Fear, fight, familiarize: the experiences of people living with relapsing-remitting multiple sclerosis and taking oral medication.

Int J Qual Stud Health Well-being. 2019 Dec;14(1):1648946

Authors: Van Reenen E, Van Der Borg W, Visse M, Van Der Meide H, Visser L

Abstract
Purpose: In addition to becoming familiar with the life changing event of having a chronic illness and exploring its meaning in daily life, people with relapsing-remitting Multiple Sclerosis (RRMS) are faced with important decisions about immunomodulating treatment. Biomedical research on the use of Disease Modifying Therapies (DMTs) mostly focuses on adherence, conceptualized and understood as a behavioral act leading to a desired outcome. Less attention has been paid to the meaning for a person with RRMS of starting and continuing the use of DMTs. Studies on the experiences of people with RRMS taking orally administered DMTs are lacking. The aim of this phenomenological study was to examine the experiences of people with RRMS taking oral medication. Methods: The study was guided by Interpretative Phenomenological Analysis (IPA) and Phenomenology of Practice. 25 persons with RRMS participated in in-depth interviews. Results: In general, participants of this study find themselves in alternating phases that vary by degree of experienced unfamiliarity or familiarity with concern to one's illness, one's changing body, and one's new life. The meaning of taking medication is closely related to these phases. Conclusions: Adherence serves a purpose in the lifeworlds of participants. Medication is the embodiment of this purpose. The pill has inherent meaning.

PMID: 31390951 [PubMed - indexed for MEDLINE]

Evaluating the optimal dose of teicoplanin with therapeutic drug monitoring: not too high for adverse event, not too low for treatment efficacy.

Eur J Clin Microbiol Infect Dis. 2019 Nov;38(11):2113-2120

Authors: Kim SH, Kang CI, Huh K, Cho SY, Chung DR, Lee SY, Kim YJ, Peck KR

Abstract
Therapeutic drug monitoring (TDM) of teicoplanin is aimed at minimizing the clinical impact of pharmacokinetic variability; however, its benefits are still being defined. We performed a retrospective study of teicoplanin TDM focusing on the dose-serum concentration relationship and clinical outcomes in a clinical setting. From January 2017 to December 2018, patients receiving teicoplanin ≥ 72 h with TDM were enrolled. Patients were divided into three groups: non-loading (NL) group, low-dose loading (LD) group (loading dose < 9 mg/kg), and high-dose loading (HD) group (≥ 9 mg/kg). Serum teicoplanin trough concentration (Cmin) and adverse events (AEs) were evaluated in each regimen. A subgroup of patients with bacteremia was analyzed to evaluate clinical efficacy. Among 65 patients, 12, 18, and 35 were grouped in NL, LD, and HD, respectively. Achievement rates of Cmin > 20 mg/L within 10 days were significantly different among the groups (25.0%, 38.9%, and 68.6% in the NL, LD, and HD groups, respectively; P = 0.014). Fourteen patients (21.5%) had AEs, and higher Cmin over 10 days (adjusted odds ratio 2.08 per every 20 mg/L increases, 95% CI 1.13-3.84, P = 0.019) and age ≥ 65 years (P = 0.009) were identified as independent risk factors. In the subgroup analysis, HD regimen (P = 0.050) and high mean Cmin over 10 days (P = 0.025) were significantly associated with treatment success. Although HL regimen could achieve Cmin targets and improve clinical outcome during teicoplanin treatment, high Cmin was associated with AEs during treatment. Routine TDM can be helpful to optimize teicoplanin administration.

PMID: 31372903 [PubMed - indexed for MEDLINE]

Metatox - Web application for generation of metabolic pathways and toxicity estimation.

J Bioinform Comput Biol. 2019 02;17(1):1940001

Authors: Rudik A, Bezhentsev V, Dmitriev A, Lagunin A, Filimonov D, Poroikov V

Abstract
Xenobiotics biotransformation in humans is a process of the chemical modifications, which may lead to the formation of toxic metabolites. The prediction of such metabolites is very important for drug development and ecotoxicology studies. We created the web-application MetaTox ( http://way2drug.com/mg ) for the generation of xenobiotics metabolic pathways in the human organism. For each generated metabolite, the estimations of the acute toxicity (based on GUSAR software prediction), organ-specific carcinogenicity and adverse effects (based on PASS software prediction) are performed. Generation of metabolites by MetaTox is based on the fragments datasets, which describe transformations of substrates structures to a metabolites structure. We added three new classes of biotransformation reactions: Dehydrogenation, Glutathionation, and Hydrolysis, and now metabolite generation for 15 most frequent classes of xenobiotic's biotransformation reactions are available. MetaTox calculates the probability of formation of generated metabolite - it is the integrated assessment of the biotransformation reactions probabilities and their sites using the algorithm of PASS ( http://way2drug.com/passonline ). The prediction accuracy estimated by the leave-one-out cross-validation (LOO-CV) procedure calculated separately for the probabilities of biotransformation reactions and their sites is about 0.9 on the average for all reactions.

