[Medication administration practices in elderly residential facilities in Ile de France Region in 2014: findings and room for improvement].

Sante Publique. 2016 Nov 25;28(5):623-632

Authors: de Saunière A, Bonneau L, Donio V, Godinot V, Flouzat JP, Bensasson G, Code C, Galay G, Pige D

Abstract
The institutions expressed great interest in medication administration systems and tools designed to monitor all stages of medication administration. A dozen simple and pragmatic improvement actions were identified and listed in the Ile-de-France Regional Health Agency action plan to improve medication administration management of in EHPAD.</ce:para>.

PMID: 28155738 [PubMed - indexed for MEDLINE]

Therapeutic monitoring of the immuno-modulating drugs in systemic lupus erythematosus.

Expert Rev Clin Immunol. 2017 Jan;13(1):35-41

Authors: Mok CC

Abstract
INTRODUCTION: Despite the emergence of newer immunomodulating agents for systemic lupus erythematosus (SLE), a substantial proportion of patients still do not respond optimally. While the mechanisms for the differential responses to drug therapy are unclear, variation in drug exposure with the same dosing protocol related to pharmacogenetic and pharmacokinetic factors may contribute. This article discusses the use of therapeutic drug monitoring (TDM) to optimize therapies in SLE patients. Areas covered: Evidence on the relationship between blood levels and efficacy/toxicity of immuno-modulating drugs such as hydroxychloroquine (HCQ), mycophenolate mofetil (MMF) and the calcineurin inhibitors that are often used in SLE. Expert commentary: Current data suggest a correlation between exposure and efficacy of HCQ and MMF in SLE. The relationship between HCQ or MMF blood concentrations and their adverse effects requires further elucidation. The serum trough level of tacrolimus does not appear to correlate with clinical response in lupus nephritis but is associated with toxic effects. Owing to the paucity of data, the 'optimal' blood levels of these agents in SLE have yet to be determined by large population pharmacokinetic studies. Nevertheless, TDM enables early identification of non-adherence and over-exposure to these SLE medications so that dosing adjustment can be performed to minimize toxicities and wastage.

PMID: 27417340 [PubMed - indexed for MEDLINE]

Prophylactic immunoglobulin therapy in secondary immune deficiency - an expert opinion.

Expert Rev Clin Immunol. 2016 Sep;12(9):921-6

Authors: Agostini C, Blau IW, Kimby E, Plesner T

Abstract
INTRODUCTION: In primary immunodeficiency (PID), immunoglobulin replacement therapy (IgRT) for infection prevention is well-established and supported by a wealth of clinical data. On the contrary, very little evidence-based data is available on the challenges surrounding the use of IgRT in secondary immune deficiencies (SID), and most published guidelines are mere extrapolations from the experience in PID.
AREAS COVERED: In this article, four European experts provide their consolidated opinion on open questions surrounding the prophylactic use of IgRT in SID, based on their clinical experience. The main topics are IgRT initiation, route of administration, dose optimization, and therapy discontinuation. The authors hope this discussion will be of assistance to practicing physicians in their daily decision-making. Expert commentary: Although growing experience indicates that IgRT could play an important role in the management of SID, very little robust evidence is available to guide clinical practice. The authors stress the urgent need for new studies in the field and discuss points they find of importance to design them adequately.

PMID: 27415820 [PubMed - indexed for MEDLINE]

Defining conditions where long-term glucocorticoid treatment has an acceptably low level of harm to facilitate implementation of existing recommendations: viewpoints from an EULAR task force.

Ann Rheum Dis. 2016 Jun;75(6):952-7

Authors: Strehl C, Bijlsma JW, de Wit M, Boers M, Caeyers N, Cutolo M, Dasgupta B, Dixon WG, Geenen R, Huizinga TW, Kent A, de Thurah AL, Listing J, Mariette X, Ray DW, Scherer HU, Seror R, Spies CM, Tarp S, Wiek D, Winthrop KL, Buttgereit F

Abstract
There is convincing evidence for the known and unambiguously accepted beneficial effects of glucocorticoids at low dosages. However, the implementation of existing recommendations and guidelines on the management of glucocorticoid therapy in rheumatic diseases is lagging behind. As a first step to improve implementation, we aimed at defining conditions under which long-term glucocorticoid therapy may have an acceptably low level of harm. A multidisciplinary European League Against Rheumatism task force group of experts including patients with rheumatic diseases was assembled. After a systematic literature search, breakout groups critically reviewed the evidence on the four most worrisome adverse effects of glucocorticoid therapy (osteoporosis, hyperglycaemia/diabetes mellitus, cardiovascular diseases and infections) and presented their results to the other group members following a structured questionnaire for final discussion and consensus finding. Robust evidence on the risk of harm of long-term glucocorticoid therapy was often lacking since relevant study results were often either missing, contradictory or carried a high risk of bias. The group agreed that the risk of harm is low for the majority of patients at long-term dosages of ≤5 mg prednisone equivalent per day, whereas at dosages of >10 mg/day the risk of harm is elevated. At dosages between >5 and ≤10 mg/day, patient-specific characteristics (protective and risk factors) determine the risk of harm. The level of harm of glucocorticoids depends on both dose and patient-specific parameters. General and glucocorticoid-associated risk factors and protective factors such as a healthy lifestyle should be taken into account when evaluating the actual and future risk.

