binding of minocycline was assessed using AutoDock Vina.
RESULTS: Among the 25 cases, 80% were female, median age was 19years and median latency from drug start to DILI onset was 318days. At presentation, 76% had acute hepatocellular liver injury, median ALT 1,077U/L (range: 63 to 2,333), median bilirubin 4.5mg/dl (range: 0.2 to 16.7), and 90% had a +ANA. During follow-up, 50% were treated with corticosteroids and no participants died or required a liver transplant. A significant association was noted between HLA-B∗35:02 and risk for minocycline DILI; a 16% carrier frequency in DILI cases compared to 0.6% in population controls (odds ratio: 29.6, 95% CI: 7.8-89.8, p=2.5×10-8). Verification of HLA-B∗35:02 imputation was confirmed by sequence-based HLA typing. HLA-B∗35:02 carriers had similar presenting features and outcomes compared to non-carriers. In silico modeling studies support the hypothesis that direct binding of minocycline to this novel HLA risk allele might be an important initiating event in minocycline DILI.
CONCLUSION: HLA-B∗35:02 is a rare HLA allele that was more frequently identified in the 25 minocycline DILI cases compared to population controls. If confirmed in other cohorts, this HLA allele may prove to be a useful diagnostic marker of minocycline DILI.
LAY SUMMARY: Development of liver injury following prolonged use of minocycline for acne is a rare but potentially severe form of drug-induced liver injury. Our study demonstrates that individuals who are HLA-B∗35:02 carriers are at increased risk of developing minocycline related liver injury. These results may help doctors more rapidly and confidently diagnose affected patients and possibly reduce the risk of liver injury in individuals receiving minocycline going forward.

PMID: 28323125 [PubMed - indexed for MEDLINE]

Proper Management of Medications to Limit Errors: What the Oral Surgeon Should Know to Limit Medication Errors and Adverse Drug Events.

Oral Maxillofac Surg Clin North Am. 2017 May;29(2):141-149

Authors: Sarasin DS, Mauer JE

Abstract
Providing safe and effective ambulatory anesthesia is a key component in delivering optimal care to oral and maxillofacial patients. Unfortunately, medication errors and adverse drug events (ADEs) occur in offices, as they do in hospital operating rooms. Preparing and delivering medication seems simple. In reality, this is a complex process with multiple opportunities for drug errors leading to actual or potential ADEs. This article reviews medication errors and ADEs, introduces a medication safety paradigm for oral and maxillofacial surgery facilities, and provides practical safety initiatives that can be implemented to achieve the goal of optimal anesthesia patient care and safety.

PMID: 28259386 [PubMed - indexed for MEDLINE]

Daikenchuto for reducing postoperative ileus in patients undergoing elective abdominal surgery.

Cochrane Database Syst Rev. 2018 Apr 05;4:CD012271

Authors: Hoshino N, Takada T, Hida K, Hasegawa S, Furukawa TA, Sakai Y

Abstract
BACKGROUND: Postoperative ileus is a major complication for persons undergoing abdominal surgery. Daikenchuto, a Japanese traditional medicine (Kampo), is a drug that may reduce postoperative ileus.
OBJECTIVES: To assess the efficacy and safety of Daikenchuto for reducing prolonged postoperative ileus in persons undergoing elective abdominal surgery.
SEARCH METHODS: We searched the following databases on 3 July 2017: CENTRAL, MEDLINE, Embase, ICHUSHI, WHO (World Health Organization) International Clinical Trials Registry Platform (ICTRP), EU Crinical Trials registry (EU-CTR), UMIN Clinical Trials Registry (UMIN-CTR), ClinicalTrials.gov, The Japan Society for Oriental Medicine (JSOM), American Society of Clinical Oncology (ASCO), Society of American Gastrointestinal and Endscopic Surgeons (SAGES). We set no limitations on language or date of publication.
SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing Daikenchuto with any control condition in adults, 18 years of age or older, undergoing elective abdominal surgery.
DATA COLLECTION AND ANALYSIS: We applied standard methodological procedures expected by Cochrane. Two review authors independently reviewed the articles identified by literature searches, extracted data, and assessed risk of bias of the included studies using the Cochrane software Review Manager 5.
MAIN RESULTS: We included seven RCTs with a total of 1202 participants. Overall, we judged the risk of bias as low in four studies and high in three studies. We are uncertain whether Daikenchuto reduced time to first flatus (mean difference (MD) -11.32 hours, 95% confidence interval (CI) -17.45 to -5.19; two RCTs, 83 participants; very low-quality evidence), or time to first bowel movement (MD -9.44 hours, 95% CI -22.22 to 3.35; four RCTs, 500 participants; very low-quality evidence) following surgery. There was little or no difference in time to resumption of regular solid food following surgery (MD 3.64 hours, 95% CI -24.45 to 31.74; two RCTs, 258 participants; low-quality evidence). There were no adverse events in either arm of the five RCTs that reported on drug-related adverse events (risk difference (RD) 0.00, 95% CI -0.02 to 0.02, 568 participants, low-quality evidence). We are uncertain of the effect of Daikenchuto on patient satisfaction (MD 0.09, 95% CI -0.19 to 0.37; one RCT, 81 participants; very low-quality of evidence). There was little or no difference in the incidence of any re-interventions for postoperative ileus before leaving hospital (risk ratio (RR) 0.99, 95% CI 0.06 to 15.62; one RCT, 207 participants; moderate-quality evidence), or length of hospital stay (MD -0.49 days, 95% CI -1.21 to 0.22; three RCTs, 292 participants; low-quality evidence).
AUTHORS' CONCLUSIONS: Evidence from current literature was unclear whether Daikenchuto reduced postoperative ileus in patients undergoing elective abdominal surgery, due to the small number of participants in the meta-analyses. Very low-quality evidence means we are uncertain whether Daikenchuto improved postoperative flatus or bowel movement. Further well-designed and adequately powered studies are needed to assess the efficacy of Daikenchuto.

