Characteristics and outcomes of patients with hyperthyroidism attending a hospital endocrine clinic-A retrospective study.

Endocrinol Diabetes Metab. 2019 Jan;2(1):e00046

Authors: Sim SY, Lethem C, Coppini DV

Abstract
Aims: A study looking at the distribution, management and outcomes of patients referred to a secondary care endocrine clinic with a diagnosis of hyperthyroidism.
Methods: Retrospective longitudinal study of 442 patients referred over a 15-year period (2002-2017) with a diagnosis of hyperthyroidism to a secondary care endocrine clinic. Information on demographics, diagnosis, treatments and outcomes was recorded as patients attended for clinic visits. Patients were initially treated with 1-2 courses of thionamides and subsequently referred for radioiodine or surgery in cases of relapse.
Results: Patients (75% female, age range 17-91 years) were treated with thionamides for an average of 295 days. As expected, the majority of patients had Graves Disease (GD) (80%), followed by those with multinodular goitre (MNG) (8.6%), amiodarone-induced hyperthyroidism (6.7%) and toxic nodule (3.7%). Drug-induced remission rates were best seen in patients with GD (43%), and side effects necessitating change in treatment were relatively low (2.5%). In 121 patients who received radioiodine, hypothyroidism occurred in 50% of patients and was commoner in patients with GD (65%) than in those with MNG (22%) and toxic nodule (6.3%).
Conclusions: This study is only one of a few reporting on the characteristics of patients with hyperthyroidism attending a typical secondary care endocrine clinic. Whilst we appreciate its limitations, we encourage similar methods of collecting valuable real world data to facilitate conduction of specialist peer review visits in other similar clinic settings.

PMID: 30815574 [PubMed]

[Immunogenicity of inacitivated quadrivalent influenza vaccine in adults aged 18-64 years: A systematic review and Meta-analysis].

Zhonghua Liu Xing Bing Xue Za Zhi. 2018 Dec 10;39(12):1636-1641

Authors: Meng ZY, Zhang JY, Zhang ZG, Luo D, Yang XM

Abstract
Objective: To evaluate the immunogenicity of inactivated quadrivalent influenza vaccine (QIV) in adults aged 18-64 years, through a Meta-analysis. Methods: Literature was retrieved by searching the Medline, Cochrane Library, Science Direct in the past decade. All the studies were under random control trial (RCT) and including data related to immunogenicity which involving sero-protection rate (SPR) and sero-conversion rate (SCR) of the QIV, versus inactivated trivalent influenza vaccine (TIV) in the population aged 18 to 64. Revman 5.3 software was employed to manipulate the pooled date of the included literature. Result: A total of 8 studies for the SPR and SCR of the shared strains (two A lineage and one B lineage) were included. There appeared no significant differences in the response rates between the two vaccines. As for QIV versus TIV (B/Yamagata), the pooled RR of the SPR for B/Victoria was 1.28 (95%CI: 1.08-1.51, P<0.05), with the pooled RR of the SCR for B/Victoria as 1.94 (95%CI: 1.50-2.50, P<0.05). For QIV versus TIV (B/Victoria), the pooled RR of the SPR for B/Yamagata as 1.10 (95%CI: 1.02-1.18, P<0.05), and the pooled RR of SCR for B/Yamagata as 1.99 (95%CI: 1.34-2.97, P<0.05). Conclusion: In the population aged 18-64 years, inactivated QIV was equivalently immunogenic against the shared three strains included in the activated TIV while a superior immunogenic effect was noticed in the vaccine strain which did not include the inactivated QIV.

PMID: 30572392 [PubMed - indexed for MEDLINE]

Adverse drug reactions.

