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Platelet Function Test Use for Patients with Coronary Artery Disease in the Early 2020s.

J Clin Med. 2020 Jan 10;9(1):

Authors: Fontana P, Roffi M, Reny JL

Abstract
In the field of antithrombotics, precision medicine is of particular interest, as it may lower the incidence of potentially life-threatening side effects. Indeed, antiplatelet drugs such as P2Y12 inhibitors are one of the most common causes of emergency admissions for drug-related adverse events. The last ten years have seen a continuous debate on whether platelet function tests (PFTs) should be used to tailor antiplatelet drugs to cardiovascular patients. Large-scale randomized studies investigating the escalation of antiplatelet therapies according to the results of PFTs were mostly negative. Potent P2Y12 inhibitors are recommended as a first-line treatment in acute coronary syndrome patients, bringing the bleeding risk at the forefront. De-escalation from prasugrel or ticagrelor to clopidogrel is now considered, with or without the use of a PFT. This review covers recent advances in escalation and de-escalation strategies based on PFTs in various clinical settings. It also describes the main features of the most popular platelet function tests as well as the potential added value of genetic testing. Finally, we detail practical suggestions on how PFTs could be used in clinical practice.

PMID: 31936845 [PubMed]

Critical View on the Usage of Ribavirin in Already Existing Psychostimulant-Use Disorde.

Curr Pharm Des. 2020 Jan 14;:

Authors: Petković B, Kesić S, Pešić V

Abstract
Substance-use disorder represents a frequently hidden non-communicable chronic disease. Patients with intravenous drug addiction are at high risk of direct exposure to a variety of viral infections and are considered to be the largest subpopulation infected with the hepatitis C virus. Ribavirin is a synthetic nucleoside analog that has been used as an integral component of hepatitis C therapy. However, ribavirin medication is quite often associated with pronounced psychiatric adverse effects. It is not well understood to what extent ribavirin per se contributes to changes in drug-related neurobehavioral disturbances, especially in the case of psychostimulant drugs such as amphetamine. It is now well-known that repeated amphetamine usage produces psychosis in humans and behavioral sensitization in animals. On the other hand, ribavirin has an affinity for adenosine A1 receptors that antagonistically modulate the activity of dopamine D1 receptors, which play a critical role in the development of behavioral sensitization. This review will focus on the current knowledge of neurochemical/neurobiological changes that exist in the psychostimulant drug-addicted brain itself and the antipsychotic-like efficiency of adenosine agonists. Particular attention will be paid to the potential side effects of ribavirin therapy, and the opportunities and challenges related to its application in already existing psychostimulant-use disorder.

PMID: 31939725 [PubMed - as supplied by publisher]

Protective effects of Ginkgo biloba L. against natural toxins, chemical toxicities, and radiation: A comprehensive review.

Phytother Res. 2019 Nov;33(11):2821-2840

Authors: Omidkhoda SF, Razavi BM, Hosseinzadeh H

Abstract
Nowadays in our developing and industrial world, humans' health or even their life is threatened by exposure to poisons. In this situation, detecting a protective compound could be helpful and interesting. In the present article, we collected and reviewed all studies, which have been conducted so far about the protective effects of Ginkgo biloba L. (GB), one of the most ancient medicinal tree species, against toxicities induced by chemical toxic agents, natural toxins, and also radiation. In overall, investigations showed that GB exerts the antioxidant, antiinflammatory, antiapoptotic, and antigenotoxicity effects in different toxicities. There are also some special mechanisms about its protective effects against some specific toxic agents, such as acetylcholine esterase inhibition in the aluminium neurotoxicity or membrane-bond phosphodiesterase activation in the triethyltin toxicity. Ginkgolide A was the most investigated active ingredient of G. biloba leaf extract as a protective compound against toxicities, which had the similar effects of total extract. A few clinical studies have been conducted in this field, which demonstrated the beneficial effects of GB against toxic agents. However, the promising effects of this valuable herbal extract will practically remain useless without carrying out more clinical studies and proving its effects on human beings.

PMID: 31429152 [PubMed - indexed for MEDLINE]

Académie nationale de pharmacie.

Ann Biol Clin (Paris). 2019 Jun 01;77(3):355-356

Authors:

PMID: 31219425 [PubMed - indexed for MEDLINE]

Pylera® plus ranitidine vs Pylera® plus esomeprazole in first-line treatment of Helicobacter pylori infection: Two pilot studies.

