19 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 2017/10/31

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.

Doxorubicin effect is enhanced by sphingosine-1-phosphate signaling antagonist in breast cancer.

J Surg Res. 2017 Nov;219:202-213

Authors: Katsuta E, Yan L, Nagahashi M, Raza A, Sturgill JL, Lyon DE, Rashid OM, Hait NC, Takabe K

Abstract
BACKGROUND: Doxorubicin is one of the most commonly used chemotherapeutic drugs for breast cancer; however, its use is limited by drug resistance and side effects. We hypothesized that adding FTY720, a sphingosine-1-phosphate (S1P) receptor functional antagonist, to doxorubicin would potentiate its effects by suppression of drug-induced inflammation.
MATERIALS AND METHODS: The Cancer Genome Atlas, Gene Expression Omnibus data sets, and National Cancer Institute-60 panel were used for gene expressions and gene set enrichment analysis. E0771 syngeneic mammary tumor cells were used. OB/OB mice fed with western high-fat diet were used as an obesity model.
RESULTS: STAT3 expression was significantly increased after doxorubicin treatment in human breast cancer that implicates that doxorubicin evokes inflammation. Expression of sphingosine kinase 1, the enzyme that produces S1P and links inflammation and cancer, tended to be higher in doxorubicin-resistant human cancer and cell lines. In a murine breast cancer model, sphingosine kinase 1, S1P receptor 1, interleukin 6, and STAT3 were overexpressed in the doxorubicin-treated group, whereas all of them were significantly suppressed with addition of FTY720. Combination therapy synergistically suppressed cancer growth both in vitro and in vivo. Furthermore, combination therapy showed higher efficacy in an obesity breast cancer model, where high body mass index demonstrated trends toward worse disease-free and overall survival, and high-serum S1P levels in human patients and volunteers.
CONCLUSIONS: We found that FTY720 enhanced the efficacy of doxorubicin by suppression of drug-induced inflammation, and combination therapy showed stronger effect in obesity-related breast cancer.

PMID: 29078883 [PubMed - in process]

[Secukinumab-induced subacute-cutaneous lupus erythematosus].

Hautarzt. 2017 Oct 26;:

Authors: Wehrmann C, Sondermann W, Körber A

Abstract
We report about a 52-year-old woman with onset of drug-induced lupus erythematosus (DILE) in sun-exposed areas, under therapy with secukinumab. Topical therapy with a steroid class 3 for 4 weeks showed substantial improvement. The systemic therapy was switched to ustekinumab. DILE is a rare but notable side effect of biologicals in 0.5-1% of the patients and also possible under therapy with IL-17 inhibition. Switch of the biological agent is necessary in most cases.

PMID: 29075868 [PubMed - as supplied by publisher]

An open-label study to assess the feasibility and tolerability of rilmenidine for the treatment of Huntington's disease.

J Neurol. 2017 Oct 26;:

Authors: Underwood BR, Green-Thompson ZW, Pugh PJ, Lazic SE, Mason SL, Griffin J, Jones PS, Rowe JB, Rubinsztein DC, Barker RA

Abstract
Preclinical data have shown that rilmenidine can regulate autophagy in models of Huntington's disease (HD), providing a potential route to alter the disease course in patients. Consequently, a 2-year open-label study examining the tolerability and feasibility of rilmenidine in mild-moderate HD was undertaken. 18 non-demented patients with mild to moderate HD took daily doses of 1 mg Rilmenidine for 6 months and 2 mg for a further 18 months followed by a 3-month washout period. The primary outcome was the number of withdrawals and serious adverse events. Secondary outcomes included safety parameters and changes in disease-specific variables, such as motor, cognitive and functional performance, structural MRI and serum metabolomic analysis. 12 patients completed the study; reasons for withdrawal included problems tolerating study procedures (MRI, and venepuncture), depression requiring hospital admission and logistical reasons. Three serious adverse events were recorded, including hospitalisation for depression, but none were thought to be drug-related. Changes in secondary outcomes were analysed as the annual rate of change in the study group. The overall change was comparable to changes seen in recent large observational studies in HD patients, though direct statistical comparisons to these studies were not made. Chronic oral administration of rilmenidine is feasible and well-tolerated and future, larger, placebo-controlled, studies in HD are warranted.
TRIAL REGISTRATION: EudraCT number 2009-018119-14.