Anaesthesia. 2018 Jan;73 Suppl 1:76-84

Authors: Patton K, Borshoff DC

Abstract
Adverse drug reactions are a cause of significant morbidity and mortality to patients and a source of financial burden to the healthcare system. Of the wide spectrum of adverse drug reactions, the most concerning to the anaesthetist remain anaphylaxis and malignant hyperthermia. Although the incidence of anaphylaxis under anaesthesia is difficult to ascertain, it occurs commonly enough that most anaesthetists will manage at least one case in their career. The wide range of drugs given in the peri-operative period and the variable presentation in the anaesthetised patient can delay diagnosis and treatment, and adversely affect outcome. Furthermore, despite improvements in testing, causative drugs can still be difficult to identify, as adverse reactions may be mediated by mechanisms other than IgE activation. With an increase in the reporting of anaphylaxis to newer anaesthetic drugs such as sugammadex, combined with change over the recent decades in the most likely causative peri-operative agents, it is imperative anaesthetists remain up to date on recent developments. In addition, they should be vigilant to patient characteristics, including pharmacogenetic variations that may predispose to adverse drug reactions, in order to help minimise risks of a reaction. The severity of adverse drug reactions to peri-operative drugs means morbidity and mortality remain high.

PMID: 29313907 [PubMed - indexed for MEDLINE]

A unified frame of predicting side effects of drugs by using linear neighborhood similarity.

BMC Syst Biol. 2017 12 14;11(Suppl 6):101

Authors: Zhang W, Yue X, Liu F, Chen Y, Tu S, Zhang X

Abstract
BACKGROUND: Drug side effects are one of main concerns in the drug discovery, which gains wide attentions. Investigating drug side effects is of great importance, and the computational prediction can help to guide wet experiments. As far as we known, a great number of computational methods have been proposed for the side effect predictions. The assumption that similar drugs may induce same side effects is usually employed for modeling, and how to calculate the drug-drug similarity is critical in the side effect predictions.
RESULTS: In this paper, we present a novel measure of drug-drug similarity named "linear neighborhood similarity", which is calculated in a drug feature space by exploring linear neighborhood relationship. Then, we transfer the similarity from the feature space into the side effect space, and predict drug side effects by propagating known side effect information through a similarity-based graph. Under a unified frame based on the linear neighborhood similarity, we propose method "LNSM" and its extension "LNSM-SMI" to predict side effects of new drugs, and propose the method "LNSM-MSE" to predict unobserved side effect of approved drugs.
CONCLUSIONS: We evaluate the performances of LNSM and LNSM-SMI in predicting side effects of new drugs, and evaluate the performances of LNSM-MSE in predicting missing side effects of approved drugs. The results demonstrate that the linear neighborhood similarity can improve the performances of side effect prediction, and the linear neighborhood similarity-based methods can outperform existing side effect prediction methods. More importantly, the proposed methods can predict side effects of new drugs as well as unobserved side effects of approved drugs under a unified frame.

PMID: 29297371 [PubMed - indexed for MEDLINE]

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 2019/02/28

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.

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

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

These pubmed results were generated on 2019/02/27

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.

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

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

These pubmed results were generated on 2019/02/27

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.

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 2019/02/26

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.

Early phase I study of a 99mTc labeled anti-PD-L1 single domain antibody in SPECT/CT assessment of programmed death ligand-1 expression in non-small cell lung cancer.

J Nucl Med. 2019 Feb 22;:

Authors: Xing Y, Chand G, Liu C, Cook GJR, O' Doherty J, Zhao L, Wong NCL, Meszaros LK, Ting HH, Zhao J