PMID: 29619778 [PubMed - as supplied by publisher]

Type B adverse drug reactions reported by an immunoallergology department.

Pharm Pract (Granada). 2018 Jan-Mar;16(1):1070

Authors: Costa MJ, Herdeiro MT, Polónia JJ, Ribeiro-Vaz I, Botelho C, Castro E, Cernadas J

Abstract
Objective: Characterization of the adverse drug reactions (ADR) reported by the immunoallergology department (IAD), Centro Hospitalar de São João (Porto), to the Northern Pharmacovigilance Centre (NPC).
Methods: An observational, descriptive and retrospective study was conducted, based in a spontaneous report system. Participants were all the patients from the IAD, with suspected ADR, reported to NPC by specialists after the study was completed.
Results: Studied population had a median age of 41 years, with the predominance of the female gender (73.2%). Allergic rhinitis and asthma were the most frequent comorbidities. All studied ADR were type B, 89.6% were serious, 86.4% unexpected and 2.6% associated with drugs that presented less than 2 years in the market. The most represented drug classes were the non-steroidal anti-inflammatory drugs (NSAIDs) (52.6%) and antibiotics (25.2%). Skin symptoms represented 61.2% of the reported complaints. About 52.9% of these ADR occurred in less than one hour after intake. The most frequent ADR treatment at the time of the reaction was drug interruption (86.2%), followed by the prescription of anti-histamines (42.2%).
Conclusions: Reported ADR to NPC by the Drug Alert Unit were mainly serious, unexpected, associated with NSAIDs and antibiotics and related with marketing authorization medicines older than two years. These results could be very useful to develop strategies to prevent the clinical and economic consequences of ADR.

PMID: 29619134 [PubMed]

Cost-effectiveness of cladribine tablets, alemtuzumab and natalizumab in the treatment of relapsing-remitting multiple sclerosis with high disease activity in England.

J Med Econ. 2018 Apr 05;:1-23

Authors: Hettle R, Harty G, Wong SL

Abstract
AIMS: Cladribine tablets is the first oral short-course treatment approved for highly active relapsing multiple sclerosis (MS). The Association of British Neurologists guidelines currently recommend two infusion therapies, alemtuzumab and natalizumab, to treat high disease activity relapsing remitting MS (HDA-RRMS). This analysis assessed the cost-effectiveness of cladribine tablets in HDA-RRMS compared with alemtuzumab and natalizumab, from the perspective of the National Health Service (NHS) in England.
MATERIALS AND METHODS: A cohort-based Markov model with 11 health states (10 Expanded Disability Status Scale [EDSS] plus death) was developed. Transition matrices from the British Columbia registry were used to model the natural history of EDSS. Treatment effect on EDSS was modelled using hazard ratios for 6-month confirmed disability progression from an indirect treatment comparison (ITC). Relapses and drug-related adverse events were modelled via annualized relapse rates and event probabilities, with associated costs and quality-adjusted life year (QALY) losses. Utilities were derived from trials and the literature, and costs from NHS and literature sources. Uncertainty was assessed via probabilistic and deterministic sensitivity analyses.
RESULTS: Cladribine tablets was dominant (i.e., less costly and more effective) versus alemtuzumab and natalizumab in pairwise comparisons, and the dominant strategy in fully incremental analyses. Incremental cost was driven largely by drug acquisition and administration costs, and incremental QALY gain largely by differences in delayed EDSS progression. Cladribine tablets had a 93% probability of being cost-effective at a threshold of GBP 30,000 per QALY gained, and remained dominant across the scenario analyses tested. The greatest influence on results was the treatment effect on disability progression derived from the ITC.
LIMITATIONS: Uncertainty over the efficacy of DMT beyond trial durations. In line with other comparative effectiveness analyses, the network meta-analysis informing this cost-effectiveness analysis was associated with a degree of uncertainty. No treatment switching analyses were undertaken.
CONCLUSIONS: Cladribine tablets are a cost-effective alternative to alemtuzumab and natalizumab in the treatment of HDA-RRMS from the perspective of the NHS in England.

