The pharmacotherapy of cirrhosis: concerns and proposed investigations and solutions.

J Clin Pharm Ther. 2016 Dec;41(6):587-591

Authors: Hilscher MB, Odell LJ, Myhre LJ, Prokop L, Talwalkar J

Abstract
WHAT IS KNOWN AND OBJECTIVE: The presence of cirrhosis has a multifaceted impact on hepatic drug metabolism. An area of concern and uncertainty in the care of patients with cirrhosis is the safe use of both prescription and over-the-counter medications.
COMMENT: Retrospective studies indicate a high incidence of adverse drug reactions (ADRs) among patients with cirrhosis related to use of certain medication classes including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and non-steroidal anti-inflammatory drugs. Conversely, use of appropriate medications, such as statins, may be decreased in this population due to fear of precipitating hepatotoxicity.
WHAT IS NEW AND CONCLUSION: Pharmacotherapy in cirrhosis is an area of uncertainty and heterogeneity in clinical practice. Prescribing and dosing guidelines are needed to decrease the risk of serious ADRs in this high-risk patient population.

PMID: 27576303 [PubMed - indexed for MEDLINE]

Letter in response to "Efficacy and effectiveness of anti-digoxin antibodies in chronic digoxin poisonings from the DORA study (ATOM-1)".

Clin Toxicol (Phila). 2017 01;55(1):63

Authors: Wang JJ, Regina A, Hoffman RS

PMID: 27491930 [PubMed - indexed for MEDLINE]

Further evidence that a variant of the gene NUDT15 may be an important predictor of azathioprine-induced toxicity in Chinese subjects: a case report.

J Clin Pharm Ther. 2016 Oct;41(5):572-4

Authors: Ailing Z, Jing Y, Jingli L, Yun X, Xiaojian Z

Abstract
WHAT IS KNOWN AND OBJECTIVE: Thiopurine methyltransferase (TPMT) enzyme is an important component in the metabolism of azathioprine (AZA). Its mutation may lead to AZA-induced toxicity. The dysfunctional genetic variant TPMT *3C is of low frequency among Asians. Moreover, AZA-induced toxicity still occurs in some patients with normal TPMT activity. This suggests that additional factors, including other genetic variants, may contribute to such toxicity. Recent studies described a strong association between a variant of the NUDT15, a gene that mediates the hydrolysis of some nucleoside diphosphate derivatives, and thiopurine-related myelosuppression in Asians. We report the first case of a Chinese patient with AZA-induced severe toxicity with no clinically significant TPMT variant but with the NUDT15 c.415C>T allele.
CASE SUMMARY: A 40-year-old Chinese patient with PBC-AIH overlap syndrome had been receiving for one month, azathioprine (50 mg/day) and methylprednisolone (24 mg/day) based on his TPMT*3C wild-type genotype. The patient developed serious myelosuppression and hair loss. AZA was stopped, and the patient was given liver-protective drugs and supportive treatment. TPMT and NUDT15 gene sequencing suggests that NUDT15 c.415C>T mutation was the likely cause of the adverse reaction.
WHAT IS NEW AND CONCLUSION: NUDT15 c.415C>T may be another predictor of AZA-induced leukocytopenia. If further well-controlled studies validate this association with sufficient predictive power, NUDT15 and TPMT genotyping before starting AZA treatment may become appropriate.

PMID: 27381176 [PubMed - indexed for MEDLINE]

Anticholinergic medicines in an older primary care population: a cross-sectional analysis of medicines' levels of anticholinergic activity and clinical indications.

J Clin Pharm Ther. 2016 Oct;41(5):486-92

Authors: Magin PJ, Morgan S, Tapley A, McCowan C, Parkinson L, Henderson KM, Muth C, Hammer MS, Pond D, Mate KE, Spike NA, McArthur LA, van Driel ML