Abstract
Purpose: Immunotherapy with checkpoint inhibitor programmed cell death 1 (PD-1)/programmed death ligand (PD-L1) antibodies demonstrates improvements in treatment of advanced non-small cell lung cancer (NSCLC). Treatment stratification depends on immunohistochemical PD-L1 measurement of biopsy material, an invasive method that does not account for spatiotemporal heterogeneity. Using a single domain antibody (sdAb), NM-01, against PD-L1, radiolabeled site-specifically with technetium-99m (99mTc) for single photon emission computed tomography (SPECT) imaging, we aimed to assess the safety, radiation dosimetry and imaging characteristics of this radiopharmaceutical and correlate tumor uptake with PD-L1 immunohistochemistry results. Methods: Sixteen patients (mean age 61.7 years, 11 male) with NSCLC were recruited. Primary tumor PD-L1 expression was measured by immunohistochemistry. NM-01 was radiolabeled with [99mTc(OH2)3(CO)3]+ complex binding to its C-terminal hexahistidine tag. Administered activity was 3.8-10.4 MBq/kg, corresponding to 100 µg or 400 µg of NM-01. Whole body planar and thoracic SPECT/CT scans were performed at 1 and 2h post-injection in all patients and 5 patients had additional imaging at 10mins, 3 and 24h for radiation dosimetry calculations. All patients were monitored for adverse events. Results: No drug-related adverse events occurred in this study. The mean effective dose was 8.84×10-3 ± 9.33×10-4 mSv/MBq (3.59 ± 0.74 mSv per patient). Tracer uptake was observed in the kidneys, spleen, liver and bone marrow. SPECT primary tumor-blood pool ratios (T:BP) varied from 1.24 to 2.3 (mean = 1.79) at 1h and 1.24 to 3.53 (mean = 2.22) at 2h (P = 0.005). 2h primary T:BP ratios correlated with PD-L1 immunohistochemistry results (r=0.68, P = 0.014). 2h T:BP was lower in tumors with ≤1% PD-L1 expression (1.89 vs 2.49, P = 0.048). Nodal and bone metastases showed tracer uptake. Heterogeneity (>20%) between primary tumor and nodal T:BP was present in 4 of 12 patients. Conclusion: This first in human study demonstrates that 99mTc-labeled anti-PD-L1-sdAb SPECT/CT imaging is safe and associated with acceptable dosimetry. Tumor uptake is readily visible against background tissues, particularly at 2h when the T:BP ratio correlates with PD-L1 immunohistochemistry results.

PMID: 30796165 [PubMed - as supplied by publisher]

Safety of tiotropium in patients with asthma.

Ther Adv Respir Dis. 2019 Jan-Dec;13:1753466618824010

Authors: Dusser D, Ducharme FM

Abstract
Given the high proportion of patients with asthma who remain uncontrolled despite controller treatment, there remains a need for the development of more effective treatment options with a proven safety and tolerability profile. Recently, asthma guidelines have evolved to incorporate new therapies, including long-acting muscarinic antagonists (LAMAs) and biologics. Here we focus on the safety profile of tiotropium, a LAMA, using data from the large-scale UniTinA-asthma® clinical trial program, which investigated the use of tiotropium in over 6000 patients with asthma who remained symptomatic despite receiving inhaled corticosteroids (ICS) maintenance therapy, with or without other adjunct therapies. The large number of patients included allows robust analysis of safety and tolerability. Overall, a similar incidence of patients reporting any adverse event (AE) was observed in the tiotropium (5 µg and 2.5 µg) and placebo groups. Asthma worsening, decreased peak expiratory flow, and upper respiratory tract infections were the most frequently reported AEs. Serious AEs (SAEs) and investigator-defined drug-related AEs were infrequently reported across all treatment groups, including the placebo group, and there were no deaths in any study. Reports of side effects typically associated with anticholinergic drugs, such as dry mouth and urinary retention, were either infrequent or not reported in children, adolescents or adults. The similar proportions of tiotropium- versus placebo-treated patients reporting AEs and SAEs in African-American and Japanese populations, as well as in elderly patients, contribute to the accumulating evidence of the safety and tolerability of tiotropium across broad ethnic and age populations.

PMID: 30795731 [PubMed - in process]

Use of metformin to treat pregnant women with polycystic ovary syndrome (PregMet2): a randomised, double-blind, placebo-controlled trial.