PMID: 30866738 [PubMed - indexed for MEDLINE]

Systematic analysis and identification of unexpected interactions from the neuroprotein drug interactome in hydrocephalus pharmacological intervention.

J Bioinform Comput Biol. 2019 02;17(1):1950002

Authors: Lu Y, Yuan L, Chen X, Zhang A, Zhang P, Zou D

Abstract
Hydrocephalus is a neurological condition caused by an abnormal accumulation of cerebrospinal fluid; pharmacological intervention of the disease has been found to elicit a variety of adverse drug reactions (ADRs) in central nervous system (CNS) by unexpectedly targeting certain functional neuroproteins. Here, a systematic neuroprotein drug interactome (SNDI) is created for 11 hydrocephalus drugs/metabolites plus 20 control drugs across 518 druggable pockets on the surface of 472 CNS neuroproteins via a large-scale molecular docking approach. Heuristic clustering analysis of the SNDI profile divides the 31 investigated drug ligands into a distinct panel and a background panel; the former consists of two hydrocephalus drugs (Furosemide and Triamterene) and their respective metabolites (Furosemide glucuronide and Hydroxytriamterene) that are inferred to have generally high affinity towards the whole array of neuroprotein pockets. A total of 13 neuroproteins are enriched in gene ontology semantic mining as putative unexpected targets of the distinct panel, and their intermolecular interactions with hydrocephalus drugs/metabolites are investigated in detail using dynamics simulation and energetics analysis. We also perform kinase assay and viability test to substantiate the interactome analysis. It is found that the Furosemide and Triamterene have significant cytotoxic effects on normal human astrocytes, in which the Triamterene can inhibit the neurokinase ROCK2, a representative of putative unexpected targets, with a high activity, which is comparable with the sophisticated ROCK2 inhibitor Fasudil.

PMID: 30866733 [PubMed - indexed for MEDLINE]

Adverse Events and Their Risk Factors Following Intra-articular Corticosteroid Injections of the Ankle or Subtalar Joint.

Foot Ankle Int. 2019 Jun;40(6):622-628

Authors: Anderson SE, Lubberts B, Strong AD, Guss D, Johnson AH, DiGiovanni CW

Abstract
BACKGROUND: Little data exists regarding the incidence of adverse events and their associated risk factors following intra-articular corticosteroid injection of the ankle and subtalar joint. The aim of this study was to determine the complication rate associated with such injections and to identify any predictive risk factors.
METHODS: Adult patients who had received an intra-articular ankle or subtalar joint injection between January 2000 and April 2016 at one of 3 regional hospitals (2 level 1 trauma centers and 1 community hospital) were included. Patients with prior intra-articular injection of corticosteroid into the ankle or subtalar joint were excluded. Explanatory variables were sex, age, race, body mass index, diabetes status, tobacco use, presence of fluoroscopic guidance, location of intra-articular injection, and administering physician's years of experience.
RESULTS: Of the 1708 patients included in the final cohort, 99 patients (5.8%) had a total of 104 adverse events within 90 days postinjection. The most prevalent types of adverse events were postinjection flare in 78 patients (4.6% of total cohort, 75% of adverse events) followed by skin reaction in 10 patients (0.6% of total cohort, 9% of adverse events). No infections were noted. Multivariable logistic regression analysis found that intra-articular injection in the subtalar ( P = .004) was independently associated with development of an adverse event. Fluoroscopic guidance was not found to be protective of an adverse event compared to nonguided injections ( P = .476).
CONCLUSION: The adverse event rate following intra-articular ankle or subtalar joint corticosteroid injection was 5.8%, with postinjection flare being the most common complication. Infections following injection were not reported. Injection into the subtalar joint was independently associated with the development of an adverse event after intra-articular corticosteroid injection, and this was not mitigated by the use of fluoroscopic guidance.
LEVEL OF EVIDENCE: Level III, retrospective comparative study.