PMID: 29075837 [PubMed - as supplied by publisher]

Assessment of drug therapy problems among patients with cervical cancer at Kenyatta National Hospital, Kenya.

Gynecol Oncol Res Pract. 2017;4:15

Authors: Degu A, Njogu P, Weru I, Karimi P

Abstract
BACKGROUND: Although cervical cancer is preventable, it is still the second leading cause of cancer deaths among women in the world. Further, it is estimated that around 5-10% of hospital admissions are due to drug related problems (DRPs), of which 50% are avoidable. In cancer therapy, there is an immense potential for DRPs due to the high toxicity of most chemotherapeutic regimens. Hence, this study sought to assess DRPs among patients with cervical cancer at Kenyatta National Hospital (KNH).
METHODS: A cross-sectional study was conducted at the oncology units of KNH. A total of 81 study participants were recruited through simple random sampling. Data were collected from medical records and interviewing patients. The appropriateness of medical therapy was evaluated by comparing with National Compressive Cancer Network and European Society for Medical Oncology practice guideline of cervical cancer treatment protocol. The degree of adherence was determined using eight-item Morisky medication adherence scale. The likelihood of drug interaction was assessed using Medscape, Micromedex and Epocrates drug interaction checkers. The data were entered in Microsoft Excel and analysed using statistical software STATA version 13.0. Descriptive statistics such as mean, percent and frequency were used to summarise patients' characteristics. Univariable and multivariable binary logistic regression were used to investigate the potential predictors of DRPs.
RESULT: A total of 215 DRPs were identified from 76 patients, translating to a prevalence of 93.8% and a mean of 2.65 ± 1.22 DRPs. The predominant proportion of DRPs (48.2%) was identified in patients who had been treated with chemoradiation regimens. Adverse drug reactions 56(69.1%) and drug interactions 38(46.9%) were the most prevalent DRPs. Majority (67.9%) of the study population were adherent to their treatment regimens. Forgetfulness 18(69.2%), expensive medications 4(15.4%) and side effects of medications 4(15.4%) were the main reasons for medication non-adherence. Patients with advanced stage cervical cancer were 15.4 times (AOR = 15.4, 95% CI = 1.3-185.87, p = 0.031) more likely to have DRPs as compared to patients with early stage disease.
CONCLUSION: Adverse drug reactions, drug interactions, and need of additional drug therapy were the most common DRPs identified among cervical cancer patients. Advanced stage cervical cancer was the only predictor of DRPs.

PMID: 29075505 [PubMed]

A Data-Driven Approach to Predicting Successes and Failures of Clinical Trials.

Cell Chem Biol. 2016 Oct 20;23(10):1294-1301

Authors: Gayvert KM, Madhukar NS, Elemento O

Abstract
Over the past decade, the rate of drug attrition due to clinical trial failures has risen substantially. Unfortunately it is difficult to identify compounds that have unfavorable toxicity properties before conducting clinical trials. Inspired by the effective use of sabermetrics in predicting successful baseball players, we sought to use a similar "moneyball" approach that analyzes overlooked features to predict clinical toxicity. We introduce a new data-driven approach (PrOCTOR) that directly predicts the likelihood of toxicity in clinical trials. PrOCTOR integrates the properties of a compound's targets and its structure to provide a new measure, the PrOCTOR score. Drug target network connectivity and expression levels, along with molecular weight, were identified as important indicators of adverse clinical events. Our method provides a data-driven, broadly applicable strategy to identify drugs likely to possess manageable toxicity in clinical trials and will help drive the design of therapeutic agents with less toxicity.

PMID: 27642066 [PubMed - indexed for MEDLINE]

12 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 2017/10/27

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.

Comparison of capecitabine and oxaliplatin with S-1 as adjuvant chemotherapy in stage III gastric cancer after D2 gastrectomy.