Lancet Diabetes Endocrinol. 2019 Feb 18;:

Authors: Løvvik TS, Carlsen SM, Salvesen Ø, Steffensen B, Bixo M, Gómez-Real F, Lønnebotn M, Hestvold KV, Zabielska R, Hirschberg AL, Trouva A, Thorarinsdottir S, Hjelle S, Berg AH, Andræ F, Poromaa IS, Mohlin J, Underdal M, Vanky E

Abstract
BACKGROUND: Women with polycystic ovary syndrome (PCOS) have an increased risk of pregnancy complications. Epi-analysis of two previous randomised controlled trials that compared metformin with placebo during pregnancy in women with PCOS showed a significant reduction in late miscarriages and preterm births in the metformin group. The aim of this third randomised trial (PregMet2) was to test the hypothesis that metformin prevents late miscarriage and preterm birth in women with PCOS.
METHODS: PregMet2 was a randomised, placebo-controlled, double-blind, multicentre trial done at 14 hospitals in Norway, Sweden, and Iceland. Singleton pregnant women with PCOS aged 18-45 years were eligible for inclusion. After receiving information about the study at their first antenatal visit or from the internet, women signed up individually to participate in the study. Participants were randomly assigned (1:1) to receive metformin or placebo by computer-generated random numbers. Randomisation was in blocks of ten for each country and centre; the first block had a random size between one and ten to assure masking. Participants were assigned to receive oral metformin 500 mg twice daily or placebo during the first week of treatment, which increased to 1000 mg twice daily or placebo from week 2 until delivery. Placebo tablets and metformin tablets were identical and participants and study personnel were masked to treatment allocation. The primary outcome was the composite incidence of late miscarriage (between week 13 and week 22 and 6 days) and preterm birth (between week 23 and week 36 and 6 days), analysed in the intention-to-treat population. Secondary endpoints included the incidence of gestational diabetes, preeclampsia, pregnancy-induced hypertension, and admission of the neonate to the neonatal intensive care unit. We also did a post-hoc individual participant data analysis of pregnancy outcomes, pooling data from the two previous trials with the present study. The study was registered with ClinicalTrials.gov, number NCT01587378, and EudraCT, number 2011-002203-15.
FINDINGS: The study took place between Oct 19, 2012, and Sept 1, 2017. We randomly assigned 487 women to metformin (n=244) or placebo (n=243). In the intention-to-treat analysis, our composite primary outcome of late miscarriage and preterm birth occurred in 12 (5%) of 238 women in the metformin group and 23 (10%) of 240 women in the placebo group (odds ratio [OR] 0·50, 95% CI 0·22-1·08; p=0·08). We found no significant differences for our secondary endpoints, including incidence of gestational diabetes (60 [25%] of 238 women in the metformin group vs 57 [24%] of 240 women in the placebo group; OR 1·09, 95% CI 0·69-1·66; p=0·75). We noted no substantial between-group differences in serious adverse events in either mothers or offspring, and no serious adverse events were considered drug-related by principal investigators. In the post-hoc pooled analysis of individual participant data from the present trial and two previous trials, 18 (5%) of 397 women had late miscarriage or preterm delivery in the metformin group compared with 40 (10%) of 399 women in the placebo group (OR 0·43, 95% CI 0·23-0·79; p=0·004).
INTERPRETATION: In pregnant women with PCOS, metformin treatment from the late first trimester until delivery might reduce the risk of late miscarriage and preterm birth, but does not prevent gestational diabetes.
FUNDING: Research Council of Norway, Novo Nordisk Foundation, St Olav's University Hospital, and Norwegian University of Science and Technology.

PMID: 30792154 [PubMed - as supplied by publisher]

Drug-Induced Liver Injury Caused by Kratom Use as an Alternative Pain Treatment Amid an Ongoing Opioid Epidemic.