PMID: 30866653 [PubMed - indexed for MEDLINE]

Study design, process and outcome indicators of post-authorization studies aimed at evaluating the effectiveness of risk minimization measures in the EU PAS Register.

Br J Clin Pharmacol. 2019 03;85(3):476-491

Authors: Farcas A, Huruba M, Mogosan C

Abstract
Risk minimization measures (RMMs) represent an essential tool for preventing the occurrence of safety-related outcomes. The evaluation of RMMs effectiveness is essential to prove their success and ensure protection of public health. The aim of this qualitative review was to assess the design, process and outcome indicators used for attesting successful implementation of RMMs. We searched the EU Post-Authorization Studies Register up to 30 June 2018 for studies having the scope defined as 'effectiveness evaluation'. Study titles and objectives were screened to select the ones evaluating the effectiveness of RMMs. We described and assessed the extent to which these studies aligned with Good Pharmacovigilance Practices guidelines recommendations. Out of 360 registered studies, we identified 35 studies on evaluation of RMMs effectiveness, 29 being eligible for review. Twenty-six studies evaluated additional RMMs, employed in case routine interventions are considered insufficient. All studies assessed process indicators, five also assessing outcome indicators, thus using a dual-evidence approach as recommended by the guidelines. However, none of the latter used a pre-post design, comparing the frequency of the adverse outcome before and after the implementation of RMMs. Behaviour and knowledge were the most often assessed process indicators. Outcome indicators included occurrence of adverse reactions, pregnancy, off-label use and medication errors. Only four studies had an established threshold, all for process indicators. Stricter adherence to existing recommendations would allow for a more robust design for reaching established endpoints for RMM effectiveness evaluation. It would also infer harmonization, facilitate review and further more detailed guidance on conducting these studies.

PMID: 30497102 [PubMed - indexed for MEDLINE]

The impact of tacrolimus exposure on extrarenal adverse effects in adult renal transplant recipients.

Br J Clin Pharmacol. 2019 03;85(3):516-529

Authors: Campagne O, Mager DE, Brazeau D, Venuto RC, Tornatore KM

Abstract
AIMS: Tacrolimus has been associated with notable extrarenal adverse effects (AEs), which are unpredictable and impact patient morbidity. The association between model-predicted tacrolimus exposure metrics and standardized extrarenal AEs in stable renal transplant recipients was investigated and a limited sampling strategy (LSS) was developed to predict steady-state tacrolimus area under the curve over a 12-h dosing period (AUCss,0-12h ).
METHODS: All recipients receiving tacrolimus and mycophenolic acid ≥6 months completed a 12-h cross-sectional observational pharmacokinetic-pharmacodynamic study. Patients were evaluated for the presence of individual and composite gastrointestinal, neurological, and aesthetic AEs during the study visit. The associations between AEs and tacrolimus exposure metrics generated from a published population pharmacokinetic model were investigated using a logistic regression analysis in NONMEM 7.3. An LSS was determined using a Bayesian estimation method with the same patients.
RESULTS: Dose-normalized tacrolimus AUCss,0-12h and apparent clearance were independently associated with diarrhoea, dyspepsia, insomnia and neurological AE ratio. Dose-normalized tacrolimus maximum concentration was significantly correlated with skin changes and acne. No AE associations were found with trough concentrations. Using limited sampling at 0, 2h; 0, 1, 4h; and 0, 1, 2, 4h provided a precise and unbiased prediction of tacrolimus AUC (root mean squared prediction error < 10%), which was not well characterized using trough concentrations only (root mean squared prediction error >15%).
CONCLUSIONS: Several AEs (i.e. diarrhoea, dyspepsia, insomnia and neurological AE ratio) were associated with tacrolimus dose normalized AUCss,0-12h and clearance. Skin changes and acne were associated with dose-normalized maximum concentrations. To facilitate clinical implementation, a LSS was developed to predict AUCss,0-12h values using sparse patient data to efficiently assess projected immunosuppressive exposure and potentially minimize AE manifestations.

PMID: 30414331 [PubMed - indexed for MEDLINE]

HLA-C*12:02 is strongly associated with Xuesaitong-induced cutaneous adverse drug reactions.