PLoS One. 2017;12(10):e0186362

Authors: Cho JH, Lim JY, Cho JY

Abstract
AIM: To compare capecitabine and oxaliplatin (XELOX) with S-1 as adjuvant chemotherapy in stage III gastric cancer after D2 gastrectomy.
METHODS: Clinical data from 206 patients who received XELOX or S-1 regimens as adjuvant chemotherapy in stage III gastric cancer were collected. Patients were divided into 2 groups according to regimen; the groups were XELOX (n = 114) and S-1 monotherapy (n = 92).
RESULTS: 3-year disease-free survival (DFS) was higher in the S-1 group than in the XELOX group (66.6% vs 59.1%; p = 0.636). 3-year overall survival (OS) was 75.6% in the S-1 group and 69.6% in the XELOX group (p = 0.495). But, the difference was not statistically significant. Especially, for patients with stage IIIC disease, 3-year overall survival was 55.2% in the XELOX group and 39.0% in the S-1 group (hazard ratio, HR 0.50, 95% confidence interval, CI 0.23-1.10; p = 0.075). In multivariate analysis, N stage (HR, 5.639; 95% CI, 1.297-24.522; p = 0.021) and cycle completion as planned (HR, 5.734; 95% CI, 3.007-10.936; p<0.001) were independent predictors of overall survival.
CONCLUSION: Adjuvant XELOX and S-1 regimen did not prove anything superior for stage III gastric cancer in this study. But, XELOX had a tendency to be superior to S-1 in stage IIIC gastric cancer after D2 gastrectomy although the difference was not statistically significant. N stage and cycle completion as planned were prognostic factors.

PMID: 29040299 [PubMed - indexed for MEDLINE]

Safety of Quadrivalent Meningococcal Conjugate Vaccine in Children 2-10 Years.

Pediatr Infect Dis J. 2017 Nov;36(11):1087-1092

Authors: Tartof SY, Sy LS, Ackerson BK, Hechter RC, Haag M, Slezak JM, Luo Y, Fischetti CA, Takhar HS, Miao Y, Solano Z, Jacobsen SJ, Tseng HF

Abstract
BACKGROUND: Quadrivalent meningococcal conjugate vaccine is recommended for children, adolescents and adults at increased risk of meningococcal disease. In 2011, MenACWY-CRM (Menveo, GSK, Siena, Italy) was approved for children 2-10 years of age in the United States. Although no safety concerns arose from clinical trials, it remains important to monitor its safety in routine clinical settings.
METHODS: Kaiser Permanente Southern California members 2-10 years old who received MenACWY-CRM between September 2011 and September 2014 were included. Electronic health records were searched using a validated algorithm to identify 26 prespecified events of interests (EOIs) and serious medically attended events (SMAEs) from inpatient or emergency settings up to 1 year after MenACWY-CRM vaccination. SMAEs were categorized by International Classification of Diseases, 9th revision diagnostic categories. All events were reviewed to confirm the diagnosis and symptom onset date. The study was descriptive (NCT01452438); no statistical tests were performed.
RESULTS: Among 387 vaccinated children, 327 with ≥6 months membership before vaccination were analyzed. Among EOIs, 9 asthma cases and 1 myasthenia gravis case underwent chart review which confirmed 1 incident asthma case occurring 237 days after concomitant vaccination with MenACWY-CRM and typhoid vaccine. Thirty-one children experienced SMAEs, most commonly because of unrelated injury and poisoning. The remaining events occurred sporadically after vaccination and most were unlikely related to vaccination based on medical record review.
CONCLUSIONS: One incident EOI of asthma late in the 1-year observation period and sporadic distribution of SMAEs were observed. These data do not suggest safety concerns associated with MenACWY-CRM vaccination in children 2-10 years old.

PMID: 28719502 [PubMed - indexed for MEDLINE]

Tafenoquine for malaria prophylaxis in adults: An integrated safety analysis.

