The usefulness of listening social media for pharmacovigilance purposes: a systematic review.

Expert Opin Drug Saf. 2018 Nov;17(11):1081-1093

Authors: Convertino I, Ferraro S, Blandizzi C, Tuccori M

Abstract
INTRODUCTION: Social media mining could be a possible strategy to retrieve drug safety information. The mining of social media is a complex process under progressive evolution, falling into three broad categories: listening (safety data reporting), engaging (follow-up), and broadcasting (risk communication). This systematic review is aimed at evaluating the usefulness and quality of proto-signals by social media listening. Areas covered: In this systematic search, performed according to MOOSE and PRISMA statements, we selected studies, published in MEDLINE, EMBASE, and Google Scholar until 31 December 2017, that listened at least one social media to identify proto-adverse drug events and proto-signals. Expert opinion: The selected 38 studies identified serious and unexpected proto-adverse drug events characterized by poorer information quality as compared with spontaneous reporting databases. This feature allows rarely the evaluation of causal relationships. Proto-signals identified by social media listening had the potential of anticipating pre-specified known signals in only six studies. Moreover, the personal perception of patients reported in social media could be used to implement effective risk communication strategies. However, signal detection in social media cannot be currently recommended for routine pharmacovigilance, due to logistic and technical issues.

PMID: 30285501 [PubMed - indexed for MEDLINE]

Challenging Cases: Management of Immune-Related Toxicity.

Am Soc Clin Oncol Educ Book. 2018 May 23;(38):179-183

Authors: Weber JS

Abstract
The approvals of six checkpoint inhibitory antibodies since 2011 have established immunotherapy for cancer as a fifth treatment modality after chemotherapy, surgery, radiation, and targeted therapy. Long-lasting responses have been observed in melanoma, non-small cell lung cancer, renal cell cancer, and head and neck cancer, to name a few, and more approvals for these drugs undoubtedly are coming in the near future. The application of checkpoint inhibitors has expanded well beyond melanoma, and, with wider use, the management of the immune-related adverse events (irAEs) that accompany these drugs has received increased attention. In this work, several patient cases are presented that highlight how to optimally manage these unique toxicities and that illustrate the basic principles of care for patients who receive checkpoint inhibition.

PMID: 30231403 [PubMed - indexed for MEDLINE]

Once-a-Day Trazodone in the Treatment of Depression in Routine Clinical Practice.

Pharmacology. 2018;102(3-4):206-212

Authors: Češková E, Šedová M, Kellnerová R, Starobová O

Abstract
OBJECTIVE: The aim of the study was to evaluate the efficacy, tolerability, and safety of once-a day trazodone tablets (Trittico Prolong® 300 mg) in patients with moderate to severe depression in routine clinical practice.
METHODS: Men and women ≥18 years old with Montgomery-Åsberg Depression Rating Scale (MADRS) scores > 21 and Clinical Global Impression - Severity (CGI/S) ≥4 were included in this post-authorization, non-interventional, observational prospective safety study, conducted in 8 psychiatric centers in the Czech -Republic. The acute treatment phase lasted 5 weeks: 1 week of titration and 4 weeks of full-dose treatment. Patients had follow-up visits 9 and 21 weeks after commencing -treatment.
RESULTS: Overall, 85 patients were enrolled in the study, of which 80 completed the acute treatment of 5 weeks. There were significant decreases in the overall MADRS score from the baseline mean value of 27.4-21.2 at week 1 (p < 0.001), and a further decrease to 7.9 at week 5 (p < 0.001). The severity of depression according to CGI/S gradually declined. Most patients reported improvement after 6 days of trazodone treatment. The most frequent adverse drug reactions (ADRs) reported were somnolence and fatigue.
CONCLUSIONS: Trazodone, in the new extended-release formulation, had very good effects in clinical practice, both in previously untreated depressive episodes and in episodes not responsive to previous antidepressive therapy.