Pharmacogenomics J. 2019 06;19(3):277-285

Authors: Yan S, Xiong H, Shao F, Zhang W, Yang F, Qi Z, Chen S, He L, Jiang M, Su Y, Zhu H, Qin S, Zhu Q, Luo X, Xing Q

Abstract
Xuesaitong (XST) is mainly used to treat cardiovascular and cerebrovascular diseases, sometimes causing cutaneous adverse drug reactions (cADRs) with unknown mechanisms of pathogenicity or risk factors. We aimed to verify whether human leukocyte antigen (HLA) alleles are associated with XST-related cADRs in Han Chinese population. We carried out an association study including 12 subjects with XST-induced cADRs, 283 controls, and 28 XST-tolerant subjects. Five out of 12 patients with XST-induced cADRs carried HLA-C*12:02, and all of them received XST via intravenous drip. The carrier frequency of HLA-C*12:02 was significantly high compare to that of the control population (Pc = 4.4 × 10-4, odds ratio (OR) = 21.75, 95% CI = 5.78-81.88). Compared with that of the XST-tolerant group, the patients who received XST through intravenous drip presented a higher OR of cADRs (Pc = 0.011, OR = 27.00, 95% CI = 2.58-282.98). The results suggest that HLA-C*12:02 is a potentially predictive marker of XST-induced cADRs in Han Chinese, especially when XST is administered via intravenous drip.

PMID: 30237582 [PubMed - indexed for MEDLINE]

Cross-ethnicity tagging SNPs for HLA alleles associated with adverse drug reaction.

Pharmacogenomics J. 2019 06;19(3):230-239

Authors: Erlichster M, Goudey B, Skafidas E, Kwan P

Abstract
Reduction of adverse drug reaction (ADR) incidence through screening of predisposing human leucocyte antigen (HLA) alleles is a promising approach for many widely used drugs. However, application of these associations has been limited by the cost burden of HLA genotyping. Use of single nucleotide polymorphisms (SNPs) that can approximate ('tag') HLA alleles of interest has been proposed as a cost-effective and simple alternative to conventional genotyping. However, most reported SNP tags have not been validated and there is concern regarding clinical utility of this approach due to tagging inconsistency across different populations. We assess the ability of 67 previously reported and 378 novel tagging SNPs, identified here in 5 HLA reference panels, to tag 15 ADR-associated HLA alleles in a panel of 955 ethnically diverse samples. Tags for 8 HLA alleles of interest were identified with 100% sensitivity and >95% specificity. These SNPs may act as a reliable genotyping approach for the routine screening of patients, without the need to account for patient ethnicity.

PMID: 30093715 [PubMed - indexed for MEDLINE]

First-line combination therapy versus first-line monotherapy for primary hypertension.