J Investig Med High Impact Case Rep. 2019 Jan-Dec;7:2324709619826167

Authors: Osborne CS, Overstreet AN, Rockey DC, Schreiner AD

Abstract
Kratom ( Mitragyna speciosa) is a prevalent medicinal plant used mainly for the stimulant and analgesic properties provided through multiple alkaloid compounds. Over the past decade, use of kratom has increased despite the limited knowledge of toxicities and adverse side effects. With the current opioid epidemic, both patients and providers are seeking alternative methods to treat both addiction and pain control, and kratom as an alternative means of treatment has increasingly entered the mainstream. In this article, we present the clinical course of a 47-year-old male who developed fatigue, pruritus, and abnormal liver tests (with a mixed hepatocellular/cholestatic pattern) approximately 21 days after beginning kratom. After extensive evaluation including a negligible alcohol history, negative hepatitis serologies, and inconclusive imaging, the patient was diagnosed with drug-induced liver injury (DILI) caused by kratom. Nine months after his liver tests returned to normal, he took kratom again, and after a latency of 2 days, he developed fatigue, pruritus, and loss of appetite along with abnormal liver tests (with the same biochemical profile as previously), consistent with a positive rechallenge. We believe, through the use of the Roussel-Uclaf Causality Assessment Method and expert opinion, that this is a highly likely or definite example of kratom-induced DILI. With the gaining popularity of this drug, it appears that DILI may be an important complication of kratom for providers to recognize.

PMID: 30791718 [PubMed - in process]

Adverse Events and Factors Associated with Potentially Avoidable Use of General Anesthesia in Cesarean Deliveries.

Anesthesiology. 2019 Feb 13;:

Authors: Guglielminotti J, Landau R, Li G

Abstract
WHAT WE ALREADY KNOW ABOUT THIS TOPIC: Neuraxial anesthesia is recommended in lieu of general anesthesia for cesarean deliveriesThe association of general anesthesia without a clinical indication with adverse events in cesarean deliveries remains poorly understood WHAT THIS MANUSCRIPT TELLS US THAT IS NEW: In New York State, 5.7% of cesarean sections without a clinical indication for general anesthesia are performed with general anesthesiaThe use of potentially avoidable general anesthesia in these patients is associated with an increased risk of anesthesia-related complications, surgical site infection, and venous thromboembolism, but not death or cardiac arrest BACKGROUND:: Compared with neuraxial anesthesia, general anesthesia for cesarean delivery is associated with increased risk of maternal adverse events. Reducing avoidable general anesthetics for cesarean delivery may improve safety of obstetric anesthesia care. This study examined adverse events, trends, and factors associated with potentially avoidable general anesthetics for cesarean delivery.
METHODS: This retrospective study analyzed cesarean delivery cases without a recorded indication for general anesthesia or contraindication to neuraxial anesthesia in New York State hospitals, 2003 to 2014. Adverse events included anesthesia complications (systemic, neuraxial-related, and drug-related), surgical site infection, venous thromboembolism, and the composite of death or cardiac arrest. Anesthesia complications were defined as severe if associated with death, organ failure, or prolonged hospital stay.
RESULTS: During the study period, 466,014 cesarean deliveries without a recorded indication for general anesthesia or contraindication to neuraxial anesthesia were analyzed; 26,431 were completed with general anesthesia (5.7%). The proportion of avoidable general anesthetics decreased from 5.6% in 2003 to 2004 to 4.8% in 2013 to 2014 (14% reduction; P < 0.001). Avoidable general anesthetics were associated with significantly increased risk of anesthesia complications (adjusted odds ratio, 1.6; 95% CI, 1.4 to 1.9), severe complications (adjusted odds ratio, 2.9; 95% CI, 1.6 to 5.2), surgical site infection (adjusted odds ratio, 1.7; 95% CI, 1.5 to 2.1), and venous thromboembolism (adjusted odds ratio, 1.9; 95% CI, 1.3 to 3.0), but not of death or cardiac arrest. Labor neuraxial analgesia rate was one of the most actionable hospital-level factors associated with avoidable general anesthetics. Relative to hospitals with a rate greater than or equal to 75%, the adjusted odds ratio of avoidable general anesthetics increased to 1.3 (95% CI, 1.2 to 1.4), 1.6 (95% CI, 1.5 to 1.7), and 3.2 (95% CI, 3.0 to 3.5) as the rate decreased to 50 to 74.9%, 25 to 49.9%, and less than 25%, respectively.
CONCLUSIONS: Compared with neuraxial anesthesia, avoidable general anesthetics are associated with increased risk of adverse maternal outcomes.