PMID: 30099450 [PubMed - indexed for MEDLINE]

Quantification of Idelalisib in Human Plasma by Ultra-Performance Liquid Chromatography Coupled to Mass Spectrometry in Negative Ionization Mode.

Ther Drug Monit. 2018 04;40(2):237-244

Authors: Huynh HH, Roessle C, Sauvageon H, Plé A, Madelaine I, Thieblemont C, Mourah S, Goldwirt L

Abstract
BACKGROUND: Idelalisib is the first orally active selective phosphatidylinositol 3-kinase delta inhibitor approved by Food and Drug Administration and European Medicines Agency in 2014 for the treatment of several types of blood cancer. Idelalisib is widely used as a monotherapy or in combination with rituximab, bendamustine, or ofatumumab with a significant efficacy. However, idelalisib has shown increased risk of infection and a higher frequency of serious adverse events. It may be useful to determine idelalisib concentration in human plasma to adjust dose and to manage adverse effects in clinical practice.
METHODS: After a single-step protein precipitation of plasma samples, the chromatographic separation was performed using an ultra-high performance liquid chromatography system coupled with mass tandem spectrometry in a negative ionization mode using isotope-labeled internal standard. This method was validated by studies of its linearity, accuracy, imprecision, limit of quantification, recovery, matrix effect, selectivity, and stability.
RESULTS: The quantification method was linear from 10 to 2500 ng/mL with a 5 ng/mL lower limit of quantification that encompasses the clinical range of drug concentration. The intraday and interday imprecisions were below 8.1% and 11.4%, respectively. The recoveries and matrix effect of idelalisib were 85.6% ± 1.2% and 95.7% ± 3.0%, respectively, which are consistent, precise, and reproducible (coefficient of variation % < 15%). Peak plasma concentration and trough plasma concentration ranges of idelalisib reached 1591-1937 ng/mL and 256.3-303.3 ng/mL, respectively, in 3 follicular lymphoma patients treated with idelalisib 150 mg twice a day.
CONCLUSIONS: A robust and sensitive liquid chromatography-tandem mass spectrometry method was developed and validated to quantify idelalisib concentration in human plasma. This method was effectively applied to 3 follicular lymphoma patients.

PMID: 29529009 [PubMed - indexed for MEDLINE]

Oral lichen planus - Differential diagnoses, serum autoantibodies, hematinic deficiencies, and management.

J Formos Med Assoc. 2018 Sep;117(9):756-765

Authors: Chiang CP, Yu-Fong Chang J, Wang YP, Wu YH, Lu SY, Sun A

Abstract
Oral lichen planus (OLP) is a chronic inflammatory oral mucosal disease that occurs more frequently in middle-aged and elderly female patients. Previous studies indicate that OLP is a T-cell dysfunction-induced localized autoimmune disease. Clinically, six types of OLP, namely reticular, papular, plaque-like, atrophic/erosive, ulcerative, and bullous types, can be identified. OLP more commonly affects buccal mucosa, tongue, and gingiva. It always has a bilateral and symmetric distribution of the oral lesions. Plaque-like and atrophic/erosive OLP may be misdiagnosed as oral leukoplakia and oral erythroleukoplakia, respectively. Our previous study found serum autoantibodies in 195 (60.9%) of the 320 OLP patients. Specific serum anti-nuclear, anti-smooth muscle, anti-mitochondrial, gastric parietal cell, thyroglobulin, and thyroid microsomal autoantibodies are present in 28.1%, 8.4%, 1.6%, 26.3%, 21.3%, and 24.4% of 320 OLP patients, respectively. Furthermore, we also discovered that 21.9%, 13.6%, 7.1%, 0.3%, and 14.8% of 352 OLP patients have hemoglobin, iron, vitamin B12, and folic acid deficiencies, and abnormally high serum homocysteine level, respectively. Therefore, it is very important to examine the serum autoantibody, hematinic and homocysteine levels in OLP patients before starting the treatments for OLP patients. Because OLP is an immunologically-mediated disease, corticosteroids are the drugs of choice for treatment of OLP.

