A Randomized Clinical Trial of the Efficacy and Safety of Sitagliptin Compared with Dapagliflozin in Patients with Type 2 Diabetes Mellitus and Mild Renal Insufficiency: The CompoSIT-R Study.

Diabetes Obes Metab. 2018 Jul 18;:

Authors: Scott R, Morgan J, Zimmer Z, Lam RLH, O'Neill EA, Kaufman KD, Engel SS, Raji A

Abstract
AIMS: To compare the efficacy and safety of the DPP-4 inhibitor sitagliptin with the SGLT-2 inhibitor dapagliflozin in patients with type 2 diabetes and mild renal insufficiency.
MATERIALS AND METHODS: Patients with HbA1c 7.0 to 9.5% (53 to ≤80 mmol/mol) and eGFR 60 to <90 mL/min/1.73m2 on metformin (≥1500 mg/day) ± sulfonylurea were randomized to sitagliptin 100 mg (N=307) or dapagliflozin 5 mg titrated to 10 mg (N=306) once-daily for 24 weeks. A longitudinal data analysis model was used to test the primary hypothesis that sitagliptin is non-inferior to dapagliflozin in reducing HbA1c at Week 24, with superiority to be tested if non-inferiority is met.
RESULTS: Baseline mean HbA1c (% [mmol/mol]) was 7.7 (60.9) and 7.8 (61.2), and mean eGFR (mL/min/1.73m2 ) was 79.4 and 76.9 for the sitagliptin and dapagliflozin groups, respectively. After 24 weeks, the between-group difference in LS mean (95% CI) changes from baseline in HbA1c was -0.15% (-0.26,-0.04) (-1.67 mmol/mol [-2.86,-0.48]), p=0.006, meeting the prespecified criteria for declaring both non-inferiority and superiority of sitagliptin vs. dapagliflozin. HbA1c goal of <7% (<53 mmol/mol) was met by 43% (sitagliptin) and 27% (dapagliflozin) of patients. No meaningful between-group difference was observed in a pre-specified analysis of 2-hour incremental post-prandial glucose excursion. Review of adverse events (AEs) was notable for a lower incidence of drug-related AEs with sitagliptin compared with dapagliflozin.
CONCLUSIONS: In patients with type 2 diabetes, mild renal insufficiency and inadequate glycemic control on metformin ± sulfonylurea, sitagliptin treatment resulted in greater improvement in glycemic control compared with dapagliflozin and was generally well-tolerated. This article is protected by copyright. All rights reserved.

PMID: 30019498 [PubMed - as supplied by publisher]

Effect of Fluconazole on the Pharmacokinetics Properties of Imrecoxib, a Novel NSAID: A Single-center, Open-label, Self-controlled Study in Healthy Chinese Male Volunteers.

Clin Ther. 2018 Jul 13;:

Authors: Zuo CZ, Gong Y, Hou XY, Zhang YF, Peng WX, Zhu RH, Zhong DF, Chen XY

Abstract
PURPOSE: Imrecoxib is one type of cyclooxygenase-2 inhibitor with the capability of reducing the potential cardiovascular risk caused by other NSAIDs. Co-administration with other medications can affect the cytochrome P450 (CYP) 2C9 enzyme function; thus, imrecoxib metabolism can be affected. The purpose of this research was to evaluate the effects of fluconazole, which is known to inhibit CYP2C9, on imrecoxib's pharmacokinetic (PK) parameters.
METHODS: In this single-center, single-arm, open-label, self-controlled study, 12 healthy Chinese male volunteers (mean [SD] age, 22.6 [2.43] years) received the following 2 treatments separated by a washout period of 8days under a fasting state: (1) a single oral dose of imrecoxib 100 mg; and (2) fluconazole 200mg/d over 6days followed by concurrent dosing of imrecoxib 100mg and fluconazole 200mg. Plasma concentrations of imrecoxib (M0) and its metabolites (4'-hydroxymethyl metabolite [M1] and 4'-carboxylic acid metabolite [M2]) for PK analysis were obtained at 0 (baseline) and 0.5, 1, 1.5, 2, 3, 4, 8, 12, 24, 48, and 72hours after imrecoxib dosing. Safety and tolerability assessments were performed throughout the study.
FINDINGS: All subjects completed the study. There was 1 adverse event; drug-induced liver damage in 1 subject occurred after he received imrecoxib plus fluconazole, and the subject recovered without any sequelae. Coadministration with fluconazole resulted in much higher plasma imrecoxib concentrations, with an increase of 88% in Cmax and 72% in AUC0-t compared with only imrecoxib treatment, which showed that fluconazole may increase plasma exposure to imrecoxib. Fluconazole also caused a small, but not clinically relevant, decrease in M1 and M2 mean Cmax (13% and 14%, respectively), but there was minimal change in M1 and M2 mean AUC0-t (3% and 2%). However, there were no statistically significant differences in vital signs, clinical laboratory test results, ECGs, or adverse events between treatments.
IMPLICATIONS: Concurrent administration of imrecoxib and fluconazole did not seem to change imrecoxib's safety profile. The ratio (imrecoxib + fluconazole/imrecoxib) for AUC0-t was 1.72 (90% CI, 1.41-2.11) and for Cmax it was 1.88 (90% CI, 1.59-2.21). Hence, it is necessary to adjust the imrecoxib dose when it is concurrently used with other CYP2C9 inhibitors.