PMID: 26933146 [PubMed - indexed for MEDLINE]

Efficacy and safety of tofacitinib following inadequate response to conventional synthetic or biological disease-modifying antirheumatic drugs.

Ann Rheum Dis. 2016 Jul;75(7):1293-301

Authors: Charles-Schoeman C, Burmester G, Nash P, Zerbini CA, Soma K, Kwok K, Hendrikx T, Bananis E, Fleischmann R

Abstract
OBJECTIVES: Biological disease-modifying antirheumatic drugs (bDMARDs) have shown diminished clinical response following an inadequate response (IR) to ≥1 previous bDMARD. Here, tofacitinib was compared with placebo in patients with an IR to conventional synthetic DMARDs (csDMARDs; bDMARD-naive) and in patients with an IR to bDMARDs (bDMARD-IR).
METHODS: Data were taken from phase II and phase III studies of tofacitinib in patients with rheumatoid arthritis (RA). Patients received tofacitinib 5 or 10 mg twice daily, or placebo, as monotherapy or with background methotrexate or other csDMARDs. Efficacy endpoints and incidence rates of adverse events (AEs) of special interest were assessed.
RESULTS: 2812 bDMARD-naive and 705 bDMARD-IR patients were analysed. Baseline demographics and disease characteristics were generally similar between treatment groups within subpopulations. Across subpopulations, improvements in efficacy parameters at month 3 were generally significantly greater for both tofacitinib doses versus placebo. Clinical response was numerically greater with bDMARD-naive versus bDMARD-IR patients (overlapping 95% CIs). Rates of safety events of special interest were generally similar between tofacitinib doses and subpopulations; however, patients receiving glucocorticoids had more serious AEs, discontinuations due to AEs, serious infection events and herpes zoster. Numerically greater clinical responses and incidence rates of AEs of special interest were generally reported for tofacitinib 10 mg twice daily versus tofacitinib 5 mg twice daily (overlapping 95% CIs).
CONCLUSIONS: Tofacitinib demonstrated efficacy in both bDMARD-naive and bDMARD-IR patients with RA. Clinical response to tofacitinib was generally numerically greater in bDMARD-naive than bDMARD-IR patients. The safety profile appeared similar between subpopulations.
TRIAL REGISTRATION NUMBERS: (NCT00413660, NCT0050446, NCT00603512, NCT00687193, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385).

PMID: 26275429 [PubMed - indexed for MEDLINE]

[PULMONARY FIBROSIS INDUCED BY ANTI־TNF-Αlpha TREATMENT].

Harefuah. 2016 Oct;155(10):600-603

Authors: Baum S, Schachter O, Barzilai A

Abstract
INTRODUCTION: TNFα-targeted therapies have emerged as a new class of drugs in the treatment of various inflammatory diseases, including psoriasis. With the increasing use and longer follow-up periods of TNFα targeted therapies, a spectrum of immunological adverse events have been described, ranging from asymptomatic immunological alterations to life-threatening systemic diseases such as pulmonary fibrosis. We present a case of a 66 year old man diagnosed with psoriasis who developed pulmonary fibrosis three years after initiation of Etanercept (Enbrel) for his skin disease.
CONCLUSIONS: We presented a rare case of a patient who developed pulmonary fibrosis, possibly triggered by anti-TNFα treatment. We suggest that adverse effects related to anti-TNFα should be evaluated carefully, considering pulmonary fibrosis as a possible side effect, especially among patients with risk factors for its development.
DISCUSSION: There are growing numbers of reports of the paradoxical induction of pulmonary interstitial disease due to TNFα blockers, yet most of them are uncontrolled studies in patients with rheumatoid arthritis or other autoimmune diseases that can involve the lungs. Therefore, definitive conclusions are not possible at this stage. Recent studies described the poor prognosis of pulmonary fibrosis secondary to anti-TNFα therapy, with the mortality rate of up to 60% among patients with previous pulmonary disease. Coexisting or previous therapy with Methotrexate had stronger association with the development of drug-induced pulmonary fibrosis.

PMID: 28530055 [PubMed - in process]

Post-marketing withdrawal of anti-obesity medicinal products because of adverse drug reactions: a systematic review.