PMID: 29472048 [PubMed - indexed for MEDLINE]

Therapeutic Drug Monitoring of Second-Generation Antipsychotics for the Estimation of Early Drug Effect in First-Episode Psychosis: A Cross-sectional Assessment.

Ther Drug Monit. 2018 04;40(2):257-267

Authors: Bustillo M, Zabala A, Querejeta I, Carton JI, Mentxaka O, González-Pinto A, García S, Meana JJ, Eguiluz JI, Segarra R

Abstract
BACKGROUND: Studies on therapeutic drug monitoring (TDM) of second-generation antipsychotics (SGAs) have provided conflicting results regarding the association between dose, plasma concentrations, and drug effect and have focused rather on analyzing how individual drugs work. No study has attempted to process data from different SGAs globally to offer a panoramic view of the utility of TDM in clinical practice, and data on patients with first-episode psychosis (FEP) are lacking. This study aimed to assess the relationship between dose, plasma concentrations, and drug effect in a sample of patients with FEP, regardless of the SGA prescribed.
METHODS: Data from 64 compliant patients treated with the same SGA during a 2-month follow-up were recorded. Clinical symptoms were assessed using the Positive and Negative Symptoms Scale and the Montgomery-Åsberg Depression Rating Scale. Adverse effects were rated using the Udvalg für Kliniske Undersogelser scale. SGA doses were standardized to chlorpromazine equivalents, and patients were classified into 3 different ranges according to their plasma concentrations (subtherapeutic, therapeutic, and supratherapeutic).
RESULTS: Plasma concentration ranges were proportionally related to dose. Patients with supratherapeutic plasma concentrations were treated with doses significantly higher than those with subtherapeutic concentrations. Dose and plasma concentrations were not associated with early drug effect.
CONCLUSIONS: TDM seems unable to accurately estimate the early effects of SGAs in FEP. Ours is the first study to categorize plasma concentrations of SGAs into ranges for joint processing of data from a larger number of patients.

PMID: 29369974 [PubMed - indexed for MEDLINE]

Weighing in on the risks and benefits of probiotic use in HIV-infected and immunocompromised populations.

Benef Microbes. 2018 Feb 27;9(2):239-246

Authors: Happel AU, Barnabas SL, Froissart R, Passmore JS

Abstract
Probiotics are used in the prophylaxis and treatment of several conditions, including irritable bowel syndrome, diarrhoea, necrotising enterocolitis (NEC) and colic in infants. Despite the long history of probiotic use in humans, there is still significant debate about their efficacy and safety, particularly in HIV-infected and immunocompromised individuals. Here, we reviewed the safety and adverse event (AE) reporting from clinical trials that have tested probiotics in at risk populations, including HIV-infected individuals, the terminally ill and elderly, and neonates. Our analysis suggests that the benefits of probiotic therapy outweigh their potential risks in HIV-infected populations, and in the treatment of colic and NEC in low birth weight or premature neonates. Most case reports of severe AEs were in the elderly and terminally ill, or in those with additional severe medical conditions. We conclude that probiotic use, as adjunctive treatment, is effective and safe in the majority of patients including HIV-infected individuals, although special care should be taken in individuals with extreme immunosuppression and severe medical conditions in all ages.

PMID: 29345159 [PubMed - indexed for MEDLINE]

Computational analysis of calculated physicochemical and ADMET properties of protein-protein interaction inhibitors.

Sci Rep. 2017 04 11;7:46277

Authors: Lagorce D, Douguet D, Miteva MA, Villoutreix BO

Abstract
The modulation of PPIs by low molecular weight chemical compounds, particularly by orally bioavailable molecules, would be very valuable in numerous disease indications. However, it is known that PPI inhibitors (iPPIs) tend to have properties that are linked to poor Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) and in some cases to poor clinical outcomes. Previously reported in silico analyses of iPPIs have essentially focused on physicochemical properties but several other ADMET parameters would be important to assess. In order to gain new insights into the ADMET properties of iPPIs, computations were carried out on eight datasets collected from several databases. These datasets involve compounds targeting enzymes, GPCRs, ion channels, nuclear receptors, allosteric modulators, oral marketed drugs, oral natural product-derived marketed drugs and iPPIs. Several trends are reported that should assist the design and optimization of future PPI inhibitors, either for drug discovery endeavors or for chemical biology projects.