PMID: 30017171 [PubMed - as supplied by publisher]

Treatment of inherited bone marrow failure syndromes beyond transplantation.

Hematology Am Soc Hematol Educ Program. 2017 12 08;2017(1):96-101

Authors: Calado RT, Clé DV

Abstract
Despite significant progress in transplantation by the addition of alternative hematopoietic stem cell sources, many patients with inherited bone marrow failure syndromes are still not eligible for a transplant. In addition, the availability of sequencing panels has significantly improved diagnosis by identifying cryptic inherited cases. Androgens are the main nontransplant therapy for bone marrow failure in dyskeratosis congenita and Fanconi anemia, reaching responses in up to 80% of cases. Danazol and oxymetholone are more commonly used, but virilization and liver toxicity are major adverse events. Diamond-Blackfan anemia is commonly treated with corticosteroids, but most patients eventually become refractory to this treatment and toxicity is limiting. Growth factors still have a role in inherited cases, especially granulocyte colony-stimulating factor in congenital neutropenias. Novel therapies are warranted and thrombopoietin receptor agonists, leucine, quercetin, and novel gene therapy approaches may benefit inherited cases in the future.

PMID: 29222242 [PubMed - indexed for MEDLINE]

Dispensability of Annual Laboratory Follow-Up After More than 2 Years of Valproic Acid Use: A Systematic Review.

CNS Drugs. 2017 Nov;31(11):939-957

Authors: Meijboom RW, Grootens KP

Abstract
BACKGROUND: The necessity of annual laboratory follow-up in patients treated with valproic acid (VPA) is controversial.
OBJECTIVE: We investigated the need for annual laboratory follow-up of liver enzymes, electrolytes, and full blood count (FBC) in patients treated with VPA.
PATIENTS AND METHODS: A systematic search in Evidence-Based Medicine Reviews (EBMR), MEDLINE, and EMBASE was undertaken in December 2016 to identify all published articles investigating or citing valproic acid, liver function disorders, electrolyte disorders, and FBC deviations.
RESULTS: This review included 108 articles. As the number of participants and duration of the study was not adequate in most studies to detect rare adverse events, studies did not demonstrate a clear prevalence of hepatotoxicity. While a transient increase of transaminases is common and seldom harmful, severe hepatotoxicity is a rare phenomenon and is not prevented by routine laboratory monitoring. VPA had no relevant effect on serum calcium, sodium, potassium, and albumin. The prevalence of FBC varied from 0.6 to 27.8%, occurred mostly in the first 2 years of therapy, and was usually asymptomatic.
CONCLUSIONS: Long-term monitoring in VPA treatment is only necessary when there have been dose adjustments, co-medication switches, or co-morbidity. In uncomplicated cases, annual laboratory follow-up may be discontinued after 2 years of VPA treatment. Encouraging patients to be vigilant is more effective in the detection of hepatotoxicity than laboratory testing. Follow-up of FBC at 3-6 months, 1 year, and 2 years after start or after a dose increase of VPA or interacting medication is sufficient.

PMID: 29214384 [PubMed - indexed for MEDLINE]

Comparing Safety and Efficacy of "Third-Generation" Antiepileptic Drugs: Long-Term Extension and Post-marketing Treatment.