Abstract
WHAT IS KNOWN AND OBJECTIVES: Adverse clinical outcomes have been associated with cumulative anticholinergic burden (to which low-potency as well as high-potency anticholinergic medicines contribute). The clinical indications for which anticholinergic medicines are prescribed (and thus the 'phenotype' of patients with anticholinergic burden) have not been established. We sought to establish the overall prevalence of prescribing of anticholinergic medicines, the prevalence of prescribing of low-, medium- and high-potency anticholinergic medicines, and the clinical indications for which the medicines were prescribed in an older primary care population.
METHODS: This was a cross-sectional analysis of a cohort study of Australian early-career general practitioners' (GPs') clinical consultations - the Registrar Clinical Encounters in Training (ReCEnT) study. In ReCEnT, GPs collect detailed data (including medicines prescribed and their clinical indication) for 60 consecutive patients, on up to three occasions 6 months apart. Anticholinergic medicines were categorized as levels 1 (low-potency) to 3 (high-potency) using the Anticholinergic Drug Scale (ADS).
RESULTS: During 2010-2014, 879 early-career GPs (across five of Australia's six states) conducted 20 555 consultations with patients aged 65 years or older, representing 35 506 problems/diagnoses. Anticholinergic medicines were prescribed in 10·4% [95% CIs 9·5-10·5] of consultations. Of the total anticholinergic load of prescribed medicines ('community anticholinergic load') 72·7% [95% CIs 71·0-74·3] was contributed by Level 1 medicines, 0·8% [95% CIs 0·5-1·3] by Level 2 medicines and 26·5% [95% CIs 24·8-28·1] by Level 3 medicines. Cardiac (40·0%), Musculoskeletal (16·9%) and Respiratory (10·6%) were the most common indications associated with Level 1 anticholinergic prescription. For Level 2 and 3 medicines (combined data), Psychological (16·1%), Neurological (16·1%), Musculoskeletal (15·7%) and Urological (11·1%) indications were most common.
WHAT IS NEW AND CONCLUSION: Anticholinergic medicines are frequently prescribed in Australian general practice, and the majority of the 'community' anticholinergic burden is contributed by 'low'-anticholinergic potency medicines whose anticholinergic effects may be largely 'invisible' to prescribing GPs. Furthermore, the clinical 'phenotype' of the patient with high anticholinergic burden may be very different to common stereotypes (patients with urological, psychological or neurological problems), potentially making recognition of risk of anticholinergic adverse effects additionally problematic for GPs.

PMID: 27349795 [PubMed - indexed for MEDLINE]

Comparison of high-dose intravenous immunoglobulin (IVIG) in a 5% and a 10% solution does not reveal a significantly different spectrum of side-effects.

J Eur Acad Dermatol Venereol. 2016 Dec;30(12):e186-e188

Authors: Rappold LC, Denk K, Enk AH, Hadaschik EN

PMID: 26551028 [PubMed - indexed for MEDLINE]

The immunogenicity and safety of a Hib-MenAC vaccine: a non-inferiority randomized, observer-blind trial in infants aged 3-5 months.

Expert Rev Vaccines. 2017 May;16(5):515-524

Authors: Wang YX, Tao H, Hu JL, Li JX, Dai WM, Sun JF, Liu P, Tang J, Liu WY, Zhu FC

Abstract
BACKGROUND: The objective of this study was to evaluate the immunogenicity and safety of the novel combined Haemophilus influenzae type b-Neisseria meningitidis serogroup A and C-tetanus toxoid conjugate vaccine (Hib-MenAC).
METHODS: We conducted a non-inferiority, randomized, observer-blind, positive control clinical trial in 900 healthy infants aged between 3-5 months in Funing County, Jiangsu Province, China. Participants were randomly allocated, in a ratio of 2:1 (block = 6), to receive experimental combined Hib-MenAC vaccines co-administrated with placebo or the co-administration of licensed Hib vaccine and MenAC vaccine, according to a three-dose immunization schedule. The seroconversion of antibody titer against meningococcal serogroups A, C and Hib was the primary endpoint.
RESULTS: The experimental vaccines was non-inferior to the licensed two control vaccines. Participants receiving experimental Hib-MenAC vaccines showed a seroconversion rate of 99.0%, 96.1% and 97.7% for rSBA-MenA, rSBA-MenC and anti-PRP antibodies, respectively. The Hib-MenAC vaccine did not result in an increase in adverse reaction, and no serious adverse event was judged to be related to the vaccination.
CONCLUSIONS: The novel combined Hib-MenAC conjugate vaccine was safe and highly immunogenic in infants aged between 3 to 5 months.

PMID: 28277801 [PubMed - indexed for MEDLINE]

Deprescribing in older people.