PMID: 28397808 [PubMed - indexed for MEDLINE]

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15 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 2018/11/27

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.

Hydroxymethylglutaryl-CoA reductase inhibitors (statins) for the treatment of sepsis in adults - a systematic review and meta-analysis.

Clin Microbiol Infect. 2018 Nov 22;:

Authors: Pertzov B, Eliakim-Raz N, Atamna H, Trestioreanu AZ, Yahav D, Leibovici L

Abstract
BACKGROUND: The pleiotropic effect of Hydroxymethylglutaryl-CoA reductase inhibitors (statins) might have a beneficial effect in sepsis through several mechanisms.
OBJECTIVES: To assess the efficacy and safety of statins, compared to placebo, for the treatment of sepsis in adults.
DATA SOURCES: We searched the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2017, Issue 12), OVID MEDLINE (from 1966 to January 2018), Embase (Ovid SP, from 1974 to January 2018) and LILACS (from 1986 to January 2018). We also searched the trial registries ISRCTN and ClinicalTrials.gov to January 2018.
STUDY ELIGIBILITY CRITERIA: Randomized controlled trials comparing the treatment of statins versus placebo in adult patients who were hospitalized due to sepsis.
PARTICIPANTS: Adults (16 years and older) hospitalized due to sepsis or that developed sepsis during admission INTERVENTIONS: Treatment with hydroxymethylglutaryl-CoA reductase inhibitors (statins) versus no treatment or placebo.
METHODS: We performed a systematic review of all randomized controlled trials published until January 2018, assessing the efficacy and safety of statins in sepsis treatment. Two primary outcomes were assessed: 30-day overall mortality and deterioration to severe sepsis during management. Secondary outcomes were hospital mortality, need for mechanical ventilation and drug related adverse events.
RESULTS: Fourteen trials evaluating 2628 patients were included. Statins did not reduce 30-day all-cause mortality neither in all patients (risk ratio (RR) 0.96, 95% confidence interval (CI) 0.83-1.10), nor in a subgroup of patients with severe sepsis (RR 0.97, 95% CI 0.84-1.12). The certainty of evidence for both outcomes was high. There was no change in the rate of adverse events between study arms (RR 1.24, 95% CI 0.94 to 1.63). The certainty of evidence for this outcome was high.
CONCLUSIONS: The use of statin therapy in adults for the indication of sepsis is not recommended.

PMID: 30472427 [PubMed - as supplied by publisher]

AMBIsome Therapy Induction OptimisatioN (AMBITION): High Dose AmBisome for Cryptococcal Meningitis Induction Therapy in sub-Saharan Africa: Study Protocol for a Phase 3 Randomised Controlled Non-Inferiority Trial.

Trials. 2018 Nov 23;19(1):649

Authors: Lawrence DS, Youssouf N, Molloy SLF, Alanio A, Alufandika M, Boulware DR, Boyer-Chammard T, Chen T, Dromer F, Hlupeni A, Hope W, Hosseinipour MC, Kanyama C, Lortholary O, Loyse A, Meya DB, Mosepele M, Muzoora C, Mwandumba HC, Ndhlovu CE, Niessen L, Schutz C, Stott KE, Wang D, Lalloo DG, Meintjes G, Jaffar S, Harrison TS, Jarvis JN