CNS Drugs. 2017 Nov;31(11):959-974

Authors: Kwok CS, Johnson EL, Krauss GL

Abstract
Four "third-generation" antiepileptic drugs (AEDs) were approved for adjunctive treatment of refractory focal onset seizures during the past 10 years. Long-term efficacy and safety of the drugs were demonstrated in large extension studies and in reports of subgroups of patients not studied in pivotal trials. Reviewing extension study and post-marketing outcome series for the four newer AEDs-lacosamide, perampanel, eslicarbazepine acetate and brivaracetam-can guide clinicians in treating and monitoring patients. AED extension studies evaluate treatment retention, drug tolerability, and drug safety during individualized treatment with flexible dosing and thus provide information not available in rigid pivotal trials. Patient retention in the studies ranged from 75 to 80% at 1 year and from 36 to 68% at 2-year treatment intervals. Safety findings were generally similar to those of pivotal trials, with no major safety risks identified and with several specific adverse drug effects, such as hyponatremia, reported. The third-generation AEDs, some through new mechanisms and others with improved tolerability compared to related AEDs, provide new options in efficacy and tolerability.

PMID: 29204953 [PubMed - indexed for MEDLINE]

22 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 2018/07/18

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.

Acute Lidocaine Toxicity; a Case Series.

Emerg (Tehran). 2018;6(1):e38

Authors: Rahimi M, Elmi M, Hassanian-Moghaddam H, Zamani N, Soltaninejad K, Forouzanfar R, Shadnia S

Abstract
Introduction: Parenteral form of lidocaine is the best-known source of lidocaine poisoning. This study aimed to evaluate the characteristics of acute lidocaine toxicity .
Methods: In this retrospective cross-sectional study, demographics, clinical presentation, laboratory findings, and outcome of patients intoxicated with lidocaine (based on ICD10 codes) admitted to Loghman Hakim Hospital, during April 2007 to March 2014 were analyzed.
Results: 30 cases with the mean age of 21.83 ± 6.57 year were studied (60% male). All subjects had used either 6.5% lidocaine spray or 2% topical formulations of lidocaine. The mean consumed dose of lidocaine was 465 ± 318.17 milligrams. The most frequent clinical presentations were nausea and vomiting (50%), seizure (33.3%), and loss of consciousness (16.7%). 22 (73.3%) cases had normal sinus rhythm, 4 (13.3%) bradycardia, 2 (6.7%) ventricular tachycardia, and 2 (6.7%) had left axis deviation. 11 (36.6%) cases were intubated and admitted to intensive care unit (ICU) for 6.91 ± 7.16 days. Three patients experienced status epilepticus that led to cardiac arrest, and death (all cases with suicidal intention).
Conclusion: Based on the results of this study, most cases of topical lidocaine toxicity were among < 40-year-old patients with a male to female ratio of 1.2, with suicidal attempt in 90%, need for intensive care in 36.6%, and mortality rate of 10%.

PMID: 30009240 [PubMed]

Evaluation of preventable adverse drug reactions by implementation of the nationwide network of prospective drug utilization review program in Korea.

PLoS One. 2018;13(4):e0195434

Authors: Lee J, Noh Y, Lee S

Abstract
BACKGROUND: A prospective Drug Utilization Review (DUR) program has been implemented in Korea to improve the quality and safety of medication use.
OBJECTIVE: To evaluate the influence of the DUR program in reducing incidence of preventable adverse drug reactions (pADRs).
METHODS: This study was performed using administrative data from the Health Insurance Review and Assessment Service (HIRA). The claims data for all adult patients with adverse drug events (ADE)-related diagnoses from 2009 to 2014 were obtained. Incidence rates of first-time and repeat pADRs prior to and after DUR program implementation were evaluated. Quarterly trends in incidence rates of overall ADE, allergic reactions, and ADRs were analyzed.
RESULTS: Data extraction covering the period from 2009 to 2014 led to the identification of 3,927,662 records. First-time pADR rates decreased gradually after implementation of the DUR program (change in slope: -0.016, p = 0.02). The program had a similar influence on repeat pADR rates (change in slope: -0.006, p≤0.01). The program did not decrease rates of first-time or repeat allergic reactions (change in slope: 0.018, p = 0.07 and 0.003, p = 0.04, respectively). In the cohort aged ≤65 years, first-time pADR rate reduction was significant (28.2% [27.1-29.3] in ≤18 years, and 19.8% [18.1-21.5] in 19-64 years). In contrast, first-time pADR rate was increased by 0.6% [-0.7-1.9] in patients ≥65 years.
CONCLUSION: Implementation of the prospective DUR program effectively reduced the number of pADRs. In the future, to reduce non-preventable ADRs such as allergic reactions, provision of clinical information including allergy history should be added to the DUR program.