BMC Med. 2016 Nov 29;14(1):191

Authors: Onakpoya IJ, Heneghan CJ, Aronson JK

Abstract
BACKGROUND: We identified anti-obesity medications withdrawn since 1950 because of adverse drug reactions after regulatory approval, and examined the evidence used to support such withdrawals, investigated the mechanisms of the adverse reactions, and explored the trends over time.
METHODS: We conducted searches in PubMed, the World Health Organization database of drugs, the websites of drug regulatory authorities, and selected full texts, and we hand searched references in retrieved documents. We included anti-obesity medications that were withdrawn between 1950 and December 2015 and assessed the levels of evidence used for making withdrawal decisions using the Oxford Centre for Evidence-Based Medicine criteria.
RESULTS: We identified 25 anti-obesity medications withdrawn between 1964 and 2009; 23 of these were centrally acting, via monoamine neurotransmitters. Case reports were cited as evidence for withdrawal in 80% of instances. Psychiatric disturbances, cardiotoxicity (mainly attributable to re-uptake inhibitors), and drug abuse or dependence (mainly attributable to neurotransmitter releasing agents) together accounted for 83% of withdrawals. Deaths were reportedly associated with seven products (28%). In almost half of the cases, the withdrawals occurred within 2 years of the first report of an adverse reaction.
CONCLUSIONS: Most of the drugs that affect monoamine neurotransmitters licensed for the treatment of obesity over the past 65 years have been withdrawn because of adverse reactions. The reasons for withdrawal raise concerns about the wisdom of using pharmacological agents that target monoamine neurotransmitters in managing obesity. Greater transparency in the assessment of harms from anti-obesity medications is therefore warranted.

PMID: 27894343 [PubMed - indexed for MEDLINE]

Immunogenicity and Safety of an AS03-Adjuvanted H7N9 Pandemic Influenza Vaccine in a Randomized Trial in Healthy Adults.

J Infect Dis. 2016 Dec 01;214(11):1717-1727

Authors: Madan A, Segall N, Ferguson M, Frenette L, Kroll R, Friel D, Soni J, Li P, Innis BL, Schuind A

Abstract
BACKGROUND:  Almost 700 cases of human infection with avian influenza A/H7N9 have been reported since 2013. Pandemic preparedness strategies include H7N9 vaccine development.
METHODS:  We evaluated an inactivated H7N9 vaccine in an observer-blind study in healthy adults aged 18-64 years. Participants (420) were randomized to receive 1 of 4 AS03-adjuvanted vaccines (low or medium dose of hemagglutinin with AS03A or AS03B), one nonadjuvanted vaccine, or placebo. The coprimary immunogenicity objective determined whether adjuvanted vaccines elicited an immune response against the vaccine-homologous virus, 21 days after the second vaccine dose per US and European licensure criteria in the per-protocol cohort (n = 389).
RESULTS:  All adjuvanted vaccines met regulatory acceptance criteria. In groups receiving adjuvanted formulations, seroconversion rates were ≥85.7%, seroprotection rates ≥91.1%, and geometric mean titers ≥92.9% versus 23.2%, 28.6%, and 17.2 for the nonadjuvanted vaccine. The AS03 adjuvant enhanced immune response at antigen-sparing doses. Injection site pain occurred more frequently with adjuvanted vaccines (in ≤98.3% of vaccinees) than with the nonadjuvanted vaccine (40.7%) or placebo (20.0%). None of the 20 serious adverse events reported were related to vaccination.
CONCLUSIONS:  Two doses of AS03-adjuvanted H7N9 vaccine were well tolerated and induced a robust antibody response at antigen-sparing doses in healthy adults.
CLINICAL TRIALS REGISTRATION:  NCT01999842.

PMID: 27609809 [PubMed - indexed for MEDLINE]

Mosquito bite immunization with radiation-attenuated Plasmodium falciparum sporozoites: safety, tolerability, protective efficacy and humoral immunogenicity.

Malar J. 2016 Jul 22;15(1):377

Authors: Hickey BW, Lumsden JM, Reyes S, Sedegah M, Hollingdale MR, Freilich DA, Luke TC, Charoenvit Y, Goh LM, Berzins MP, Bebris L, Sacci JB, De La Vega P, Wang R, Ganeshan H, Abot EN, Carucci DJ, Doolan DL, Brice GT, Kumar A, Aguiar J, Nutman TB, Leitman SF, Hoffman SL, Epstein JE, Richie TL