Abstract
BACKGROUND: Cryptococcal meningitis (CM) is a major cause of mortality in HIV programmes in Africa despite increasing access to antiretroviral therapy (ART). Mortality is driven in part by limited availability of amphotericin-based treatment, drug-induced toxicities of amphotericin B deoxycholate and prolonged hospital admissions. A single, high-dose of liposomal amphotericin (L-AmB, Ambisome) on a fluconazole backbone has been reported as non-inferior to 14 days of standard dose L-AmB in reducing fungal burden. This trial examines whether single, high-dose L-AmB given with high-dose fluconazole and flucytosine is non-inferior to a seven-day course of amphotericin B deoxycholate plus flucytosine (the current World Health Organization [WHO] recommended treatment regimen).
METHODS: An open-label phase III randomised controlled non-inferiority trial conducted in five countries in sub-Saharan Africa: Botswana, Malawi, South Africa, Uganda and Zimbabwe. The trial will compare CM induction therapy with (1) a single dose (10 mg/kg) of L-AmB given with 14 days of fluconazole (1200 mg/day) and flucytosine (100 mg/kg/day) to (2) seven days amphotericin B deoxycholate (1 mg/kg/day) given alongside seven days of flucytosine (100 mg/kg/day) followed by seven days of fluconazole (1200 mg/day). The primary endpoint is all-cause mortality at ten weeks with a non-inferiority margin of 10% and 90% power. Secondary endpoints are early fungicidal activity, proportion of grade III/IV adverse events, pharmacokinetic parameters and pharmacokinetic/pharmacodynamic associations, health service costs, all-cause mortality within the first two and four weeks, all-cause mortality within the first ten weeks (superiority analysis) and rates of CM relapse, immune reconstitution inflammatory syndrome and disability at ten weeks. A total of 850 patients aged ≥ 18 years with a first episode of HIV-associated CM will be enrolled (425 randomised to each arm). All patients will be followed for 16 weeks. All patients will receive consolidation therapy with fluconazole 800 mg/day to complete ten weeks of treatment, followed by fluconazole maintenance and ART as per local guidance.
DISCUSSION: A safe, sustainable and easy to administer regimen of L-AmB that is non-inferior to seven days of daily amphotericin B deoxycholate therapy may reduce the number of adverse events seen in patients treated with amphotericin B deoxycholate and shorten hospital admissions, providing a highly favourable and implementable alternative to the current WHO recommended first-line treatment.
TRIAL REGISTRATION: ISRCTN, ISRCTN72509687 . Registered on 13 July 2017.

PMID: 30470259 [PubMed - in process]

The spectrum of cutaneous adverse events during Encorafenib and Binimetinib treatment in BRAF mutant advanced melanoma.

J Eur Acad Dermatol Venereol. 2018 Nov 23;:

Authors: Graf NP, Koelblinger P, Galliker N, Conrad S, Barysch M, Mangana J, Dummer R, Cheng PF, Goldinger SM

Abstract
BACKGROUND: BRAF inhibitor encorafenib alone and in combination with MEK inhibitor binimetinib improves survival in BRAF mutated melanoma patients. So far, the range of cutaneous adverse events has been characterized only for established BRAF inhibitors (vemurafenib, dabrafenib) and MEK inhibitors (trametinib, cobimetinib).
OBJECTIVE: The aim of this study was to investigate cutaneous adverse events emerging in melanoma patients treated with encorafenib and binimetinib.
METHODS: Patients treated with BRAF and MEK inhibitors in clinical trials at the University Hospital of Zurich were identified. Frequency and features of cutaneous adverse events as well as their management were assessed based on the prospectively collected clinical and histopathological data. The events emerging during encorafenib and/or binimetinib therapy were compared to other BRAF and MEK inhibitors at the institution and in the literature.
RESULTS: The most frequent cutaneous adverse events observed in patients treated with encorafenib alone (n=24) were palmoplantar hyperkeratosis (54%), palmoplantar erythrodysesthesia (58%) and alopecia (46%). Drug-induced papulopustular eruptions prevailed in patients with binimetinib monotherapy (n=25). The most frequent cutaneous adverse events in patients treated with encorafenib/binimetinib (n=49) was palmoplantar hyperkeratosis (10%).
CONCLUSION: Compared to data published for established BRAFi, encorafenib monotherapy showed less hyperproliferative cutaneous adverse events. In contrast, palmoplantar hyperkeratosis and palmoplantar erythrodysesthesia seem to occur more often. The combination encorafenib with binimetinib is well tolerated and induces few cutaneous adverse events. This article is protected by copyright. All rights reserved.