PMID: 29641617 [PubMed - indexed for MEDLINE]

Drug-related problems and changes in drug utilization after medication reviews in nursing homes in Oslo, Norway.

Scand J Prim Health Care. 2017 Dec;35(4):329-335

Authors: Fog AF, Kvalvaag G, Engedal K, Straand J

Abstract
OBJECTIVE: We describe the drug-related problems (DRPs) identified during medication reviews (MRs) and the changes in drug utilization after MRs at nursing homes in Oslo, Norway. We explored predictors for the observed changes.
DESIGN: Observational before-after study.
SETTING: Forty-one nursing homes.
INTERVENTION: MRs performed by multidisciplinary teams during November 2011 to February 2014.
SUBJECTS: In all, 2465 long-term care patients.
MAIN OUTCOME MEASURES: DRPs identified by explicit criteria (STOPP/START and NORGEP) and drug-drug interaction database; interventions to resolve DRPs; drug use changes after MR.
RESULTS: A total of 6158 DRPs were identified, an average of 2.6 DRPs/patient, 2.0 for regular and 0.6 for pro re nata (prn) drugs. Of these patients, 17.3% had no DRPs. The remaining 82.7% of the patients had on average 3.0 DRPs/patient. Use of unnecessary drugs (43.5%), excess dosing (12.5%) and lack of monitoring of the drug use (11%) were the most frequent DRPs. Opioids and psychotropic drugs were involved in 34.4% of all DRPs. The mean number of drugs decreased after the MR from 6.8 to 6.3 for regular drugs and from 3.0 to 2.6 for prn drugs. Patients with DRPs experienced a decrease of 1.1 drugs after MR (0.5 for regular and 0.6 for prn drugs). The reduction was most pronounced for the regular use of antipsychotics, antidepressants, hypnotics/sedatives, diuretics, antithrombotic agents, antacid drugs; and for prn use of anxiolytics, opioids, hypnotics/sedatives, metoclopramide and NSAIDs.
CONCLUSION: The medication review resulted in less drug use, especially opioids and psychotropic drugs.

PMID: 29096573 [PubMed - indexed for MEDLINE]

Drug-, herb- and dietary supplement-induced liver injury.

Arch Argent Pediatr. 2017 Dec 01;115(6):e397-e403

Authors: Cavalieri ML, D'Agostino D

Abstract
Drug- and substance-induced liver injury accounts for approximately 20% of pediatric cases of acute liver failure. It is caused by two mechanisms: direct and idiosyncratic hepatotoxicity. Direct hepatotoxicity is the result of the administration of a drug with intrinsic toxicity and is dose-dependent (e.g., acetaminophen). Idiosyncratic hepatotoxicity is unpredictable, uncommon, variable in presentation, and doseindependent. The clinical, histological, and laboratory manifestations include hepatitis, which is generally asymptomatic but with a significant increase of liver enzymes; cholestasis, accompanied with jaundice, pruritus, prominent elevation of alkaline phosphatase, and mild elevation of aminotransferases; or mixed, with elements of both hepatitis and cholestasis. Time to recovery is variable, depending on the type of liver injury. Early detection and discontinuation of the causative drug is the most effective and important step for the fast resolution of histological and clinical changes, thus reducing severe liver injury.

PMID: 29087122 [PubMed - indexed for MEDLINE]

Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.

Ann Oncol. 2017 Jul 01;28(suppl_4):iv119-iv142

Authors: Haanen JBAG, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, Jordan K, ESMO Guidelines Committee

PMID: 28881921 [PubMed - indexed for MEDLINE]

Management of infusion reactions to systemic anticancer therapy: ESMO Clinical Practice Guidelines.

Ann Oncol. 2017 Jul 01;28(suppl_4):iv100-iv118

Authors: Roselló S, Blasco I, García Fabregat L, Cervantes A, Jordan K, ESMO Guidelines Committee

PMID: 28881914 [PubMed - indexed for MEDLINE]

Predictors on admission of functional decline among older patients hospitalised for acute care: A prospective observational study.