PMID: 29618273 [PubMed - as supplied by publisher]

Drug evaluation studies in neonates: how to overcome the current limitations.

Expert Rev Clin Pharmacol. 2018 Apr;11(4):387-396

Authors: Allegaert K, Smits A, van den Anker JN

Abstract
INTRODUCTION: Regulatory initiatives have stimulated drug research in infants, but the potential impact of drugs to improve health outcome in neonates remains underexplored. Areas covered: In this review, we focus on current limitations in drug evaluation studies and how to overcome these. The low volume of studies has additional weaknesses such as single center studies, non-commercial sponsorship, overrepresentation of high postulated risk reductions, and underrepresentation of therapeutic exploratory studies. Master protocols and selection criteria for neonatal centers to participate in studies are useful to improve logistics related to performance. Limitations also relate to inaccurate assessment of drug effects (efficacy/safety). This is because of poor symptom recognition, case definitions, and suboptimal data on adverse drug reactions (ADRs) epidemiology. To overcome these limitations, it is necessary to develop core outcome sets, reference values, and specific ADR tools. The limitations identified and approaches suggested to improve drug evaluation are illustrated using neonatal abstinence syndrome as an example. Expert commentary: We anticipate to see an evolving neonatal clinical pharmacology discipline driven by neonatal pathophysiology and knowledge. Multidisciplinary collaborative efforts between health care providers, academia, pharmaceutical industry, advocacy groups and regulatory agencies are crucial to improve the impact of drug evaluation studies in neonates.

PMID: 29421929 [PubMed - indexed for MEDLINE]

[The clinical analysis of frontline nilotinib vs imatinib therapies for newly diagnosed chronic myeloid leukemia in chronic phase].

Zhonghua Nei Ke Za Zhi. 2017 Nov 01;56(11):810-815

Authors: Yin H, Chen LF, Cui JK, Xiong YY, You Y, Zou P, Li WM

Abstract
Objective: To compare the clinical efficacy and safety of nilotinib and imatinib as frontline therapy in newly diagnosed patients with chronic myeloid leukemia in chronic phase(CML-CP). Methods: Until December 31st 2016, 18 patients using nilotinib and 83 using imatinib were recruited in our study. The efficacy and safety of two groups were evaluated. Results: A total of 101 patients with CML-CP included 18 receiving nilotinib and 83 imatinib. The optimal response rates at 3, 6, 12 and 18 months in nilotinib and imatinib group were 88.9% (16/18) vs 57.3% (47/82) (P=0.012), 82.4% (14/17) vs 55.7% (44/79) (P=0.041), 9/12 vs 63.9% (39/61) (P=0.460), 6/9 vs 68.9% (31/45) (P=0.896) respectively. The optimal response rates by 3 months in low sokal risk group on nilotinib and imatinib were 9/9 vs 76.5%(26/34) (P=0.107), in intermediate and high sokal risk group were 7/8 vs 45.2%(14/31) (P=0.032). At the end of follow-up, the rate of major molecular response (MMR) in nilotinib group was 72.2%, which was higher than 56.6% in imatinib group (P=0.021). The rate of complete cytogenetic response (CCyR) in nilotinib group was 100%, which was higher than 71.1% in imatinib group (P = 0.002). Progression free survival (PFS) rates in nilotinib and imatinib groups were 94.4% and 98.8% (P=0.019) respectively; whereas event free survival (EFS) rates were 88.9% and 48.2% (P=0.045). The incidence of drug related adverse reactions in nilotinib and imatinib was similar with only minor proportion of grade 3/4 adverse reactions. Conclusions: Nilotinib achieves a deeper molecular response in a shorter time than imatinib in newly diagnosed patients with CML-CP, especially in patients with high risk outcome. Good safety is obtained in both groups so as to ensure a long-term administration and improving prognosis.

PMID: 29136709 [PubMed - indexed for MEDLINE]