Cochrane Database Syst Rev. 2020 Feb 06;2:CD010316

Authors: Garjón J, Saiz LC, Azparren A, Gaminde I, Ariz MJ, Erviti J

Abstract
BACKGROUND: This is the first update of a review originally published in 2017. Starting with one drug and starting with a combination of two drugs are strategies suggested in clinical guidelines as initial treatment of hypertension. The recommendations are not based on evidence about clinically relevant outcomes. Some antihypertensive combinations have been shown to be harmful. The actual harm-to-benefit balance of each strategy is unknown.
OBJECTIVES: To determine if there are differences in clinical outcomes between monotherapy and combination therapy as initial treatment for primary hypertension.
SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to April 2019: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 2005), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We used no language restrictions. We also searched clinical studies repositories of pharmaceutical companies, reviews of combination drugs on the US Food and Drug Administration and European Medicines Agency websites, and lists of references in reviews and clinical practice guidelines.
SELECTION CRITERIA: We included randomised, double-blind trials with at least 12 months' follow-up in adults with primary hypertension (systolic blood pressure/diastolic blood pressure 140/90 mmHg or higher, or 130/80 mmHg or higher if participants had diabetes), which compared combination of two first-line antihypertensive drugs with monotherapy as initial treatment. Trials had to include at least 50 participants per group and report mortality, cardiovascular mortality, cardiovascular events, or serious adverse events.
DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, evaluated the risk of bias, and performed data entry. The primary outcomes were mortality, serious adverse events, cardiovascular events, and cardiovascular mortality. Secondary outcomes were withdrawals due to drug-related adverse effects, reaching blood pressure control (as defined in each trial), and blood pressure change from baseline. Analyses were based on the intention-to-treat principle. We summarised data on dichotomous outcomes as risk ratios (RR) with 95% confidence intervals (CI).
MAIN RESULTS: This update included one new study in which a subgroup of participants met our inclusion criteria. As none of the four included studies focused solely on people initiating antihypertensive treatment, we asked investigators for data for this subgroup. One study (PREVER-treatment 2016) used a combination of thiazide-type diuretic/potassium-sparing diuretic; as the former is not indicated in monotherapy, we analysed this study separately. The three original trials in the main comparison (monotherapy: 335 participants; combination therapy: 233 participants) included outpatients, mostly European and white people. Two trials only included people with type 2 diabetes; the remaining trial excluded people treated with diabetes, hypocholesterolaemia, or cardiovascular drugs. The follow-up was 12 months in two trials and 36 months in one trial. It is very uncertain whether combination therapy versus monotherapy reduces total mortality (RR 1.35, 95% CI 0.08 to 21.72), cardiovascular mortality (zero events reported), cardiovascular events (RR 0.98, 95% CI 0.22 to 4.41), serious adverse events (RR 0.77, 95% CI 0.31 to 1.92), or withdrawals due to adverse effects (RR 0.85, 95% CI 0.53 to 1.35); all outcomes had 568 participants, and the evidence was rated as of very low certainty due to serious imprecision and for using a subgroup that was not defined in advance. The confidence intervals were extremely wide for all important outcomes and included both appreciable harm and benefit. The PREVER-treatment 2016 trial, which used a combination therapy with potassium-sparing diuretic (monotherapy: 84 participants; combination therapy: 116 participants), included outpatients. This trial was conducted in Brazil and had a follow-up of 18 months. The number of events was very low and confidence intervals very wide, with zero events reported for cardiovascular mortality and withdrawals due to adverse events. It is very uncertain if there are differences in clinical outcomes between monotherapy and combination therapy in this trial.
AUTHORS' CONCLUSIONS: The numbers of included participants, and hence the number of events, were too small to draw any conclusion about the relative efficacy of monotherapy versus combination therapy as initial treatment for primary hypertension. There is a need for large clinical trials that address the review question and report clinically relevant endpoints.

PMID: 32026465 [PubMed - in process]

Clove oil based co-surfactant free microemulsion of flurbiprofen: Improved solubility with ameliorated drug-induced gastritis.

Pak J Pharm Sci. 2019 Nov;32(6(Supplementary)):2787-2793

Authors: Tanzeem MU, Asghar S, Khalid SH, Asif M, Ullah MS, Khan IU, Khalid I, Faran SA, Rehman A, Gohar UF, Hussain T

Abstract
Flurbiprofen, an NSAID, is a water insoluble drug that is also notorious for gastric irritation and inflammation. This study was aimed at using a natural gastrprotective oil as the internal phase to develop flurbiprofen micro emulsion (ME) to improve it solubility and ameliorate its gastric side effects. Upon screening of ME components for drug solubility, clove oil, tween 80 and transcutol were identified as the oil, surfactant and co surfactant, respectively, with higher flurbiprofen solubility. Pseudo-ternary phase diagrams revealed that the ME made with surfactant only and without co-surfactant displayed the similar ME region as made with the mixture of surfactant and co-surfactant. Furthermore, drug loaded oil was also used to draw pseudo-ternary phase diagram and a very little decrease in the ME region was observed. Therefore, co-surfactant free flurbiprofen loaded ME was developed to avoid side effects associated with the use of excessive surfactant quantities. ME were found to possess size in the range of 11-41 nm with PDI <0.5 and a slightly negative charge. Conductivity, pH and refractive indices of the selected MEs were well in the range. Drug release studies indicated maximum drug release from MEs within 5 min. Analysis of the gastric mucosa of rats after oral administration of drug solution and drug loaded ME confirmed that clove oil based ME provided significant protection against the NSAIDs induced gastric damage.

PMID: 32024615 [PubMed - in process]

Rhabdomyolysis: a rare adverse effect of levetiracetam.