PMID: 30789362 [PubMed - as supplied by publisher]

Biotherapeutics: Challenges and Opportunities for Predictive Toxicology of Monoclonal Antibodies.

Int J Mol Sci. 2018 Nov 21;19(11):

Authors: Johnson DE

Abstract
Biotherapeutics are a rapidly growing portion of the total pharmaceutical market accounting for almost one-half of recent new drug approvals. A major portion of these approvals each year are monoclonal antibodies (mAbs). During development, non-clinical pharmacology and toxicology testing of mAbs differs from that done with chemical entities since these biotherapeutics are derived from a biological source and therefore the animal models must share the same epitopes (targets) as humans to elicit a pharmacological response. Mechanisms of toxicity of mAbs are both pharmacological and non-pharmacological in nature; however, standard in silico predictive toxicological methods used in research and development of chemical entities currently do not apply to these biotherapeutics. Challenges and potential opportunities exist for new methodologies to provide a more predictive program to assess and monitor potential adverse drug reactions of mAbs for specific patients before and during clinical trials and after market approval.

PMID: 30469350 [PubMed - indexed for MEDLINE]

Molecular Mechanisms for Species Differences in Organic Anion Transporter 1, OAT1: Implications for Renal Drug Toxicity.

Mol Pharmacol. 2018 07;94(1):689-699

Authors: Zou L, Stecula A, Gupta A, Prasad B, Chien HC, Yee SW, Wang L, Unadkat JD, Stahl SH, Fenner KS, Giacomini KM

Abstract
Species differences in renal drug transporters continue to plague drug development with animal models failing to adequately predict renal drug toxicity. For example, adefovir, a renally excreted antiviral drug, failed clinical studies for human immunodeficiency virus due to pronounced nephrotoxicity in humans. In this study, we demonstrated that there are large species differences in the kinetics of interactions of a key class of antiviral drugs, acyclic nucleoside phosphonates (ANPs), with organic anion transporter 1 [(OAT1) SLC22A6] and identified a key amino acid residue responsible for these differences. In OAT1 stably transfected human embryonic kidney 293 cells, the Km value of tenofovir for human OAT1 (hOAT1) was significantly lower than for OAT1 orthologs from common preclinical animals, including cynomolgus monkey, mouse, rat, and dog. Chimeric and site-directed mutagenesis studies along with comparative structure modeling identified serine at position 203 (S203) in hOAT1 as a determinant of its lower Km value. Furthermore, S203 is conserved in apes, and in contrast alanine at the equivalent position is conserved in preclinical animals and Old World monkeys, the most related primates to apes. Intriguingly, transport efficiencies are significantly higher for OAT1 orthologs from apes with high serum uric acid (SUA) levels than for the orthologs from species with low serum uric acid levels. In conclusion, our data provide a molecular mechanism underlying species differences in renal accumulation of nephrotoxic ANPs and a novel insight into OAT1 transport function in primate evolution.

PMID: 29720497 [PubMed - indexed for MEDLINE]

Antiepileptic drug treatment of generalized tonic-clonic seizures: An evaluation of regulatory data and five criteria for drug selection.