Helicobacter. 2019 Oct;24(5):e12606

Authors: Ciccaglione AF, Cellini L, Marzio L

Abstract
BACKGROUND: Several studies have shown that Pylera® (three-in-one capsules containing 140 mg bismuth potassium subcitrate, 125 metronidazole, and tetracycline 125 mg) in association with omeprazole or esomeprazole is a good option in the treatment of Helicobacter pylori infection. In particular, the adjunction of a PPI to Pylera® may be useful to overcome metronidazole resistance. However, omeprazole and its derivatives can promote greater bismuth absorption and enhance its toxicity. The H2 receptor antagonist (H2RA) ranitidine seems to induce less bismuth absorption and as a consequence less systemic toxicity.
AIM: To evaluate whether Pylera® in combination with esomeprazole or with ranitidine is equally effective in the treatment of H. pylori infection.
MATERIAL AND METHODS: Two separate groups of patients were treated simultaneously. One group was treated with Pylera® three capsules qid plus esomeprazole 40 mg bid for 10 days (group A), and the other group was treated with Pylera® three capsules qid plus ranitidine 300 mg bid for 10 days (group B). H. pylori eradication was defined as a negative result in 13 C urea breath test performed at least 8 weeks after the end of treatment with a delta-over-baseline value less than 5.
RESULTS: Thirty-two patients were recruited for group A and thirty-three patients in group B. Eradication rates were 93.7% (30/32) and 90.9% (30/33), respectively, at intention-to-treat analysis, and 96.6% (29/30) and 93.3% (28/30), respectively, at per-protocol analysis. Adverse events occurred in 26 patients and led to the suspension of treatment in one patient in group A and in one patient in group B.
CONCLUSION: The results showed that Pylera® plus a PPI or ranitidine were equally effective in the population studied. The high cure rates of bismuth triple therapy (without an antisecretory drug) and the lack of susceptibility testing make it impossible to exclude the possibility that the results would have been similar if neither the PPI nor the ranitidine were given.

PMID: 31168941 [PubMed - indexed for MEDLINE]

Incorporating User Generated Content for Drug Drug Interaction Extraction Based on Full Attention Mechanism.

IEEE Trans Nanobioscience. 2019 07;18(3):360-367

Authors: Xu B, Shi X, Yin Y, Zhao Z, Zheng W, Lin H, Yang Z, Wang J, Xia F

Abstract
It is crucial for doctors to fully understand the interaction between drugs in prescriptions, especially when a patient takes multiple medications at the same time during treatment. The purpose of drug drug interaction (DDI) extraction is to automatically obtain the interaction between drugs from biomedical literature. Current state-of-the-art approaches for DDI extraction task are based on artificial intelligence and natural language processing. While such existing DDI extraction methods can provide more knowledge and enhance the performance through external resources such as biomedical databases or ontologies, due to the difficulty of updating, these external resources are delayed. In fact, user generated content (UGC) is another kind of external medical resources that can be quickly updated. We are trying to use UGC resources to provide more available information for our deep learning DDI extraction method. In this paper, we present a DDI extraction approach through a new attention mechanism called full-attention which can combine the UGC information with contextual information. We conducted a series of experiments on the DDI 2013 Evaluation dataset to evaluate our method. Experiments show improved performance compared with the state of the art and UGC-DDI model achieves a competitive F-score of 0.712.

PMID: 31144641 [PubMed - indexed for MEDLINE]

Pharmacological and residual effects in randomized placebo-controlled trials. A structural causal modelling approach.

Rev Epidemiol Sante Publique. 2019 Jul;67(4):267-274

Authors: Mouchart M, Bouckaert A, Wunsch G

Abstract
BACKGROUND: Distinguishing between pharmacological and residual effects, this paper considers the problem of causal assessment in the case of a particular model, namely a Sure Outcome of Random Events (SORE) model developed for the analysis of data from a randomized placebo-controlled double-blind trial of a drug.
METHOD: This model takes into account two kinds of observable effects, a therapeutic effect and a side-effect. For each observable effect, two latent factors are considered, i.e. a pharmacological (or explained) factor and a residual (or unexplained) one.
RESULTS: The model presents a plausible mechanism generating the observed and latent outcomes, recursively decomposed into an ordered sequence of sub-mechanisms.
CONCLUSIONS: The characteristics of this model leads to a novel assessment of causality that evaluates the effect of latent variables and of the bias resulting from ignoring the structural features of the data generating process. This approach is illustrated by a numerical example, along with a case study based on a secondary analysis of real data.