Abstract
BACKGROUND: In this phase 1 clinical trial, healthy adult, malaria-naïve subjects were immunized with radiation-attenuated Plasmodium falciparum sporozoites (PfRAS) by mosquito bite and then underwent controlled human malaria infection (CHMI). The PfRAS model for immunization against malaria had previously induced >90 % sterile protection against homologous CHMI. This study was to further explore the safety, tolerability and protective efficacy of the PfRAS model and to provide biological specimens to characterize protective immune responses and identify protective antigens in support of malaria vaccine development.
METHODS: Fifty-seven subjects were screened, 41 enrolled and 30 received at least one immunization. The true-immunized subjects received PfRAS via mosquito bite and the mock-immunized subjects received mosquito bites from irradiated uninfected mosquitoes. Sera and peripheral blood mononuclear cells (PBMCs) were collected before and after PfRAS immunizations.
RESULTS: Immunization with PfRAS was generally safe and well tolerated, and repeated immunization via mosquito bite did not appear to increase the risk or severity of AEs. Local adverse events (AEs) of true-immunized and mock-immunized groups consisted of erythaema, papules, swelling, and induration and were consistent with reactions from mosquito bites seen in nature. Two subjects, one true- and one mock-immunized, developed large local reactions that completely resolved, were likely a result of mosquito salivary antigens, and were withdrawn from further participation as a safety precaution. Systemic AEs were generally rare and mild, consisting of headache, myalgia, nausea, and low-grade fevers. Two true-immunized subjects experienced fever, malaise, myalgia, nausea, and rigours approximately 16 h after immunization. These symptoms likely resulted from pre-formed antibodies interacting with mosquito salivary antigens. Ten subjects immunized with PfRAS underwent CHMI and five subjects (50 %) were sterilely protected and there was a significant delay to parasitaemia in the other five subjects. All ten subjects developed humoral immune responses to whole sporozoites and to the circumsporozoite protein prior to CHMI, although the differences between protected and non-protected subjects were not statistically significant for this small sample size.
CONCLUSIONS: The protective efficacy of this clinical trial (50 %) was notably less than previously reported (>90 %). This may be related to differences in host genetics or the inherent variability in mosquito biting behavior and numbers of sporozoites injected. Differences in trial procedures, such as the use of leukapheresis prior to CHMI and of a longer interval between the final immunization and CHMI in these subjects compared to earlier trials, may also have reduced protective efficacy. This trial has been retrospectively registered at ISRCTN ID 17372582, May 31, 2016.

PMID: 27448805 [PubMed - indexed for MEDLINE]

Effectiveness of adverse effects search filters: drugs versus medical devices.

J Med Libr Assoc. 2016 Jul;104(3):221-5

Authors: Farrah K, Mierzwinski-Urban M, Cimon K

Abstract
OBJECTIVE: The study tested the performance of adverse effects search filters when searching for safety information on medical devices, procedures, and diagnostic tests in MEDLINE and Embase.
METHODS: The sensitivity of 3 filters was determined using a sample of 631 references from 131 rapid reviews related to the safety of health technologies. The references were divided into 2 sets by type of intervention: drugs and nondrug health technologies. Keyword and indexing analysis were performed on references from the nondrug testing set that 1 or more of the filters did not retrieve.
RESULTS: For all 3 filters, sensitivity was lower for nondrug health technologies (ranging from 53%-87%) than for drugs (88%-93%) in both databases. When tested on the nondrug health technologies set, sensitivity was lower in Embase (ranging from 53%-81%) than in MEDLINE (67%-87%) for all filters. Of the nondrug records that 1 or more of the filters missed, 39% of the missed MEDLINE records and 18% of the missed Embase records did not contain any indexing terms related to adverse events. Analyzing the titles and abstracts of nondrug records that were missed by any 1 filter, the most commonly used keywords related to adverse effects were: risk, complications, mortality, contamination, hemorrhage, and failure.
CONCLUSIONS: In this study, adverse effects filters were less effective at finding information about the safety of medical devices, procedures, and tests compared to information about the safety of drugs.

PMID: 27366123 [PubMed - indexed for MEDLINE]

Rapid Responses to 2 Virus-Like Particle Norovirus Vaccine Candidate Formulations in Healthy Adults: A Randomized Controlled Trial.

J Infect Dis. 2016 Sep 15;214(6):845-53

Authors: Atmar RL, Baehner F, Cramer JP, Song E, Borkowski A, Mendelman PM, NOR-201 Study Group

Abstract
BACKGROUND: Noroviruses pose a significant public health risk, particularly in very young individuals, older adults, and individuals with underlying conditions. We assessed 2 bivalent norovirus virus-like particle (VLP) vaccine candidate formulations in healthy adults aged 18-49 years.
METHODS: Enrolled subjects (n = 454) randomly assigned among 3 groups received intramuscular placebo (saline) or vaccines containing either 15 µg or 50 µg of GI.1 VLP and 50 µg GII.4 VLP (15/50 and 50/50 formulations) adjuvanted with monophosphoryl lipid A and Al(OH)3 We present safety and immunogenicity assessments up to 28 days after vaccination.
RESULTS: No vaccine-related serious adverse events or adverse events of special interest were reported. Reactions were mainly mild to moderate, the most frequent being transient pain, in 8%, 64%, and 73% of placebo, 15/50, and 50/50 groups, respectively; transient myalgia, headache, and fatigue were the commonest systemic adverse events. Subjects assessed per protocol (n = 442) displayed rapid immune responses to vaccination, peaking by days 7-10 and persisting through day 28. GI.1 responses were highest with the 50/50 formulation, but GII.4 responses were higher with the 15/50 formulation.
CONCLUSIONS: Both candidate VLP vaccines were well tolerated and elicited robust immune responses by 7-10 days that persisted through day 28. The 15/50 formulation displayed the best balance of tolerability and immunogenicity.
CLINICAL TRIALS REGISTRATION: NCT02142504.