Epilepsy Behav. 2018 05;82:91-103

Authors: Shorvon SD, Bermejo PE, Gibbs AA, Huberfeld G, Kälviäinen R

Abstract
BACKGROUND: A generalized tonic-clonic seizure (GTCS) is the most severe form of common epileptic seizure and carries the greatest risk of harm. The aim of this review is to provide an evidence-based guide for the selection of antiepileptic drugs (AEDs) for patients with GTCSs. Eight AEDs are approved in Europe and the USA for the treatment of both primarily GTCSs (PGTCSs) and secondarily GTCSs (SGTCSs) and are considered in this paper.
METHODS: Each AED is evaluated using five criteria: (1) efficacy, by seizure type (a: PGTCSs and b: SGTCSs); (2) adverse effects; (3) interactions; (4) adherence and dosing; and (5) mechanism of action (MOA). To ensure the inclusions of robust data, only efficacy data accepted by regulatory authorities were considered, and data related to adverse effects, interactions, adherence, and MOA were all extracted from UK Summaries of Product Characteristics (SPCs).
RESULTS: (1a) There is class 1 evidence of the efficacy of only four AEDs in controlling PGTCSs (lamotrigine, levetiracetam, perampanel, and topiramate). (1b) There is no class 1 evidence of the efficacy of any AED in SGTCSs although some evidence from pooled/subgroup analyses or meta-analyses supports the use of the four AEDs (levetiracetam, perampanel, topiramate, and with less robust data for lamotrigine). (2) AEDs are associated with different, but to some extent overlapping, common adverse effect profiles but have differing idiosyncratic adverse effects. (3) Pharmacokinetic interactions are seen with most, but not all, AEDs and are most common with carbamazepine and phenytoin. (4) Good adherence is important for seizure control and is influenced by frequency of dosing, among other factors. (5) Mechanism of action is also a consideration in rationalising AED selection when switching or combining AEDs.
CONCLUSION: Ultimately, the choice of AED depends on all these factors but particularly on efficacy and adverse effects. Different patients will weigh the various factors differently, and the role of the treating physician is to provide accurate information to allow patients to make informed choices.

PMID: 29602083 [PubMed - indexed for MEDLINE]

Triplet chemotherapy with docetaxel, cisplatin and S-1 for unresectable advanced squamous cell carcinoma of the esophagus: phase I/II trial results.

Oncotarget. 2019 Jan 25;10(8):847-855

Authors: Ojima T, Nakamura M, Nakamori M, Katsuda M, Hayata K, Kitadani J, Maruoka S, Shimokawa T, Yamaue H

Abstract
Background: Although triplet regimen of docetaxel, cisplatin, and 5-FU (DCF) reportedly yields high response rates for metastatic squamous cell carcinoma of the esophagus (SCCE), it has severe toxicity. In our previous phase II trial, grade 3/4 toxicities of neutropenia occurred in 68.8% of the patients. Development of chemotherapeutic regimen that does not impair quality of life of the patients with metastatic SCCE is therefore needed. A novel chemotherapeutic regimen combining docetaxel, cisplatin, and alternate-day administration of S-1 (modified DCS) may be associated with reduction of severe adverse effects.
Methods: This study is a single center phase I/II trial of chemotherapy using modified DCS regimen for patients with recurrent/unresectable SCCE. The phase I trial adopts a '3 + 3 patient cohort', dose-escalating study design. In the phase II trial, the primary endpoint is evaluation of the overall response rate (ORR). Secondary endpoints are evaluation of drug-related toxicity, overall survival (OS), and progression-free survival (PFS).
Results: In the phase I trial, the recommended dose for docetaxel, cisplatin, and S-1 were 40 mg/m2 (day 1), 50 mg/m2 (day 1), and 80 mg/m2/day, respectively. In the phase II trial (n = 50), the ORR was 54 %. The median OS and PFS were 10 and 4 months, respectively. Grade 3/4 adverse events included neutropenia (26%), leukopenia (14%), anorexia (10%) and febrile neutropenia (6%).
Conclusion: The modified DCS therapy for patients with advanced SCCE is feasible and safe in both chemotherapeutic and perioperative periods.Registration number: UMIN000016364.

PMID: 30783514 [PubMed]

A Comment on the Post-Finasteride Syndrome.