PMID: 31056218 [PubMed - indexed for MEDLINE]

[Which follow-up for innovative treatments?]

Med Sci (Paris). 2019 Mar;35 Hors série n° 1:54-56

Authors: Campana-Salort E, Espil-Taris C, Prigent H, de Antonio M, Lebrun-Vignes B, Tiffreau V, Honnet G

PMID: 30943166 [PubMed - indexed for MEDLINE]

Profiling antimicrobial peptides from the medical maggot Lucilia sericata as potential antibiotics for MDR Gram-negative bacteria.

J Antimicrob Chemother. 2019 01 01;74(1):96-107

Authors: Hirsch R, Wiesner J, Marker A, Pfeifer Y, Bauer A, Hammann PE, Vilcinskas A

Abstract
Background: The ability of MDR Gram-negative bacteria to evade even antibiotics of last resort is a severe global challenge. The development pipeline for conventional antibiotics cannot address this issue, but antimicrobial peptides (AMPs) offer an alternative solution.
Objectives: Two insect-derived AMPs (LS-sarcotoxin and LS-stomoxyn) were profiled to assess their suitability for systemic application in humans.
Methods: The peptides were tested against an extended panel of 114 clinical MDR Gram-negative bacterial isolates followed by time-kill analysis, interaction studies and assays to determine the likelihood of emerging resistance. In further in vitro studies we addressed cytotoxicity, cardiotoxicity and off-target interactions. In addition, an in vivo tolerability and pharmacokinetic study in mice was performed.
Results: LS-sarcotoxin and LS-stomoxyn showed potent and selective activity against Gram-negative bacteria and no cross-resistance with carbapenems, fluoroquinolones or aminoglycosides. Peptide concentrations of 4 or 8 mg/L inhibited 90% of the clinical MDR isolates of Escherichia coli, Enterobacter cloacae, Acinetobacter baumannii and Salmonella enterica isolates tested. The 'all-d' homologues of the peptides displayed markedly reduced activity, indicating a chiral target. Pharmacological profiling revealed a good in vitro therapeutic index, no cytotoxicity or cardiotoxicity, an inconspicuous broad-panel off-target profile, and no acute toxicity in mice at 10 mg/kg. In mouse pharmacokinetic experiments LS-sarcotoxin and LS-stomoxyn plasma levels above the lower limit of quantification (1 and 0.25 mg/mL, respectively) were detected after 5 and 15 min, respectively.
Conclusions: LS-sarcotoxin and LS-stomoxyn are suitable as lead candidates for the development of novel antibiotics; however, their pharmacokinetic properties need to be improved for systemic administration.

PMID: 30272195 [PubMed - indexed for MEDLINE]

Artificial Intelligence Within Pharmacovigilance: A Means to Identify Cognitive Services and the Framework for Their Validation.

Pharmaceut Med. 2019 Apr;33(2):109-120

Authors: Mockute R, Desai S, Perera S, Assuncao B, Danysz K, Tetarenko N, Gaddam D, Abatemarco D, Widdowson M, Beauchamp S, Cicirello S, Mingle E

Abstract
INTRODUCTION: Pharmacovigilance (PV) detects, assesses, and prevents adverse events (AEs) and other drug-related problems by collecting, evaluating, and acting upon AEs. The volume of individual case safety reports (ICSRs) increases yearly, but it is estimated that more than 90% of AEs go unreported. In this landscape, embracing assistive technologies at scale becomes necessary to obtain a higher yield of AEs, to maintain compliance, and transform the PV professional work life.
AIM: The aim of this study was to identify areas across the PV value chain that can be augmented by cognitive service solutions using the methodologies of contextual analysis and cognitive load theory. It will also provide a framework of how to validate these PV cognitive services leveraging the acceptable quality limit approach.
METHODS: The data used to train the cognitive service were an annotated corpus consisting of 20,000 ICSRS from which we developed a framework to identify and validate 40 cognitive services ranging from information extraction to complex decision making. This framework addresses the following shortcomings: (1) needing subject-matter expertise (SME) to match the artificial intelligence (AI) model predictions to the gold standard, commonly referred to as 'ground truth' in the AI space, (2) ground truth inconsistencies, (3) automated validation of prediction missing context, and (4) auto-labeling causing inaccurate test accuracy. The method consists of (1) conducting contextual analysis, (2) assessing human cognitive workload, (3) determining decision points for applying artificial intelligence (AI), (4) defining the scope of the data, or annotated corpus required for training and validation of the cognitive services, (5) identifying and standardizing PV knowledge elements, (6) developing cognitive services, and (7) reviewing and validating cognitive services.
RESULTS: By applying the framework, we (1) identified 51 decision points as candidates for AI use, (2) standardized the process to make PV knowledge explicit, (3) embedded SMEs in the process to preserve PV knowledge and context, (4) standardized acceptability by using established quality inspection principles, and (5) validated a total of 126 cognitive services.
CONCLUSION: The value of using AI methodologies in PV is compelling; however, as PV is highly regulated, acceptability will require assurances of quality, consistency, and standardization. We are proposing a foundational framework that the industry can use to identify and validate services to better support the gathering of quality data and to better serve the PV professional.