Travel Med Infect Dis. 2017 May - Jun;17:19-27

Authors: Novitt-Moreno A, Ransom J, Dow G, Smith B, Read LT, Toovey S

Abstract
BACKGROUND: Tafenoquine is a new prophylactic antimalarial drug. The current analysis presents an integrated safety assessment of the Tafenoquine Anticipated Clinical Regimen (Tafenoquine ACR) from 5 clinical trials, including 1 conducted in deployed military personnel and 4 in non-deployed residents, which also incorporated placebo and mefloquine comparator groups.
METHODS: Adverse events (AEs) were coded according to the Medical Dictionary for Regulatory Activities (MedDRA(®), Version 15.0) and summarized. Among all subjects who had received the Tafenoquine ACR, safety findings were compared for subjects who were deployed military personnel from the Australian Defence Force (Deployed ADF) versus non-deployed residents (Resident Non-ADF).
RESULTS: The incidence of at least one AE was 80.6%, 64.1%, 67.6% and 94.9% in the mefloquine, placebo, tafenoquine Resident Non-ADF and tafenoquine Deployed ADF groups, respectively. The latter group had a higher incidence of AEs related to military deployment. AEs that occurred at ≥ 1% incidence in both tafenoquine sub-groups and at a higher frequency than placebo included diarrhea, nausea, vomiting, gastroenteritis, nasopharyngeal tract infections, and back/neck pain.
CONCLUSIONS: Weekly administration of tafenoquine for up to six months increased the incidence of gastrointestinal AEs, certain infections, and back/neck pain, but not the overall incidence of AEs versus placebo. CLINICAL TRIAL REGISTRATION NUMBERS/CLINICALTRIALS.
GOV IDENTIFIERS: NCT02491606; NCT02488980; NCT02488902.

PMID: 28495354 [PubMed - indexed for MEDLINE]

Antibody persistence up to 5 y after vaccination with a quadrivalent meningococcal ACWY-tetanus toxoid conjugate vaccine in adolescents.

Hum Vaccin Immunother. 2017 Mar 04;13(3):636-644

Authors: Quiambao BP, Bavdekar A, Dubey AP, Jain H, Kolhe D, Bianco V, Miller JM, Van der Wielen M

Abstract
Long-term protection against meningococcal disease relies on antibody persistence after vaccination. We report antibody persistence up to 5 y after vaccination in adolescents who received a single dose of either meningococcal serogroups A, C, W, Y tetanus toxoid conjugate vaccine (MenACWY-TT, Pfizer) or MenACWY polysaccharide vaccine (MenPS, GSK Vaccines) at the age of 11-17 y in the randomized controlled primary study NCT00464815. In this phase III, open, controlled, multi-center persistence follow-up study conducted in India and the Philippines (NCT00974363), antibody persistence was evaluated by a serum bactericidal antibody assay using rabbit complement (rSBA) yearly, up to year 5 after vaccination. Serious adverse events (SAEs) related to study participation were recorded. Five years after a single dose of MenACWY-TT, the percentage of participants (N = 236) with rSBA titers ≥1:8 was 97.5% for serogroup A, 88.6% for serogroup C, 86.0% for serogroup W and 96.6% for serogroup Y. The percentages in the MenPS group (N = 86) were 93.0%, 87.1%, 34.9% and 66.3%, respectively. Exploratory analysis indicated a higher percentage of subjects with rSBA titers ≥1:8 for serogroups W and Y, and higher rSBA geometric mean antibody titers for serogroups A, W and Y in the MenACWY-TT group than the MenPS group at each time point (years 3, 4 and 5). No differences between groups were observed for serogroup C. No SAEs related to study participation were reported. In conclusion, the results of this follow-up study indicate that antibodies persisted up to 5 y after a single dose of MenACWY-TT in adolescents.

PMID: 28152332 [PubMed - indexed for MEDLINE]

Safety and immunogenicity of GamEvac-Combi, a heterologous VSV- and Ad5-vectored Ebola vaccine: An open phase I/II trial in healthy adults in Russia.