PMID: 27354368 [PubMed - indexed for MEDLINE]

Safety and High Level Efficacy of the Combination Malaria Vaccine Regimen of RTS,S/AS01B With Chimpanzee Adenovirus 63 and Modified Vaccinia Ankara Vectored Vaccines Expressing ME-TRAP.

J Infect Dis. 2016 Sep 01;214(5):772-81

Authors: Rampling T, Ewer KJ, Bowyer G, Bliss CM, Edwards NJ, Wright D, Payne RO, Venkatraman N, de Barra E, Snudden CM, Poulton ID, de Graaf H, Sukhtankar P, Roberts R, Ivinson K, Weltzin R, Rajkumar BY, Wille-Reece U, Lee CK, Ockenhouse CF, Sinden RE, Gerry S, Lawrie AM, Vekemans J, Morelle D, Lievens M, Ballou RW, Cooke GS, Faust SN, Gilbert S, Hill AV

Abstract
BACKGROUND: The need for a highly efficacious vaccine against Plasmodium falciparum remains pressing. In this controlled human malaria infection (CHMI) study, we assessed the safety, efficacy and immunogenicity of a schedule combining 2 distinct vaccine types in a staggered immunization regimen: one inducing high-titer antibodies to circumsporozoite protein (RTS,S/AS01B) and the other inducing potent T-cell responses to thrombospondin-related adhesion protein (TRAP) by using a viral vector.
METHOD: Thirty-seven healthy malaria-naive adults were vaccinated with either a chimpanzee adenovirus 63 and modified vaccinia virus Ankara-vectored vaccine expressing a multiepitope string fused to TRAP and 3 doses of RTS,S/AS01B (group 1; n = 20) or 3 doses of RTS,S/AS01B alone (group 2; n = 17). CHMI was delivered by mosquito bites to 33 vaccinated subjects at week 12 after the first vaccination and to 6 unvaccinated controls.
RESULTS: No suspected unexpected serious adverse reactions or severe adverse events related to vaccination were reported. Protective vaccine efficacy was observed in 14 of 17 subjects (82.4%) in group 1 and 12 of 16 subjects (75%) in group 2. All control subjects received a diagnosis of blood-stage malaria parasite infection. Both vaccination regimens were immunogenic. Fourteen protected subjects underwent repeat CHMI 6 months after initial CHMI; 7 of 8 (87.5%) in group 1 and 5 of 6 (83.3%) in group 2 remained protected.
CONCLUSIONS: The high level of sterile efficacy observed in this trial is encouraging for further evaluation of combination approaches using these vaccine types.
CLINICAL TRIALS REGISTRATION: NCT01883609.

PMID: 27307573 [PubMed - indexed for MEDLINE]

[Adverse drug reactions in neonates hospitalized in neonatal intensive care units in Barranquilla, Colombia].

Biomedica. 2017 Apr 01;37(0):33-42

Authors: De Las Salas R, Díaz-Agudelo D

Abstract
INTRODUCTION: The appearance of adverse drug reactions in neonates is an important issue due to the lack of drug safety data.
OBJECTIVE: To identify the behavior of adverse drug reactions (ADR) in hospitalized neonates at two intensive care units in Barranquilla, Colombia.
MATERIALS AND METHODS: We conducted a cross-sectional prospective descriptive study based on patientcentered intensive pharmacosurveillance. We followed up and monitored the appearance of ADRs for six months. We used Naranjo's algorithm to assess causality, modified Hartwig and Siegel assessment scale to establish severity and Schumock and Thornton criteria to determine ADR preventability.
RESULTS: We detected 123 adverse drug reactions in 78 neonates of the 284 monitored. The cumulative incidence of ADRs was 27.4% (78/284); incidence density was 30.60 ADRs per 1,000 patients/day (78/2,549). The most affected organ system was the digestive (33.6%). Systemic anti-infective drugs were the most involved pharmacological group. Most of the ADRs were mild (58.5%), 83% were classified as probable, 16.2% as possible and 0.8% as definite.
CONCLUSIONS: ADR incidence was high in newborns, and it increased in preterm infants (less than 38 weeks of age).