PMID: 31933254 [PubMed - in process]

An investigation into the avoidability of adverse drug reactions using the LAAT and modified Hallas tools.

Medicine (Baltimore). 2020 Jan;99(1):e18569

Authors: Danjuma MI, Shokri SA, Abubeker IY, Malik AE, Abdallah IMH, Shafei MNE, Fatima H, Mahmoud M, Hussain T, Maghoub Y, Sajid J, Zouki ANE

Abstract
An adverse drug reactions avoidability tool called the Liverpool ADR avoidability assessment tool (LAAT) was recently developed (for research purposes), and subsequently validated with mixed interrater reliability (IRR). We investigated the comparative IRR of this tool in an inpatient cohort to ascertain its practical application in this setting.The patient population was comprised of 44 ADR drug pairs drawn from an observational prospective cohort of patents with ADR attending a Weill Cornell Medicine-affiliated tertiary medical Centre in Doha Qatar (Hamad General Hospital). Using the LAAT, and modified Hallas tools, 4 independent raters (2 Clinical Pharmacologists, and 2 General Physicians) assessed and scored the 44 ADR-drug pairs. Agreement proportions between the rating pairs were evaluated as well individual/overall kappa statistics and intraclass correlation coefficients. We evaluated the weight of each of the 7 questions on the LAAT tool to ascertain its determinative role.Across 44 ADR-drug pairs, the overall median Fleiss kappa using the LAAT, and modified Hallas tools were 0.67 (interquartile range (IQR) 0.55, 0.76), 0.36 (IQR, 0.23-0.71) respectively. The overall percentage pairwise agreement with the LAAT and modified Hallas tools were 78.5%, and 62.2% respectively. Exact pairwise agreement occurred in 37 out of 44 (range 0.71-1), and 27 of 44 (0.53-0.77) ADR-drug pairs using the LAAT and modified Hallas tools respectively. Using the LAAT tool, the overall intraclass correlation coefficient was 0.68 (CI 0.55, 0.79), and 0.37 (CI 0.22, 0.53) with the modified Hallas tool.We report a higher proportion of "possible" and "definite" avoidability outcomes of adverse drug reactions compared with the modified Hallas, or that reported by developers of the LAAT tool. Although initially developed for research purposes, our report has suggested for the first time a potential applicability of this tool in clinical environment as well.

PMID: 31895800 [PubMed - indexed for MEDLINE]

Beyond Pegylated Interferon-Alpha: New Treatments for Hepatitis Delta.

AIDS Rev. 2019;21(3):126-134

Authors: Deterding K, Wedemeyer H

Abstract
Persistent coinfection with the hepatitis B/D viruses (HDV) represents the most severe form of viral hepatitis. Hepatitis D often leads to liver cirrhosis, hepatic decompensation, and hepatocellular carcinoma. The current treatment options are limited as only pegylated interferon-alpha (PEG-IFNa) has efficacy against HDV. However, treatment response is still unsatisfactory with 25-40% HDV RNA suppression after 1-2 years. In addition, late HDV RNA relapses have been described during long-term follow-up. Fortunately, new treatment options for patients with chronic hepatitis delta are now on the horizon. The hepatocyte entry inhibitor bulevirtide (formerly myrcludex B) and the farnesyl transferase inhibitor lonafarnib are currently explored in patients with chronic hepatitis delta in Phase 3 clinical studies. The nucleic acid inhibitor REP-2139-Ca and PEG-IFN-lambda are studied in Phase 2 trials. We here summarize data on the efficacy of these new antiviral drugs and the existing safety data on the treatment of HDV infection.