Hum Vaccin Immunother. 2017 Mar 04;13(3):613-620

Authors: Dolzhikova IV, Zubkova OV, Tukhvatulin AI, Dzharullaeva AS, Tukhvatulina NM, Shcheblyakov DV, Shmarov MM, Tokarskaya EA, Simakova YV, Egorova DA, Scherbinin DN, Tutykhina IL, Lysenko AA, Kostarnoy AV, Gancheva PG, Ozharovskaya TA, Belugin BV, Kolobukhina LV, Pantyukhov VB, Syromyatnikova SI, Shatokhina IV, Sizikova TV, Rumyantseva IG, Andrus AF, Boyarskaya NV, Voytyuk AN, Babira VF, Volchikhina SV, Kutaev DA, Bel'skih AN, Zhdanov KV, Zakharenko SM, Borisevich SV, Logunov DY, Naroditsky BS, Gintsburg AL

Abstract
Ebola hemorrhagic fever, also known as Ebola virus disease or EVD, is one of the most dangerous viral diseases in humans and animals. In this open-label, dose-escalation clinical trial, we assessed the safety, side effects, and immunogenicity of a novel, heterologous prime-boost vaccine against Ebola, which was administered in 2 doses to 84 healthy adults of both sexes between 18 and 55 years. The vaccine consists of live-attenuated recombinant vesicular stomatitis virus (VSV) and adenovirus serotype-5 (Ad5) expressing Ebola envelope glycoprotein. The most common adverse event was pain at the injection site, although no serious adverse events were reported. The vaccine did not significantly impact blood, urine, and immune indices. Seroconversion rate was 100 %. Antigen-specific IgG geometric mean titer at day 42 was 3,277 (95 % confidence interval 2,401-4,473) in volunteers immunized at full dose. Neutralizing antibodies were detected in 93.1 % of volunteers immunized at full dose, with geometric mean titer 20. Antigen-specific response in peripheral blood mononuclear cells was also detected in 100 % of participants, as well as in CD4+ and CD8+ T cells in 82.8 % and 58.6 % of participants vaccinated at full dose, respectively. The data indicate that the vaccine is safe and induces strong humoral and cellular immune response in up to 100 % of healthy adult volunteers, and provide a rationale for testing efficacy in Phase III trials. Indeed, the strong immune response to the vaccine may elicit long-term protection. This trial was registered with grls.rosminzdrav.ru (No. 495*), and with zakupki.gov.ru (No. 0373100043215000055).

PMID: 28152326 [PubMed - indexed for MEDLINE]

Safety and immunogenicity of a Herpes Zoster subunit vaccine in Japanese population aged ≥50 years when administered subcutaneously vs. intramuscularly.

Hum Vaccin Immunother. 2017 Mar 04;13(3):574-578

Authors: Vink P, Shiramoto M, Ogawa M, Eda M, Douha M, Heineman T, Lal H

Abstract
The impact of alternate routes of vaccine administration, subcutaneous (SC) or intramuscular (IM), on the safety and immunogenicity of herpes zoster subunit candidate vaccine (HZ/su) was assessed in Japanese adults aged ≥ 50 y. During this phase III open-label study, 60 subjects were randomized (1:1) to receive HZ/su through SC or IM routes in a 0, 2 month schedule. Vaccine response rates (VRRs) and geometric mean concentrations (GMCs) of varicella zoster virus glycoprotein E (gE)-specific antibodies were determined by ELISA. Solicited and unsolicited symptoms were recorded for 7 and 30 d after each vaccination and graded 1-3 in severity. Serious adverse events (SAEs) were recorded throughout the study. At one month post-dose 2, VRRs were 100% (95% Confidence Interval (CI): 88.1-100) in both groups; anti-gE antibody GMCs were 44126.1 mIU/ml (95% CI: 36326.1-53601.0) and 45521.5 mIU/ml (95% CI; 37549.5-55185.9) in the SC and IM groups, respectively. Injection site reactions (pain, swelling and redness) were common, and observed more frequently following SC administration. Grade 3 redness and swelling were more frequently observed after SC administration. Fatigue and headache were the most frequently reported general symptoms for both routes of administration. Ten and 7 unsolicited AEs were reported in the SC and IM group, respectively. Two unsolicited AEs (1 in SC; 1 in IM) were considered related to vaccination by the investigator. Three non-fatal SAEs considered unrelated to vaccination were reported during the study. Administration of the HZ/su vaccine candidate resulted in a substantial immune response that was comparable between SC and IM subjects, but local reactogenicity may be greater for SC.