PMID: 28527264 [PubMed - in process]

Characterisation of Drug-Related Problems and Associated Factors at a Clinical Pharmacist Service-Naïve Hospital in Northern Sweden.

Drugs Real World Outcomes. 2017 May 19;:

Authors: Peterson C, Gustafsson M

Abstract
BACKGROUND: Polypharmacy and increased sensitivity to side effects cause adverse drug events, drug-drug interactions and medication errors in the elderly.
OBJECTIVE: The objective of this study was to investigate the prevalence and type of drug-related problems and associated factors among patients admitted to a clinical pharmacist service-naïve medical ward in an inland hospital in northern Sweden.
METHODS: During September-November 2015 and February-April 2016, clinical pharmacists working as part of a ward team on the medical ward conducted 103 medication reviews. Drug-related problems were identified and classified. Associated factors, drug classes and specific drugs involved were also investigated.
RESULTS: The clinical pharmacists identified 133 drug-related problems in 66% [68/103] of the study population. The most common drug-related problems in this study were inappropriate drug use and interactions. Cardiovascular drugs and psychotropic drugs were most commonly involved. Drug-related problems were more frequently observed at higher age, increasing number of drugs prescribed and in patients with reduced renal function. In the multivariate analysis, only the number of prescribed drugs was still significant.
CONCLUSION: Drug-related problems were commonly observed among patients admitted to the medical ward. Medication reviews conducted by clinical pharmacists as part of a ward team resulted in several interventions to improve the patients' drug treatment.

PMID: 28527149 [PubMed - as supplied by publisher]

A phase II study of antibody-drug conjugate, TAK-264 (MLN0264) in previously treated patients with advanced or metastatic pancreatic adenocarcinoma expressing guanylyl cyclase C.

Invest New Drugs. 2017 May 19;:

Authors: Almhanna K, Wright D, Mercade TM, Van Laethem JL, Gracian AC, Guillen-Ponce C, Faris J, Lopez CM, Hubner RA, Bendell J, Bols A, Feliu J, Starling N, Enzinger P, Mahalingham D, Messersmith W, Yang H, Fasanmade A, Danaee H, Kalebic T

Abstract
Background This phase II open-label, multicenter study evaluated the efficacy, safety, and tolerability of TAK-264 in previously treated patients with advanced or metastatic pancreatic adenocarcinoma expressing guanylyl cyclase C (GCC). Methods Patients with advanced or metastatic pancreatic adenocarcinoma expressing GCC (H-score ≥ 10) received TAK-264 1.8 mg/kg on day 1 of a 21-day cycle as a 30-min intravenous infusion for up to 1 year or until disease progression or unacceptable toxicity. The primary objective was overall response rate (ORR [complete response + partial response (PR)]). Secondary objectives included evaluations of the safety and pharmacokinetic profile of TAK-264 (NCT02202785). Results 43 patients were enrolled and treated with 1.8 mg/kg TAK-264: 11, 15, and 17 patients with low, intermediate, and high GCC expression, respectively. Median number of treatment cycles received was two (range 1-10). The ORR was 3%, including one patient with intermediate GCC expression who achieved a PR. All patients experienced ≥1 adverse events (AE). The majority of patients experienced grade 1/2 AEs affecting the gastrointestinal tract. Fifteen (35%) patients experienced ≥grade 3 drug-related AEs; five (12%) patients had a serious AE. The most common (≥10% of patients) all-grade drug-related AEs were nausea (33%), fatigue (28%), neutropenia (23%), decreased appetite (23%), vomiting (16%), asthenia (16%), and alopecia (14%). Conclusions TAK-264 demonstrated a manageable safety profile; however, the low efficacy of TAK-264 observed in this study did not support further clinical investigation.

PMID: 28527133 [PubMed - as supplied by publisher]

Management of Treatment-Related Adverse Events with Agents Targeting the MAPK Pathway in Patients with Metastatic Melanoma.

Oncologist. 2017 May 18;:

Authors: Daud A, Tsai K

Abstract
Tremendous progress has been made in the clinical landscape of advanced-stage BRAF V600-mutant melanoma treatment over the past 5 years. Targeted therapies that inhibit specific steps of the mitogen-activated protein kinase pathway have been shown to provide significant overall treatment benefit in patients with this difficult-to-treat disease. Combination therapy with BRAF and MEK inhibitors (dabrafenib plus trametinib or vemurafenib plus cobimetinib, respectively) has become standard of care. These agents are administered until disease progression or unacceptable toxicity occurs; thus, some patients may remain on maintenance therapy for an extended period of time, while toxicities may result in early discontinuation in other patients. Because the goal of treatment is to prolong survival with minimal impairment of quality of life, drug-related adverse events (AEs) require prompt management to ensure that patients derive the best possible benefit from therapy. Proper management depends on an understanding of which AEs are most likely BRAF or MEK inhibitor associated, thus providing a rationale for dose modification of the appropriate drug. Additionally, the unique safety profile of the chosen regimen may influence patient selection and monitoring. This review discusses the toxicity profiles of these agents, with a focus on the most commonly reported and serious AEs. Here, we offer practical guidance derived from our clinical experience for the optimal management of key drug-related AEs. The Oncologist 2017;22:1-11 IMPLICATIONS FOR PRACTICE: Targeted therapy with BRAF plus MEK inhibitors has become the standard of care for patients with advanced-stage BRAF V600-mutant metastatic melanoma. To provide optimal therapeutic benefit to patients, clinicians need a keen understanding of the toxicity profiles of these drugs. Prompt identification and an understanding of which adverse events are most likely BRAF or MEK inhibitor associated provide a rationale for appropriate therapy adjustments. Practical recommendations derived from clinical experience are provided for management of key drug-related toxicities.

PMID: 28526719 [PubMed - as supplied by publisher]

Intravitreous injection of AAV2-sFLT01 in patients with advanced neovascular age-related macular degeneration: a phase 1, open-label trial.

Lancet. 2017 May 16;:

Authors: Heier JS, Kherani S, Desai S, Dugel P, Kaushal S, Cheng SH, Delacono C, Purvis A, Richards S, Le-Halpere A, Connelly J, Wadsworth SC, Varona R, Buggage R, Scaria A, Campochiaro PA

Abstract
BACKGROUND: Long-term intraocular injections of vascular endothelial growth factor (VEGF)-neutralising proteins can preserve central vision in many patients with neovascular age-related macular degeneration. We tested the safety and tolerability of a single intravitreous injection of an AAV2 vector expressing the VEGF-neutralising protein sFLT01 in patients with advanced neovascular age-related macular degeneration.
METHODS: This was a phase 1, open-label, dose-escalating study done at four outpatient retina clinics in the USA. Patients were assigned to each cohort in order of enrolment, with the first three patients being assigned to and completing the first cohort before filling positions in the following treatment groups. Patients aged 50 years or older with neovascular age-related macular degeneration and a baseline best-corrected visual acuity score of 20/100 or less in the study eye were enrolled in four dose-ranging cohorts (cohort 1, 2 × 10(8) vector genomes (vg); cohort 2, 2 × 10(9) vg; cohort 3, 6 × 10(9) vg; and cohort 4, 2 × 10(10) vg, n=3 per cohort) and one maximum tolerated dose cohort (cohort 5, 2 × 10(10) vg, n=7) and followed up for 52 weeks. The primary objective of the study was to assess the safety and tolerability of a single intravitreous injection of AAV2-sFLT01, through the measurement of eye-related adverse events. This trial is registered with ClinicalTrials.gov, number NCT01024998.
FINDINGS: 19 patients with advanced neovascular age-related macular degeneration were enrolled in the study between May 18, 2010, and July 14, 2014. All patients completed the 52-week trial period. Two patients in cohort 4 (2 × 10(10) vg) experienced adverse events that were possibly study-drug related: pyrexia and intraocular inflammation that resolved with a topical steroid. Five of ten patients who received 2 × 10(10) vg had aqueous humour concentrations of sFLT01 that peaked at 32·7-112·0 ng/mL (mean 73·7 ng/mL, SD 30·5) by week 26 with a slight decrease to a mean of 53·2 ng/mL at week 52 (SD 17·1). At baseline, four of these five patients were negative for anti-AAV2 serum antibodies and the fifth had a very low titre (1:100) of anti-AAV2 antibodies, whereas four of the five non-expressers of sFLT01 had titres of 1:400 or greater. In 11 of 19 patients with intraretinal or subretinal fluid at baseline judged to be reversible, six showed substantial fluid reduction and improvement in vision, whereas five showed no fluid reduction. One patient in cohort 5 showed a large decrease in vision between weeks 26 and 52 that was not thought to be vector-related.
INTERPRETATION: Intravitreous injection of AAV2-sFLT01 seemed to be safe and well tolerated at all doses. Additional studies are needed to identify sources of variability in expression and anti-permeability activity, including the potential effect of baseline anti-AAV2 serum antibodies.
FUNDING: Sanofi Genzyme, Framingham, MA, USA.

PMID: 28526489 [PubMed - as supplied by publisher]

Efficacy of intravenous hydrocortisone administered 2-4 h prior to antivenom as prophylaxis against adverse drug reactions to snake antivenom in Sri Lanka: An open labelled randomized controlled trial.