PMID: 31532397 [PubMed - indexed for MEDLINE]

Molecular Docking: Shifting Paradigms in Drug Discovery.

Int J Mol Sci. 2019 Sep 04;20(18):

Authors: Pinzi L, Rastelli G

Abstract
Molecular docking is an established in silico structure-based method widely used in drug discovery. Docking enables the identification of novel compounds of therapeutic interest, predicting ligand-target interactions at a molecular level, or delineating structure-activity relationships (SAR), without knowing a priori the chemical structure of other target modulators. Although it was originally developed to help understanding the mechanisms of molecular recognition between small and large molecules, uses and applications of docking in drug discovery have heavily changed over the last years. In this review, we describe how molecular docking was firstly applied to assist in drug discovery tasks. Then, we illustrate newer and emergent uses and applications of docking, including prediction of adverse effects, polypharmacology, drug repurposing, and target fishing and profiling, discussing also future applications and further potential of this technique when combined with emergent techniques, such as artificial intelligence.

PMID: 31487867 [PubMed - indexed for MEDLINE]

Evaluation of anidulafungin in the treatment of intra-abdominal candidiasis: a pooled analysis of patient-level data from 5 prospective studies.

Eur J Clin Microbiol Infect Dis. 2019 Oct;38(10):1849-1856

Authors: Sganga G, Wang M, Capparella MR, Tawadrous M, Yan JL, Aram JA, Montravers P

Abstract
The incidence of nosocomial invasive fungal infections involving Candida spp. has increased markedly in recent years in patients undergoing abdominal surgery. This post hoc analysis aimed to determine the efficacy and safety of anidulafungin treatment in patients with intra-abdominal candidiasis (IAC) from five prospective studies (one comparative and four open-label) of adult surgical patients with microbiologically confirmed Candida intra-abdominal infection. Patients received an intravenous (IV) loading dose of anidulafungin 200 mg, followed by a daily 100-mg maintenance dose. Per study protocols, some patients could be switched to an oral azole after ≥ 5 or ≥ 10 days of IV treatment. Antifungal treatment was maintained for ≥ 14 days after the last positive Candida culture and resolution of symptoms. The global response rate (GRR) at the end of IV treatment (EOIVT) was the primary endpoint. GRR at the end of therapy (EOT), all-cause mortality at days 14 and 28, and safety was also evaluated. Seventy-nine patients had IAC from peritoneal fluid or hepatobiliary tract. C. albicans (72.2%) and C. glabrata (32.9%) were the most common pathogens. Overall GRR was 73.4% and 67.1% at EOIVT and EOT, respectively. All-cause mortality was 17.7% at day 14 and 24.1% at day 28 in the modified intent-to-treat population. Anidulafungin was well tolerated in this population, with most adverse events mild or moderate in severity. In these patients with IAC, anidulafungin showed a GRR at EOIVT similar to the anidulafungin registrational trial, and the results of our analysis confirmed the known safety profile of anidulafungin. ClinicalTrials.gov registration number NCT00496197, registered July 3, 2007, https://clinicaltrials.gov/ct2/show/study/NCT00496197 ; ClinicalTrials.gov registration number NCT00548262, registered October 19, 2007, https://clinicaltrials.gov/ct2/show/record/NCT00548262 ; ClinicalTrials.gov registration number NCT00537329, registered September 25, 2007, https://clinicaltrials.gov/ct2/show/record/NCT00537329 ; ClinicalTrials.gov registration number NCT00689338, registered May 29, 2008, https://clinicaltrials.gov/ct2/show/study/NCT00689338 ; ClinicalTrials.gov registration number NCT00805740, registered November 26, 2008, https://clinicaltrials.gov/ct2/show/NCT00805740.

PMID: 31280481 [PubMed - indexed for MEDLINE]

Elaboration and validation of a drug administration checklist for patients in research protocols.

Rev Gaucha Enferm. 2019;40(spe):e20180311

Authors: Cardoso ASF, Muller S, Echer IC, Rabelo-Silva ER, Boni FG, Ribeiro AS

Abstract
OBJECTIVE: To describe the elaboration and validation of a checklist as a strategy for safe drug administration.
METHOD: It is a Validation study by consensus of experts conducted from January to June 2018, in a Clinical Research Center of a university hospital. The checklist was validated by three nurses, two nursing technicians, a pharmacist, two nurse teachers and one medical teacher, all with extensive experience in drug administration and in clinical research. For the final version of the checklist, a consensus of 100% was considered.
RESULTS: A guide was prepared consisting of six items to be checked by the care team before, during and after administration of Clinical Research drugs.
CONCLUSION: The validation of the checklist provided guiding elements for the prevention of behaviors that could lead to the risk of adverse events and also allowed the care teams to seek safe strategies of care in drug administration.