PMID: 30468696 [PubMed - as supplied by publisher]

Anticholinergic discontinuation and cognitive functions in patients with schizophrenia: a pharmacist-physician collaboration in the outpatient department.

Integr Pharm Res Pract. 2018;7:161-171

Authors: Sathienluckana T, Unaharassamee W, Suthisisang C, Suanchang O, Suansanae T

Abstract
Introduction: Cognitive impairment is a core feature and shows the highest impact on functional outcome in patients with schizophrenia. There have been no previous studies investigating the role of the pharmacist in a multidisciplinary team on cognitive outcomes in patients with schizophrenia.
Purpose: We evaluated the impact of pharmacist intervention on cognitive outcomes in patients with schizophrenia by focusing on anticholinergic discontinuation.
Patients and methods: A prospective, open-label, randomized, controlled study was conducted. Patients with schizophrenia were randomly assigned to either the pharmacist intervention or usual care groups. In the pharmacist intervention group, the pharmacist identified drug-related problems (DRPs) and provided a pharmacotherapy suggestion, while there was no intervention in the usual care group. The primary outcome was mean change from baseline of executive function by using Wisconsin Card Sorting Test (WCST) perseverative errors within the pharmacist intervention group at week 12.
Results: A total of 30 patients completed the study (13 in the pharmacist intervention group and 17 in the usual care group). WCST perseverative errors at the end of the study within the pharmacist intervention group improved significantly from baseline (P=0.003). DRPs at week 12 were reduced by 85.19% and 9.76% in the pharmacist intervention and usual care groups, respectively. The most common intervention was the discontinuation of anticholinergics in patients without extrapyramidal side effects.
Conclusion: Added-on pharmacist intervention in a multidisciplinary team could help to improve cognitive functions in patients with schizophrenia by reducing DRPs and optimizing the drug therapy regimen, especially for anticholinergic discontinuation.

PMID: 30464898 [PubMed]

Intravenous catheter-related adverse events exceed drug-related adverse events in outpatient parenteral antimicrobial therapy.

J Antimicrob Chemother. 2018 Nov 20;:

Authors: Underwood J, Marks M, Collins S, Logan S, Pollara G

Abstract
Background: Drug-related adverse events (AEs) are reported to be common amongst patients receiving outpatient parenteral antimicrobial therapy (OPAT). However, comparative data regarding intravenous (iv) catheter-related AEs are lacking.
Objectives: To compare drug- and iv catheter-related AEs from a large UK OPAT centre.
Patients and methods: We reviewed 544 OPAT episodes [median (IQR) age: 57 (39-71) years, 60% male, 13% with diabetes] with a median (IQR) duration of 7 (2-18) days. Clinically significant drug- and iv catheter-related AEs were calculated as a percentage of OPAT episodes with an AE and also as AEs per 1000 iv drug/catheter days.
Results: Drug-related AEs complicated 13 (2.4%) OPAT episodes at 1.7 (95% CI 0.9-2.9) per 1000 drug days. Catheter-related AEs occurred more frequently, complicating 32 (5.9%) episodes at 5.7 (95% CI 4.2-7.9) per 1000 iv catheter days (χ2 test for difference in AE rate: P < 0.001). Non-radiologically guided midline catheters were associated with the most frequent AEs (n = 23) at 15.6 (95% CI 10.3-23.4) per 1000 iv catheter days compared with other types of iv catheters (HR 8.4, 95% CI 2.4-51.9, P < 0.004), and self-administration was associated with a higher rate of catheter-related AEs at 12.0 (95% CI 6.0-23.9) per 1000 iv catheter days (HR 4.15, 95% CI 1.7-9.1, P = 0.007).
Conclusions: Clinically significant iv catheter-related AEs occurred more frequently than drug-related AEs, especially when using non-radiologically guided midline catheters. Regular review of the need for iv therapy and switching to oral antimicrobials when appropriate is likely to minimize OPAT-related AEs.