PMID: 27936344 [PubMed - indexed for MEDLINE]

Immunogenicity and safety among laboratory workers vaccinated with Bexsero® vaccine.

Hum Vaccin Immunother. 2017 Mar 04;13(3):645-648

Authors: Hong E, Terrade A, Taha MK

Abstract
Neisseria meningitidis serogroup B is the most prevalent cause of invasive meningococcal disease in Europe and members of laboratories working on meningococci are at risk due to frequent handling. Recommendation for anti-meningococcal vaccination among these workers has been recently updated upon the licensure in Europe of Bexsero® vaccine. We tested the immunogenicity and safety of this vaccine among adults laboratory staff using the recommended schedule of 2 doses at 5 weeks interval. The vaccine was well tolerated in spite of frequent local side effects and all participants reported at least one side effect after each dose. Immunogenicity was evaluated 6 weeks and one year after the second dose. All participants showed increase in their bactericidal titers against the components of the vaccine 6 weeks after the second dose, however titers declined significantly one year later.

PMID: 27808594 [PubMed - indexed for MEDLINE]

Safety, immunogenicity and persistence of immune response to the combined diphtheria, tetanus, acellular pertussis, poliovirus and Haemophilus influenzae type b conjugate vaccine (DTPa-IPV/Hib) administered in Chinese infants.

Hum Vaccin Immunother. 2017 Mar 04;13(3):588-598

Authors: Li Y, Li RC, Ye Q, Li C, Liu YP, Ma X, Li Y, Zhao H, Chen X, Assudani D, Karkada N, Han HH, Van Der Meeren O, Mesaros N

Abstract
We conducted 3 phase III, randomized, open-label, clinical trials assessing the safety, reactogenicity (all studies), immunogenicity (Primary vaccination study) and persistence of immune responses (Booster study) to the combined diphtheria, tetanus, pertussis, poliomyelitis, and Haemophilus influenzae type b vaccine (DTPa-IPV/Hib) in Chinese infants and toddlers. In the Pilot study (NCT00964028), 50 infants (randomized 1:1) received 3 doses of DTPa-IPV/Hib at 2-3-4 (Group A) or 3-4-5 months of age (Group B). In the Primary study (NCT01086423), 984 healthy infants (randomized 1:1:1) received 3 doses of DTPa-IPV/Hib at 2-3-4 (Group A) or 3-4-5 (Group B) months of age, or concomitant DTPa/Hib and poliomyelitis (IPV) vaccination at 2-3-4 months of age (Control group); 825 infants received a booster dose of DTPa/Hib and IPV at 18-24 months of age (Booster study; NCT01449812). In the Pilot study, unsolicited symptoms were more frequent in Group A (16 versus 1 infant; mostly upper respiratory tract infection and pyrexia); this observation was attributed to an epidemic outbreak of viral infections. Non-inferiority of 3-dose primary vaccination with DTPa-IPV/Hib over separately administered DTPa/Hib and IPV was demonstrated for Group A (primary objective). Similar antibody concentrations were observed in all groups, except for anti-polyribosyl-ribitol phosphate and anti-poliovirus types 1-3 which were higher in DTPa-IPV/Hib recipients. Protective antibody levels against all vaccine antigens remained high until booster vaccination. Three-dose vaccination with DTPa-IPV/Hib had a clinically acceptable safety profile.

PMID: 27768515 [PubMed - indexed for MEDLINE]

14 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 2017/10/24

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.

First-in-man phase I study assessing the safety and pharmacokinetics of a 1-hour intravenous infusion of the doxorubicin prodrug DTS-201 every 3 weeks in patients with advanced or metastatic solid tumours.