PMID: 31038601 [PubMed - indexed for MEDLINE]

Lamotrigine drug interactions in combination therapy and the influence of therapeutic drug monitoring on clinical outcomes in paediatric patients.

Basic Clin Pharmacol Toxicol. 2019 Jul;125(1):26-33

Authors: Koristkova B, Grundmann M, Brozmanova H, Kacirova I

Abstract
The aim was to study the impact of therapeutic drug monitoring (TDM) on paediatric patients on lamotrigine therapy and the evaluation of possible drug interactions, especially in triple antiepileptic drug combinations. During the period of 2001-2015, 1308 pre-dose samples were taken from 430 patients <15 years of age as part of routine TDM. Drug interactions were evaluated using calculation of lamotrigine clearance. Valproic acid decreased lamotrigine clearance by 54% in bitherapy, and by 21% in triple therapy with carbamazepine. Carbamazepine increased lamotrigine clearance by 191% in bitherapy. Levetiracetam and topiramate had no effect. The upper limit of lamotrigine therapeutic range (TR) was exceeded in 2% of cases in monotherapy, and in 6%-7% of cases in bi- or triple therapy. About 61% of plasma levels were found within the TR during 2001-2005, compared to 75% and 74% during 2006-2010 and 2011-2015, respectively. Adverse drug reactions (ADRs) were reported in 22 cases. Higher number of supratherapeutic levels in combination therapy led to a 3-fold increase in incidence of ADRs. Seizures occurred more often daily and monthly during 2001-2005 and in patients with three or four antiepileptic drugs in combination. Carbamazepine only partially compensated for the inhibitory effect of valproic acid. Lamotrigine clearance in monotherapy in children is similar to adults, but in polytherapy was found higher susceptibility to induction. A significantly higher number of supratherapeutic lamotrigine levels were found in combinations with valproate. Despite poor correlation with TR, both seizure frequency and ADRs declined after the implementation of TDM.

PMID: 30681278 [PubMed - indexed for MEDLINE]

Fosfomycin in severe infections due to genetically distinct pan-drug-resistant Gram-negative microorganisms: synergy with meropenem.

J Antimicrob Chemother. 2019 01 01;74(1):177-181

Authors: Perdigão Neto LV, Oliveira MS, Martins RCR, Marchi AP, Gaudereto JJ, da Costa LATJ, de Lima LFA, Takeda CFV, Costa SF, Levin AS

Abstract
Background: In vitro and clinical studies using parenteral fosfomycin have suggested the possibility of using this drug against infections caused by MDR microorganisms. The aim of this study was to describe a case series of patients treated with fosfomycin who had severe infections caused by pan-drug-resistant Gram-negative bacteria.
Methods: We describe a prospective series of cases of hospitalized patients with infections caused by Gram-negative bacteria resistant to β-lactams and colistin, treated with 16 g of fosfomycin daily for 10-14 days. Isolates were tested for antimicrobial susceptibility and synergism of fosfomycin with meropenem. We tested for resistance genes and performed typing using PCR and WGS.
Results: Thirteen patients received fosfomycin (seven immunosuppressed); they had bloodstream infections (n = 11; 85%), ventilator-associated pneumonia (n = 1; 8%) and surgical site infection (n = 1; 8%), caused by Klebsiella pneumoniae (n = 9), Serratia marcescens (n = 3) and Pseudomonas aeruginosa (n = 1). Overall, eight (62%) patients were cured. Using time-kill assays, synergism between fosfomycin and meropenem occurred in 9 (82%) of 11 isolates. Typing demonstrated that K. pneumoniae were polyclonal. Eight patients (62%) had possible adverse events, but therapy was not discontinued.
Conclusions: Fosfomycin may be safe and effective against infections caused by pan-drug-resistant Gram-negative microorganisms with different antimicrobial resistance mechanisms and there seems to be synergism with meropenem.

PMID: 30376073 [PubMed - indexed for MEDLINE]

Pharmacokinetics of dolutegravir with and without darunavir/cobicistat in healthy volunteers.