Int J Trichology. 2018 Nov-Dec;10(6):255-261

Authors: Rezende HD, Dias MFRG, Trüeb RM

Abstract
The post-Finasteride syndrome (PFS) has been claimed to occur in men who have taken oral finasteride to treat hair loss or benign prostatic hyperplasia. While the incidence of persistent sexual, mental, and physical side effects despite quitting finasteride is unknown, and the condition is not recognized by the scientific community, individuals who suffer from PFS do present with very distinctive and homogenous symptoms. The concept has emerged from reports of nondermatologists, neuroendocrinological research, case reports, and uncontrolled studies. These have been scrutinized by hair experts who found that persistent sexual side effects were only documented in low-quality studies with a strong bias selection and a significant nocebo effect. Others totally dispute the credibility of the PFS. In any case, the PFS is a problem that has to be dealt with. Low-quality studies neither confirm nor refute the condition as a valid nosologic entity. Therefore, it is as inappropriate to dismiss the condition, as it would be to demonize finasteride for the treatment of male pattern hair loss. Whether the PFS represents a nocebo reaction or a real drug adverse event is irrelevant, while the best way to alleviate the emotional distress related to hair loss is to effectively treat the condition causing the problem. It is not sufficient to only discuss the plausibility of the PFS. There is a need for practical recommendations to include such important issues as patient selection and risk assessment, appropriate patient information, how to react in case of drug-related adverse events, issues of fertility and malignancy, management of the PFS, and alternatives, specifically the use of topical finasteride. It is the aim of this commentary to provide the respective information.

PMID: 30783332 [PubMed]

[Modern HIV treatment].

Internist (Berl). 2019 Feb 18;:

Authors: Lehmann C, Malin J, Suárez I, Fätkenheuer G

Abstract
Human immunodeficiency virus (HIV) infection has become a chronic disease with a favourable prognosis if adequate antiretroviral therapy (ART) is applied. Therefore, each patient with HIV infection should be treated irrespectively of clinical symptoms or of immunological status. A combination of three active drugs that have to be taken life-long has been standard for many years. The regimen contains two nucleoside reverse transcriptase inhibitors plus either an integrase inhibitor, a boosted protease inhibitor, or a non-nucleoside reverse transcriptase inhibitor. Integrase inhibitors are recommended as the third partner of choice by recent guidelines due to their high efficacy and their favourable safety profile. Many combination drugs are now available which allow a simple treatment with few tablets and in many instances a one-pill combination per day is an option. Potential interactions with drugs given for other diseases have to be taken into account, especially if a pharmacological booster is part of the regimen. Combination therapy should be changed if either virological failure (HIV RNA >200 copies/ml) or drug-related adverse events occur. In special situations (e. g. pregnancy) highly experienced experts in the field should be consulted. Novel approaches for HIV therapy include dual therapy as well as treatment with long-acting substances. Beside therapy, antiretroviral drugs are used for prevention either as post-exposure prophylaxis or as pre-exposure prophylaxis.

PMID: 30778612 [PubMed - as supplied by publisher]

Chinese consensus on management of tyrosine kinase inhibitor-associated side effects in gastrointestinal stromal tumors.

World J Gastroenterol. 2018 Dec 14;24(46):5189-5202

Authors: Li J, Wang M, Zhang B, Wu X, Lin TL, Liu XF, Zhou Y, Zhang XH, Xu H, Shen LJ, Zou J, Lu P, Zhang D, Gu WJ, Zhang MX, Pan J, Cao H, Chinese Society of Surgeons for Gastrointestinal Stromal Tumor of the Chinese Medical Doctor Association

Abstract
Tyrosine kinase inhibitors (TKIs) have improved the overall survival of patients with gastrointestinal stromal tumors (GISTs), but their side effects can impact dose intensity and, consequently, the clinical benefit. To date, no guideline or consensus has been published on the TKI-associated adverse reactions. Therefore, the Chinese Society of Surgeons for Gastrointestinal Stromal Tumor of the Chinese Medical Doctor Association organized an expert panel discussion involving representatives from gastrointestinal surgery, medical oncology, cardiology, dermatology, nephrology, endocrinology, and ophthalmology to consider the systemic clinical symptoms, molecular and cellular mechanisms, and treatment recommendations of GISTs. Here, we present the resultant evidence- and experience-based consensus to guide the management of TKI-associated side events in clinical practice.

PMID: 30581268 [PubMed - indexed for MEDLINE]