Australas J Ageing. 2017 Dec;36(4):E57-E63

Authors: Basic D, Ní Chróinín D, Conforti D, Shanley C

Abstract
OBJECTIVE: We sought to investigate the incidence of, and factors associated with, in-hospital functional decline among older acute hospital patients.
METHODS: We conducted a prospective observational study of consecutive patients admitted under geriatric medicine over 5 years. The primary outcome measure was functional decline between admission and discharge, representing deterioration in any of the following: Modified Barthel Index (MBI), independence in Timed Up and Go test or walking, and/or need for walking aid.
RESULTS: Overall, 56% (950/1693) patients (mean age 81.9 years) exhibited in-hospital functional decline. Premorbid MBI (odds ratio (OR) 1.05 per unit increase, P < 0.001), adverse drug reaction (OR 1.50, P = 0.001) and in-hospital consultation as the referral source (OR 1.57, P = 0.001) were independently associated with functional decline, adjusting for age, dementia and nursing home residence.
CONCLUSION: These factors may aid identification of vulnerable patients who might particularly benefit from targeted multidisciplinary intervention. Further studies validating this, and exploring the impact of focussed management, are needed.

PMID: 28856791 [PubMed - indexed for MEDLINE]

The Interplay between Pharmacokinetics and Pharmacodynamics.

Pediatr Rev. 2017 May;38(5):195-206

Authors: Sandritter TL, McLaughlin M, Artman M, Lowry J

PMID: 28461611 [PubMed - indexed for MEDLINE]

Common and Rare Ocular Side-effects of the Dexamethasone Implant.

Ocul Immunol Inflamm. 2017 Dec;25(6):834-840

Authors: Fassbender Adeniran JM, Jusufbegovic D, Schaal S

Abstract
PURPOSE: Expanding indications for use, and overall increased use of the slow-release dexamethasone (DEX) implant yields an opportunity to study the reported ocular side-effects and adverse events associated with this drug.
METHODS: A PubMed.gov (US National Library of Medicine, National Institutes of Health) review of literature for the search terms, "Ozurdex and complication," through December 2015.
RESULTS: Ocular hypertension and cataract are the main long-term sequelae identified in large, randomized clinical trials. Case reports have emerged regarding implant migration, complications with implantation, infection, and posterior segment sequelae, including vitreomacular traction.
CONCLUSION: DEX implant overall is well-tolerated and, with careful monitoring, can be a useful adjunct to treating macular edema associated with diabetes, retinal vein occlusion, and chronic uveitis.

PMID: 27379861 [PubMed - indexed for MEDLINE]

The affinity of antipsychotic drugs to dopamine and serotonin 5-HT2 receptors determines their effects on prefrontal-striatal functional connectivity.

Eur Neuropsychopharmacol. 2018 Jul 10;:

Authors: Tollens F, Gass N, Becker R, Schwarz AJ, Risterucci C, Künnecke B, Lebhardt P, Reinwald J, Sack M, Weber-Fahr W, Meyer-Lindenberg A, Sartorius A

Abstract
One of the major challenges of cross-species translation in psychiatry is the identification of quantifiable brain phenotypes linked to drug efficacy and/or side effects. A measure that has received increasing interest is the effect of antipsychotic drugs on resting-state functional connectivity (FC) in magnetic resonance imaging. However, quantitative comparisons of antipsychotic drug-induced alterations of FC patterns are missing. Consideration of receptor binding affinities provides a means for the effects of antipsychotic drugs on extended brain networks to be related directly to their molecular mechanism of action. Therefore, we examined the relationship between the affinities of three second-generation antipsychotics (amisulpride, risperidone and olanzapine) to dopamine and serotonin receptors and FC patterns related to the prefrontal cortex (PFC) and striatum in Sprague-Dawley rats. FC of the relevant regions was quantified by correlation coefficients and local network properties. Each drug group (32 animals per group) was subdivided into three dose groups and a vehicle control group. A linear relationship was discovered for the mid-dose of antipsychotic compounds, with stronger affinity to serotonin 5-HT2A, 5-HT2C and 5-HT1A receptors and decreased affinity to D3 receptors associated with increased prefrontal-striatal FC (p = 0.0004, r² = 0.46; p = 0.004, r² = 0.33; p = 0.002, r² = 0.37; p = 0.02, r² = 0.22, respectively). Interestingly, no correlation was observed for the low and high dose groups, and for D2 receptors. Our results indicate that drug-induced FC patterns may be linked to antipsychotic mechanism of action on the molecular level and suggest the technique's value for drug development, especially if our results are extended to a larger number of antipsychotics.

PMID: 30006253 [PubMed - as supplied by publisher]

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

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

These pubmed results were generated on 2018/07/14

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.

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

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

These pubmed results were generated on 2018/07/14

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.

16 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 2018/07/13

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.

16 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 2018/07/13

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.