J Antimicrob Chemother. 2019 01 01;74(1):149-156

Authors: Elliot ER, Cerrone M, Else L, Amara A, Bisdomini E, Khoo S, Owen A, Boffito M

Abstract
Background: Dolutegravir combined with darunavir/cobicistat is a promising NRTI-sparing and/or salvage strategy for the treatment of HIV-1 infection.
Methods: This Phase I, open-label, 57 day, crossover, pharmacokinetic (PK) study, enrolled healthy volunteers aged 18-65 years, who were randomized to one of two groups. Group 1 received dolutegravir (50 mg) once daily for 14 days followed by a 7 day washout, then a 14 day dolutegravir/darunavir/cobicistat (DTG/DRV/COBI) once-daily co-administration period followed by a 7 day washout and finally a 14 day period of darunavir/cobicistat (800/150 mg) once daily. Group 2 followed the same sequence starting with darunavir/cobicistat and concluding with dolutegravir. Each group underwent intensive PK sampling over 24 h on day 14 of each drug period and DTG/DRV/COBI concentrations were measured using validated LC-MS/MS methods.
Results: Twenty participants completed all PK phases. Thirteen were female and median age and BMI were 33.5 years and 27 kg/m2. Dolutegravir geometric mean ratios (GMR, DTG/DRV/COBI versus dolutegravir alone) and 90% CI for Cmax, AUC0-24 and C24 were 1.01 (0.92-1.11), 0.95 (0.87-1.04) and 0.9 (0.8-1.0), respectively. Darunavir GMR (DRV/COBI/DTG versus darunavir/cobicistat alone) and 90% CI for Cmax, AUC0-24 and C24 were 0.90 (0.83-0.98), 0.93 (0.86-1.00) and 0.93 (0.78-1.11), respectively. No grade 3 or 4 adverse events or laboratory abnormalities were observed.
Conclusions: Concentrations of dolutegravir and darunavir, when boosted with cobicistat, decreased by <10% during co-administration, suggesting this combination can be prescribed safely in the treatment of HIV-1, with no adjustment to current guideline-recommended dosages.

PMID: 30272231 [PubMed - indexed for MEDLINE]

Gabapentin for Pain Management after Osmotic Dilator Insertion and prior to Dilation and Evacuation: A Randomized Controlled Trial.

Contraception. 2020 Jan 09;:

Authors: Creinin MD, Schimmoeller NR, Matulich MC, Hou MY, Melo J, Chen MJ

Abstract
OBJECTIVE: To evaluate if gabapentin 600 mg reduces pain after osmotic dilator placement the day before a dilation and evacuation (D&E) procedure.
STUDY DESIGN: We conducted a double-blind, placebo-controlled, randomized (stratified by vaginal parity) trial among women undergoing osmotic dilator placement before D&E at 15 to 23 5/7 weeks gestation. Subjects received gabapentin 600 mg or placebo 30 minutes before dilator placement, with re-dosing 8 hours later. We assessed pain after dilator placement using a numeric rating scale (NRS; scale 0-10) at 5 minutes, 2, 4, and 8 hours, and at presentation for D&E. The primary outcome was median NRS pain score change from baseline to 8 hours after dilator placement. Secondary outcomes included gabapentin-related side effects and analgesic use.
RESULTS: Of 121 randomized women, we excluded three subjects (allergic reaction [placebo], randomization error, no NRS data), leaving 60 gabapentin and 58 placebo subjects. Of 110 (93%) women who provided 8-hour data, median pain score changes from baseline did not differ between gabapentin and placebo groups overall (2 vs. 2.5, p=0.52), in vaginally nulliparous women (2 vs. 4, p=0.10) or in parous women (2 vs. 1.5, p=0.37). We found no statistically significant differences in median pain score change from baseline to any timepoint overall or when stratified by parity. Beginning at 2 hours after dilator placement, more gabapentin than placebo users experienced dizziness (29/53[55%] vs. 11/53[21%], p=0.001) and tiredness (34/54[63%] vs. 17/54[31%], p=0.002). The proportion of women using narcotics did not differ between gabapentin (35/60[58%]) or placebo (40/58[69%]) users (p=0.26).
CONCLUSIONS: Gabapentin does not reduce pain with overnight osmotic dilator placement prior to D&E and causes drug-related side effects.

PMID: 31927028 [PubMed - as supplied by publisher]