Eur J Cancer. 2017 Oct 19;86:240-247

Authors: Schöffski P, Delord JP, Brain E, Robert J, Dumez H, Gasmi J, Trouet A

Abstract
PURPOSE: DTS-201 is a doxorubicin (Dox) prodrug that shows encouraging data in experimental models in terms of both efficacy and safety compared with conventional Dox. The purpose of this phase I study was to assess the safety profile, to establish the recommended dose (RD) for clinical phase II studies and to assess potential anticancer activity of the compound.
EXPERIMENTAL DESIGN: DTS-201 was administered as a 1-hour infusion every 3 weeks in eligible patients with advanced solid tumours according to common clinical phase I criteria. Dose escalation was performed according to a modified Fibonacci schema.
RESULTS: Twenty-five patients with a median age of 58 years (range, 30-72) were enrolled in the study. The median number of treatment cycles was 2 (range, 1-8). DTS-201 was administered at four dose levels (DLs) ranging from 80 to 400 mg/m(2), which is equivalent to 45-225 mg/m(2) of conventional Dox. No dose-limiting toxicity (DLT) occurred at the first two DLs. Three DLTs were observed at DL3 and DL4 (diarrhoea for DL3, vomiting and neutropenia for DL4). DL4 (400 mg/m(2)) was considered the maximum tolerated dose. Myelosuppression was the main toxicity, and NCI-CTC grade III-IV neutropenia was common at RD. Non-haematological adverse reactions were mild to moderate and included nausea, anorexia, asthenia and alopecia. No treatment-related severe cardiac adverse events were observed.
CONCLUSIONS: DTS-201 is well tolerated and safe in heavily pretreated solid tumour patients. A high equivalent dose of Dox could be delivered without severe drug-related cardiac events. DTS-201 showed evidence of clinical activity with a confirmed partial response in a patient with soft-tissue sarcoma. The recommended phase II dose is 400 mg/m(2).

PMID: 29055839 [PubMed - as supplied by publisher]

Is there a change of paradigm towards more effective treatment early in the course of apparent high-risk MS?

Mult Scler Relat Disord. 2017 Oct;17:75-83

Authors: Fernández Ó

Abstract
BACKGROUND: Aggressive, highly active, or rapidly evolving severe relapsing-remitting multiple sclerosis (RRMS) is characterized by frequent relapses and active disease on magnetic resonance imaging, ultimately leading to a high risk for rapid disability accumulation. The treatment approach for high-risk patients is evolving into a model of individualized therapy in which early initiation of high-efficacy disease-modifying therapy (DMT), which I refer to as "early and strong" therapy, is viewed as a rational strategy to prevent the irreversible damage that occurs at disease onset and early in the disease course. This approach uses an individualized benefit-risk assessment to match the level of DMT efficacy with the patient's risk of disease progression and balances it against the risk of drug-related adverse events. It also includes consideration of the patient's risk tolerance and desire for a high-efficacy treatment. This paper discusses the rationale for early treatment, and summarizes the available clinical data on high-efficacy and moderately-high efficacy DMTs in patients with high-risk RRMS.
METHODS: Literature searches were conducted using search terms "aggressive RRMS", "highly active RRMS", and "severe RRMS" alone and in conjunction with the terms "natalizumab", "fingolimod", "alemtuzumab", "mitoxantrone", and "cyclophosphamide". Studies of drug efficacy in these high-risk populations were reviewed.
RESULTS: Subgroup analyses of pivotal trials of natalizumab, fingolimod, and alemtuzumab were available, as well as an independent study of mitoxantrone and a pilot study of cyclophosphamide. In each study, DMT reduced relapses versus either placebo, active comparator, or baseline relapse rate.
CONCLUSION: Data for the high-efficacy DMTs natalizumab and alemtuzumab, and the moderately high-efficacy DMT fingolimod, suggest they are effective in this patient population. Further studies are warranted, and clinical trial data to inform treatment decisions for this high-risk group represent a significant unmet need.

PMID: 29055479 [PubMed - in process]

Everolimus in advanced, progressive, well-differentiated, nonfunctional neuroendocrine tumors: RADIANT-4 lung subgroup analysis.