Toxicon. 2016 Sep 15;120:159-65

Authors: Kularatne SA, Weerakoon K, Silva A, Maduwage K, Walathara C, Rathnayake I, Medagedara S, Paranagama R, Mendis S, Kumarasiri PV

Abstract
The prevention of adverse drug reactions to antivenom serum poses a formidable challenge in the management of snakebite. Hydrocortisone is being used concurrently with antivenom in order to prevent these adverse drug reactions without a proven benefit. However, all previous studies seemed to ignore the testing of effectiveness of hydrocortisone therapy during its pharmacological effects, which come hours later. On this principle, we aimed to test the effectiveness of intravenous hydrocortisone given 2 h or more prior to the commencement of antivenom therapy to reduce adverse drug reactions to antivenom. In an open-labelled randomized controlled trial, patients with a history of snakebite were randomly assigned to receive either 500 mg intravenous hydrocortisone bolus given 2 h or more prior to antivenom therapy (Group A) or at the time of antivenom therapy (Group B). The primary endpoint was the reduction of adverse drug reactions to antivenom of any grade of severity within the first 48 h. This trial has been registered with the "Sri Lanka Clinical Trials Registry", number SLCTR/2010/005. A total of 236 patients were randomized to group A or Group B. In the group A, 38 participants received hydrocortisone 2 h before administration of antivenom whilst 33 received hydrocortisone less than 2 h before administration of antivenom. In the Group B, 84 participants received hydrocortisone at the time of antivenom therapy. In Group A (n, 38), and Group B (n, 84), 15 patients (39%) and 29 patients (35%) developed reactions respectively and the difference is not significant (p = 0.598). Moreover, hydrocortisone therapy did not significantly reduce the occurrence of antievnom reactions of any grade of severity. Further, it didn't delay the occurrence of antivenom reactions in patients who received hydrocortisone either more than 2 h or less than 2 h before the antivenom as opposed to the control group (group B). Intravenous hydrocortisone shows no difference in the timing, rate or severity of adverse drug reactions to antivenom when administered simultaneously and up to 4 h prior to antivenom.

PMID: 27530663 [PubMed - indexed for MEDLINE]

Multiple drug-intolerant hypertension: a case series utilising a novel-treatment algorithm.

Br J Gen Pract. 2016 Apr;66(645):e285-7

Authors: Saxena M, Antoniou S, Hamedi N, Robinson P, Singh H, Mukhtar O, Kapil V, Lobo MD

PMID: 27033502 [PubMed - indexed for MEDLINE]

Medical Genetics Summaries

Book. 2012

Authors: Pratt V, McLeod H, Dean L, Malheiro A, Rubinstein W

Abstract
Phenytoin is an antiseizure medication used for the prevention of focal seizures and generalized tonic-clonic convulsions (1). Phenytoin has a narrow therapeutic index—patients that have toxic blood concentrations of phenytoin have inreased risks of acute side effects. Dosing can be complex due to pharmacokinetic factors, including patient weight, age, sex, concomitant medications, plasma binding protein stats, the presence of uremia or hyperbilirubinemia, and specific pharmacogenetic variants. As such, therapeutic drug monitoring is often used to adjust dose and maintain serum concentrations within the therapeutic range (10–20 μg/mL). CYP2C9 is one of the main enzymes involved in the metabolism of phenytoin, and variant CYP2C9 alleles are known to influence phenytoin drug levels. Individuals who carry decreased activity CYP2C9 variants may have reduced clearance rates of phenytoin and be at greater risk for dose-related side effects (2). An individual’s human leukocyte antigen B (HLA-B) genotype is a known risk factor for drug-induced hypersensitivity reactions. HLA-B has an important immunological role in pathogen recognition and response, as well as to non-pathogens such as drugs. Carriers of the variant HLA-B*15:02 allele are at high risk of developing potentially life-threatening phenytoin-induced Stevens-Johnson syndrome (SJS) and the related toxic epidermal necrolysis (TEN). The HLA-B*15:02 variant is most commonly found among individuals of Southeast Asian descent, where there is a strong association between SJS/TEN and exposure to carbamazepine. Carbamazepine is an antiseizure medication used to treat the same types of seizures as phenytoin, as well as trigeminal neuralgia and bipolar disorder. The FDA-approved drug label for phenytoin states that consideration should be given to avoiding phenytoin as an alternative for carbamazepine in patients positive for HLA-B*15:02. The label also mentions that variant CYP2C9 alleles may contribute to unusually high levels of phenytoin (1). The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends the use of an antiseizure medication other than carbamazepine, phenytoin (or its prodrug fosphenytoin) for any HLA-B*15:02 carrier regardless of CYP2C9 genotype, patient ancestry or age. CPIC also recommends consideration of at least a 25% reduction in the starting maintenance dose for patients who are CYP2C9 intermediate metabolizers and HLA-B*15:02 negative, and at least a 50% reduction for CYP2C9 poor metabolizers and HLA-B*15:02 negative, with subsequent maintenance doses adjusted based on therapeutic drug monitoring and response (Table 1) (2).

PMID: 28520374