PMID: 30462237 [PubMed - as supplied by publisher]

A phase I study of the safety and tolerability of VLX600, an Iron Chelator, in patients with refractory advanced solid tumors.

Invest New Drugs. 2018 Nov 21;:

Authors: Mody K, Mansfield AS, Vemireddy L, Nygren P, Gulbo J, Borad M

Abstract
Introduction VLX600 is a novel iron chelator designed to interfere with intracellular iron metabolism, leading to inhibition of mitochondrial respiration and bioenergetic catastrophe and resultant tumor cell death. Methods We conducted a multicenter, phase 1, dose escalation study to determine the safety and adverse event profile and the maximum tolerated dose and recommended phase 2 dose of VLX600. Other endpoints included pharmacokinetics, and preliminary evidence of anti-cancer efficacy as assessed according to RECIST 1.1 criteria. VLX600 was administered intravenously on days 1, 8, and 15 of each 28-day treatment cycle. Results Nineteen patients were enrolled, and seventeen received at least one dose of VLX600. Dose increments were reduced to 50% after dose level 3 (40 mg) due to the occurrence of a grade 3 pulmonary embolism. The study was then closed early due to slow recruitment. No maximum tolerated dose (MTD) nor RP2D had been identified at the time of study closure. Overall, the drug was well tolerated and no DLTs were observed. Fourteen patients experienced drug-related adverse events of any grade. The most frequently reported drug-related AEs were fatigue, nausea, constipation, vomiting, increased alkaline phosphatase, anemia, and decreased appetite. No formal efficacy or survival analyses were performed. No objective responses were observed, though six patients (32%) had stable disease as best response. Conclusion VLX600 was reasonably well tolerated and, together with preclinical data, there is support for further efforts to explore its activity as single agent and in combination with drugs or radiation.

PMID: 30460505 [PubMed - as supplied by publisher]

The Burden of Repeat Prescribing Medications after a Related Adverse Drug Event.

Healthc Q. 2018 Apr;21(1):36-39

Authors: Welk B, Richard L, Winick-Ng J, Shariff SZ, Clemens KK

Abstract
The use of medications such as glyburide, neuroleptics and benzodiazepines is potentially dangerous in the elderly, as they are linked to adverse drug events such as hypoglycemia and serious falls. We used administrative data from the province of Ontario to determine how often these medications are continued after a patient experiences one of these adverse events. Over a 12-year period, we identified 31,262 patients who had a hospital presentation with hypoglycemia or a fall within three months of starting the previously listed medications. Re-dispensing of these high-risk medications occurred in 55% of patients within six months of the adverse drug event. Among patients with re-dispensed therapies, about 10% had a repeat adverse drug event. These results highlight a common problem that could potentially be addressed with better medication reconciliation and health policies directed at reducing re-dispensing of high-risk medications.

PMID: 30051814 [PubMed - indexed for MEDLINE]

Review of embryo-fetal developmental toxicity studies performed for pharmaceuticals approved by FDA in 2016 and 2017.

Reprod Toxicol. 2018 Sep;80:117-125

Authors: Barrow P

Abstract
Details of embryo-fetal development (EFD) studies were compiled for all FDA drug approvals in 2016-17. Rats and rabbits were used for 63% of small molecule (SM) drugs. The cynomolgus monkey was used for 47% of biopharmaceuticals. Rodent studies using the clinical mAb or animal homologue replaced monkey studies under some circumstances. EFD studies were not required for anti-cancer drugs when the mode of action was associated with known developmental risk. One quarter of SM non-oncology drugs and all tested SM anti-cancer drugs were teratogenic in at least one species. The rat and rabbit were essentially equally sensitive to developmental toxicity. Eighty-nine percent of SM non-cancer drugs induced maternal or fetal toxicity in at least one species at below 25-times human exposure (proposed maximum exposure in the draft revised ICH S5(R3) guideline). The pregnancy and lactation labeling rule (PLLR) has brought consistency to the presentation of EFD data in drug labels.