Cancer Sci. 2017 Oct 21;:

Authors: Fazio N, Buzzoni R, Delle Fave G, Tesselaar ME, Wolin E, Van Cutsem E, Tomassetti P, Strosberg J, Voi M, Pacaud LB, Ridolfi A, Herbst F, Tomasek J, Singh S, Pavel M, Kulke MH, Valle JW, Yao JC

Abstract
In the phase 3, RADIANT-4 study, everolimus improved median progression-free survival (PFS) by 7.1 months in patients with advanced, progressive, well-differentiated (grade 1 or grade 2), nonfunctional lung or gastrointestinal neuroendocrine tumors (NETs) vs placebo (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.35-0.67; P < .00001). This exploratory analysis reports the outcomes of the subgroup of patients with lung NETs. In RADIANT-4, patients were randomized (2:1) to everolimus 10 mg/d or placebo, both with best supportive care. This is a post hoc analysis of the lung subgroup with PFS, by central radiology review, as the primary endpoint; secondary endpoints included objective response rate and safety measures. Ninety of the 302 patients enrolled in the study had primary lung NET (everolimus, n = 63 and placebo, n = 27). Median PFS (95% CI) by central review was 9.2 (6.8-10.9) months in everolimus arm vs 3.6 (1.9-5.1) months in placebo arm (HR, 0.50; 95% CI, 0.28-0.88). More patients who received everolimus (58%) experienced any tumor shrinkage compared with placebo (13%). Most frequently reported (≥ 5% incidence) grade 3-4 drug-related adverse events (everolimus vs placebo) included stomatitis (11% vs 0%), hyperglycemia (10% vs 0%), and any infections (8% vs 0%). In patients with advanced, progressive, well-differentiated, nonfunctional lung NET, treatment with everolimus was associated with a median PFS improvement of 5.6 months, with a safety profile similar to that of the overall RADIANT-4 population. These results support the use of everolimus in patients with advanced, nonfunctional lung NET. This article is protected by copyright. All rights reserved.

PMID: 29055056 [PubMed - as supplied by publisher]

Intravenous Zanamivir in Hospitalized Patients With Influenza.

Pediatrics. 2017 Oct 19;:

Authors: Bradley JS, Blumer JL, Romero JR, Michaels MG, Munoz FM, Kimberlin DW, Pahud B, DeBiasi RL, Yamamoto G, Roberts G, Hossain M, Shortino D, Yates PJ, Adams B, Peppercorn A

Abstract
BACKGROUND: Children with severe influenza infection may require parenteral therapy if oral or inhaled therapies are ineffective or cannot be administered. Results from a study investigating intravenous (IV) zanamivir for the treatment of hospitalized infants and children with influenza are presented.
METHODS: This phase II, open-label, multicenter, single-arm study assessed the safety of investigational IV zanamivir in hospitalized children with influenza. Safety outcomes included treatment-emergent adverse events (TEAEs), clinical laboratory measurements, and vital signs. Clinical outcomes, pharmacokinetics, and virologic efficacy data were collected as key secondary outcomes.
RESULTS: In total, 71 children received treatment with investigational IV zanamivir (exposure comparable to 600 mg twice daily in adults). TEAEs and serious TEAEs (STEAEs) were reported in 51 (72%) and 15 (21%) patients, respectively. The mortality rate was 7%, and median durations of hospital and ICU stays were 6 and 7.5 days, respectively. No STEAEs or deaths were considered related to IV zanamivir treatment, and no patterns of TEAEs, laboratory abnormalities, or vital signs were observed. The mean zanamivir exposures from 34 patients with normal renal function who received 12 mg/kg, 14 mg/kg, or 600 mg of IV zanamivir ranged from 64.5 to 110 hour·µg/mL. The median change from baseline in the viral load was -1.81 log10 copies per mL after 2 days of treatment.
CONCLUSIONS: The safety profile of IV zanamivir was favorable, with no drug-related STEAEs reported. The majority of children experienced virologic response and clinical improvement during the treatment course. Systemic zanamivir exposures in children were consistent with adults.

PMID: 29051331 [PubMed - as supplied by publisher]