BMJ Case Rep. 2019 Aug 26;12(8):

Authors: Thomas L, Mirza MMF, Shaikh NA, Ahmed N

Abstract
A 62-year-old previously healthy male was admitted with new onset generalised tonic-clonic seizures. Treatment was initiated with the antiepileptic levetiracetam and he had no further episodes of seizures. Creatine kinase (CPK) level was 1812 IU/L 12-hour postadmission. Despite good hydration, his CPK levels continued to rise dramatically and reached a level of 19 000 IU/L on day 5. This rise was unexplained as he did not have any further seizures and had a normal renal function. In the absence of other risk factors, the rare possibility of levetiracetam being responsible for the disproportionately high CPK was considered. Within 12 hours of withdrawal of levetiracetam, there was a downward trend in the CPK levels, with a 10-fold decrease in CPK levels over the next 4 days. This is only the ninth case reported in literature regarding this rare and potentially serious adverse effect of levetiracetam.

PMID: 31451475 [PubMed - indexed for MEDLINE]

A pharmacogenetic intervention for the improvement of the safety profile of antipsychotic treatments.

Transl Psychiatry. 2019 07 25;9(1):177

Authors: Arranz MJ, Gonzalez-Rodriguez A, Perez-Blanco J, Penadés R, Gutierrez B, Ibañez L, Arias B, Brunet M, Cervilla J, Salazar J, Catalan R

Abstract
Antipsychotic drugs fail to achieve adequate response in 30-50% of treated patients and about 50% of them develop severe and lasting side effects. Treatment failure results in poorer prognosis with devastating repercussions for the patients, carers and broader society. Our study evaluated the clinical benefits of a pharmacogenetic intervention for the personalisation of antipsychotic treatment. Pharmacogenetic information in key CYP polymorphisms was used to adjust clinical doses in a group of patients who started or switched treatment with antipsychotic drugs (PharmG+, N = 123), and their results were compared with those of a group of patients treated following existing clinical guides (PharmG-, N = 167). There was no evidence of significant differences in side effects between the two arms. Although patients who had their antipsychotic dose adjusted according to CYPs polymorphisms (PharmG+) had a bigger reduction in side effects than those treated as usual (PharmG-), the difference was not statistically significant (p > 0.05 for all comparisons). However, PharmG+ patients treated with CYP2D6 substrates that were carriers of CYP2D6 UMs or PMs variants showed a significantly higher improvement in global, psychic and other UKU side effects than PharmG- patients (p = 0.02, p = 0.05 and p = 0.01, respectively). PharmG+ clozapine treated patients with CYP1A2 or CYP2C19 UM and PMs variants also showed higher reductions in UKU scores than PharmG- clozapine patients in general. However, those differences were not statistically significant. Pharmacogenetic interventions may improve the safety of antipsychotic treatments by reducing associated side effects. This intervention may be particularly useful when considering treatment with antipsychotics with one major metabolic pathway, and therefore more susceptible to be affected by functional variants of CYP enzymes.

PMID: 31346157 [PubMed - indexed for MEDLINE]

26 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 2020/02/06

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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 2020/02/05

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.

Long-term efficacy and safety of solifenacin in pediatric patients aged 6 months to 18 years with neurogenic detrusor overactivity: results from two phase 3 prospective open-label studies.

J Pediatr Urol. 2019 Dec 27;:

Authors: Franco I, Hoebeke P, Baka-Ostrowska M, Bolong D, Davies LN, Dahler E, Snijder R, Stroosma O, Verheggen F, Newgreen D, Bosman B, Vande Walle J