PMID: 29660390 [PubMed - indexed for MEDLINE]

A randomized, placebo-controlled phase I trial of live, attenuated herpes zoster vaccine in subjects with end-stage renal disease immunized prior to renal transplantation.

Transpl Infect Dis. 2018 Jun;20(3):e12874

Authors: Miller G, Schaefer H, Yoder S, Miller R, Winokur P, Kotloff K, Klassen D, Wierzbicki M, Amegashie C, Edwards K

Abstract
BACKGROUND: Solid organ transplant recipients are at increased risk for reactivation of herpes zoster, or shingles, and have a higher frequency of serious complications including post-herpetic neuralgia. A live, attenuated shingles vaccine is effective and approved for individuals 50 years and older. The vaccine is contraindicated following transplantation, but may be used in patients with renal failure. Utilization of the vaccine has been poor in patients with end-stage renal disease, including those awaiting transplant, owing to concerns for safety, efficacy, and potential sensitization prior to transplant.
METHODS: We conducted a phase I, randomized, placebo-controlled study of the safety and immunogenicity of live, attenuated Oka strain shingles vaccine in subjects prior to or awaiting renal transplant at 3 US centers. Subjects received vaccine a minimum of 4 weeks prior to transplant.
RESULTS: The vaccine was safe and well-tolerated. There were no cases of herpes zoster or rash illness. There was no change in donor-specific antibody or calculated panel reactive antibody after vaccination during the follow-up period. There were no rejection episodes. There was a significant 2.1-fold rise in geometric mean titer of anti-VZV antibody at 5 weeks post-vaccine.
CONCLUSIONS: The data suggest that the shingles vaccine is safe in subjects with ESRD awaiting transplant. Antibody responses were similar to those seen previously in adults >50 years of age and are consistent with a protective response.

PMID: 29512282 [PubMed - indexed for MEDLINE]

Correspondence between negative symptoms and potential sources of secondary negative symptoms over time.

Eur Arch Psychiatry Clin Neurosci. 2018 Sep;268(6):603-609

Authors: Farreny A, Savill M, Priebe S

Abstract
There has been a debate in the literature about the distinction between primary and secondary negative symptoms of schizophrenia. Our aim was to study the associations between negative symptoms and potential sources of secondary negative symptoms over time. A sample of 275 participants with at least mid-moderate negative symptoms was randomized into body psychotherapy or Pilates class in a previous study. No significant differences were found between groups over time and changes in the symptom domains were modest. The present investigation considers the longitudinal correlation between variables of interest at baseline, 3 and 9 months follow-up. Measures were the Clinical Assessment Interview for Negative Symptoms (CAINS), the Positive and Negative Symptom Scale (PANSS), the Calgary Depression Scale (CDSS) and the Simpson-Angus Extrapyramidal side-effects Scale (SAS). Mixed models were computed to test the longitudinal association between these variables. In a sensitivity analysis, the dosages of antipsychotic, illness duration and allocated intervention were taken into account. Overall, the course of extrapyramidal side-effects, depressive and positive symptoms was significantly related to the course of negative symptoms. Only extrapyramidal effects were longitudinally correlated to expressive negative symptoms. The sensitivity analyses showed unaltered results for positive symptoms and depression but a lack of association between extrapyramidal effects and the CAINS outcomes. In conclusion, the unambiguous interpretation between primary and secondary negative symptoms may lead to refined treatment approaches for schizophrenia and to increased effects of the interventions.

PMID: 28577223 [PubMed - indexed for MEDLINE]