Abstract
INTRODUCTION: The standard recommended treatment for neurogenic detrusor overactivity (NDO) is clean intermittent catheterization combined with an antimuscarinic agent. However, the adverse systemic side-effects of oxybutynin, the most widely used agent, are of concern.
OBJECTIVE: To evaluate the efficacy and safety of solifenacin in pediatric patients with NDO, aged 6 months-<5 years and 5-<18 years.
STUDY DESIGN: Two open-label, baseline-controlled, phase 3 studies were conducted in pediatric patients with NDO. Patients were treated with sequential doses of solifenacin oral suspension (pediatric equivalent doses 2.5-10 mg) for 12 weeks to determine each patient's optimal dose, followed by a fixed dose ≥40-week treatment period. Primary efficacy endpoint was change from baseline in maximum cystometric capacity (MCC) after 24 weeks. Secondary endpoints included bladder compliance, bladder volume until first detrusor contraction (>15 cmH2O), number of overactive detrusor contractions (>15 cmH2O), maximum catheterized volume (MCV)/24 h, and incontinence episodes/24 h. Safety parameters were treatment-emergent adverse events (TEAEs), serious adverse events, laboratory variables, vital signs, electrocardiograms, and ocular accommodation and cognitive function assessments.
RESULTS: After 24 weeks, MCC had significantly increased compared with baseline in patients aged 6 months -<5 years and 5-<18 years (37.0 ml and 57.2 ml, respectively; P < 0.001; Fig.). Improvement was also observed after 52 weeks' treatment. Significant changes were observed from baseline to week 24 in all secondary endpoints in both age groups: increase in bladder compliance, increase in bladder volume to first detrusor contraction as a percentage of expected bladder capacity, reduction in the number of overactive detrusor contractions, increase in MCV, and decreased incontinence episodes. TEAEs were mostly mild or moderate, and there were no new drug-related TEAEs compared with adult studies. Age-related improvements were noted in ocular accommodation and cognitive function.
DISCUSSION: These long-term multicenter investigations demonstrated the efficacy and safety of solifenacin in pediatric patients with NDO. The observed increases in MCC were clinically relevant and demonstrated that an increase in fluid volume can be accommodated in the bladder prior to reaching intravesical pressures that endanger kidney function and/or are associated with leakage or discomfort. Solifenacin was well tolerated with low incidences of constipation and dry mouth (typically associated with antimuscarinics), central nervous system-related side-effects, and facial flushing.
CONCLUSION: Solifenacin was effective and well tolerated in pediatric patients with NDO, aged 6 months-<18 years, suggesting that it is a viable alternative to oxybutynin, the current standard of care. STUDIES ARE REGISTERED AT CLINICALTRIALS.GOV: NCT01981954 and NCT01565694.

PMID: 32007426 [PubMed - as supplied by publisher]

Effect of dexmedetomidine on acute kidney injury after aortic surgery: a single-centre, placebo-controlled, randomised controlled trial.

Br J Anaesth. 2020 Jan 29;:

Authors: Soh S, Shim JK, Song JW, Bae JC, Kwak YL

Abstract
BACKGROUND: Acute kidney injury (AKI) is a frequent and serious complication after aortic surgery requiring cardiopulmonary bypass (CPB). Dexmedetomidine, a selective α-2 adrenoreceptor agonist, may reduce AKI because of its sympatholytic and anti-inflammatory effects against ischaemia-reperfusion injury. We investigated the effect of dexmedetomidine administration on AKI after aortic surgery requiring CPB in a placebo-controlled randomised controlled trial.
METHODS: A total of 108 patients were randomly assigned to an infusion of dexmedetomidine or saline at a rate of 0.4 μg kg-1 h-1 for 24 h starting after anaesthetic induction. The primary outcome was the incidence of AKI, as defined by the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. The secondary outcomes included delirium and major morbidity. Safety outcomes were drug-related adverse events (bradycardia, hypotension).
RESULTS: AKI occurred in 7/54 (13%) subjects randomised to dexmedetomidine, compared with 17/54 (31%) subjects randomised to saline infusion (odds ratio=0.32; 95% confidence interval [CI], 0.12-0.86; P=0.026). Secondary outcomes, including stroke, mortality, and delirium, were similar between subjects randomised to dexmedetomidine (16/54 [30%] or saline control (22 [41%]; odds ratio=0.61 [95% CI, 0.28-1.36]). The incidence of bradycardia and hypotension was similar between groups (14/54 (26%) vs. 17/54 (32%) (odds ratio:0.76 (95%CI:0.33-1.76) and 29/54 (54%) vs. 36/54 (67%) (odds ratio:0.58 (95%CI:0.27-1.26), respectively). The length of hospital stay was shorter in the dexmedetomidine group (12 [10-17] days) vs saline control (15 [11-21] days; P=0.039).
CONCLUSIONS: Pre-emptive dexmedetomidine administration for 24 h starting after induction of anaesthesia reduced the incidence of AKI after aortic surgery requiring CPB, without any untoward side-effects related to its sedative or sympatholytic effects.
CLINICAL TRIAL REGISTRATION: NCT02607163 (www.ClinicalTrials.gov).

PMID: 32007239 [PubMed - as supplied by publisher]

The effects of fasting on drug metabolism.

Expert Opin Drug Metab Toxicol. 2020 Jan;16(1):79-85

Authors: Lammers LA, Achterbergh R, Mathôt RAA, Romijn JA

Abstract
Introduction: There is considerable variability in the rates and extent of drug metabolism between patients due to physiological, genetic, pharmacologic, environmental and nutritional factors such as fasting. This variability in drug metabolism may result in treatment failure or, conversely, in increased side effects or toxicity. Preclinical studies have shown that fasting alters drug metabolism by modulating the activity of drug metabolizing enzymes involved. However, until recently little was known about the effects of fasting on drug metabolism in humans.Areas covered: This review describes the effects of fasting on drug metabolism based on both preclinical studies and studies performed in humans.Expert opinion: A better understanding of the effects of fasting may improve the efficacy and safety of pharmacotherapy for individual patients. Fasting contributes to variability in human drug metabolism by differentially affecting drug metabolizing enzymes. Although the effects of fasting on drug metabolism appear to be small (between 10-20%), fasting may be relevant for drugs with a small therapeutic range and/or in combination with other factors that contribute to variability in drug metabolism such as physiological, genetic or pharmacological factors. Therefore, additional research on this topic is warranted.

PMID: 31851534 [PubMed - indexed for MEDLINE]

Safe use of medication in patients with cirrhosis: pharmacokinetic and pharmacodynamic considerations.

Expert Opin Drug Metab Toxicol. 2020 Jan;16(1):45-57

Authors: Weersink RA, Burger DM, Hayward KL, Taxis K, Drenth JPH, Borgsteede SD

Abstract
Introduction: The global burden of cirrhosis is rising, and clinicians increasingly face the challenge of safely prescribing medicines for complications of hepatic disease and comorbidities. Prescribing in patients with cirrhosis is complicated by alterations that can occur in the pharmacology of medicines.Areas covered: This paper provides an overview of current knowledge on the pharmacokinetics and pharmacodynamics of medicines in patients with cirrhosis. We describe the pathophysiological changes that occur and their consequences on pharmacokinetic parameters. We explain that the influence of cirrhosis on the pharmacokinetics depends on several drug and patient characteristics. Patients with cirrhosis also have an increased susceptibility to some toxicological effects of medicines, such as renal impairment and hematological toxicity, which we describe in detail. In addition, we discuss approaches to apply this knowledge in practice and improve safe medication use in patients with cirrhosis.Expert opinion: Tailored pharmacotherapy is needed to ensure safe and appropriate use of medicines in patients with cirrhosis. Clinicians are supported by freely available recommendations on safe drug use in cirrhosis published on a website. In addition, a regular evaluation of medication use in patients with cirrhosis could resolve and prevent medication-related problems.

PMID: 31810397 [PubMed - indexed for MEDLINE]

The Association Between Potential Opioid-Related Adverse Drug Events and Outcomes in Colorectal Surgery.

J Laparoendosc Adv Surg Tech A. 2019 Nov;29(11):1436-1445

Authors: Homsi J, Brovman EY, Rao N, Whang EE, Urman RD

Abstract
Introduction: Major colorectal surgery procedures are complex operations that can result in significant postoperative pain and complications. More evidence is needed to demonstrate how opioid-related adverse drug events (ORADEs) after colorectal surgery can affect hospital length of stay (LOS), hospital revenue, and what their association is with clinical conditions. By understanding the clinical and economic impact of potential ORADEs within colorectal surgery, we hope to further guide approaches to perioperative pain management in an effort to improve patient care and reduce hospital costs. Materials and Methods: We conducted a retrospective study utilizing the Centers for Medicare and Medicaid Services (CMS) Administrative Database to analyze Medicare discharges involving three colorectal surgery diagnosis-related groups (DRGs) to identify potential ORADEs. The impact of potential ORADEs on mean hospital LOS and hospital revenue was analyzed. Results: The potential ORADE rate in patients undergoing colorectal surgery was 23.92%. The mean LOS for discharges with a potential ORADE was 5.35 days longer than without an ORADE. The mean hospital revenue per day with a potential ORADE was $418 less than without an ORADE. Any type of open surgery had a statistically significant higher potential ORADE rate than the matched laparoscopic case (P < .001). Clinical conditions most strongly associated with ORADEs in colorectal surgery included septicemia, pneumonia, shock, and fluid and electrolyte disorders. Conclusion: The incidence of ORADEs in colorectal surgery is high and is associated with longer hospital stays and reduced hospital revenue. Reducing the use of opioids in the perioperative setting, such as using multimodal analgesia strategies, may lead to positive outcomes with shorter hospital stays, increased hospital revenue, and improved patient care.

PMID: 31556797 [PubMed - indexed for MEDLINE]