Maturitas. 2016 Sep;91:115-34

Authors: Page AT, Potter K, Clifford R, Etherton-Beer C

Abstract
Older people with chronic disease have great potential to benefit from their medications but are also at high risk of harm from their medications. The use of medications is particularly important for symptom control and disease progression in older people. Under-treatment means older people can miss out on the potential benefits of useful medications, while over-treatment (polypharmacy) puts them at increased risk of harm. Deprescribing attempts to balance the potential for benefit and harm by systematically withdrawing inappropriate medications with the goal of managing polypharmacy and improving outcomes. The evidence base for deprescribing in older people is growing. Studies to reduce polypharmacy have used a range of methods. Most evidence for deprescribing relates to the withdrawal of specific medications, and evidence supports attempts to deprescribe potentially inappropriate medicines (such as long-term benzodiazepines). There is also evidence that polypharmacy can be reduced by withdrawing specific medications using individualised interventions. More work is needed to identify the sub-groups of older people who may most benefit from deprescribing and the best approaches to undertaking the deprescribing interventions.

PMID: 27451330 [PubMed - indexed for MEDLINE]

Frailty, polypharmacy and deprescribing.

Drug Ther Bull. 2016 Jun;54(6):69-72

Authors:

Abstract
Multimorbidity and associated polypharmacy present a significant and increasing challenge to patients, carers and healthcare professionals.(1,2) While it is recognised that polypharmacy can be beneficial, there is considerable potential for harm, particularly through drug interactions, adverse drug events and non-adherence.(1) Such harms are amplified in people who are frail and who may require interventions to be tailored to their individual needs rather than strictly following guidance designed to manage single diseases. It is important to develop an approach that allows patients to make informed decisions and prioritise medicines for continuation or discontinuation, in order to maximise benefit and minimise harm.(1)The term 'deprescribing' has been suggested in recognition that the skills utilised in stopping medicines need to be as sophisticated as those used when initiating drug treatment.(3) Key to deprescribing, as with all medical interventions, is the active participation of the patient to ensure that their preferences and choices are taken into account. Particular care is needed when end-of-life considerations apply, so that treatment is optimised and the burden of taking medicines is minimised.(4) Although evidence is sparse, this article provides some practical observations on deprescribing.

PMID: 27284125 [PubMed - indexed for MEDLINE]

Efficacy, safety, tolerability and price of newly approved drugs in solid tumors.

Cancer Treat Rev. 2017 Apr 09;56:1-7

Authors: Barnes TA, Amir E, Templeton AJ, Gomez-Garcia S, Navarro B, Seruga B, Ocana A

Abstract
BACKGROUND: New anti-cancer drugs utilize diverse mechanisms of action. Here we evaluate their differential efficacy, safety, tolerability and price.
METHODS: Drugs approved for solid tumor treatment between 2000 and 2015 were identified and analyzed in subgroups: agents targeting oncogenes (group 1), anti-angiogenics (group 2), immunotherapy (group 3), and chemotherapy (group 4). Hazard ratios (HRs) were extracted from the registration trials and pooled in a meta-analysis. Odds ratios for toxic death, treatment discontinuation and grade 3-4 toxicity were compared to control groups. The Micromedex Red Book was used to calculate the monthly price.
RESULTS: Analysis included 74 studies comprising 48,527 patients. Progression-free survival (PFS) was improved to a greater degree with groups 1 and 2 than with groups 3 and 4, (pooled HR: 0.54, 0.56, 0.63, and 0.76 for groups 1-4 respectively, p for difference <0.001). Compared to PFS, there was a lower magnitude of improvement overall survival in all groups and the degree of benefit was less for group 4 than for other groups (pooled HR: 0.77, 0.78, 0.68, and 0.83 for groups 1-4 respectively, p for difference=0.007). Compared to control groups in individual trials, immunotherapy was associated with better safety and tolerability than other groups. Drug prices have increased over time with no significant difference between groups. There was no meaningful correlation between pricing and efficacy.
CONCLUSIONS: Compared to control groups, immunotherapeutics and drugs targeting oncogenes or angiogenesis improve efficacy to a greater degree than chemotherapy. Immunotherapy appears to have better safety and tolerability profile compared to other cancer therapies. Market price of drugs is not related to efficacy.

PMID: 28437678 [PubMed - as supplied by publisher]

Pharmacokinetics and Safety of Travoprost 0.004% Ophthalmic Solution Preserved with Polyquad in Pediatric Patients with Glaucoma.

J Ocul Pharmacol Ther. 2017 Feb 24;:

Authors: Stahl E, Bremond-Gignac D, Landry T, Curtis M, Gedif K, Al Shahwan S, Dixon ER

Abstract
PURPOSE: To evaluate the systemic pharmacokinetics (PKs) of travoprost 0.004% preserved with Polyquad(®) (TRAVATAN(®)) in pediatric patients with glaucoma or ocular hypertension.
METHODS: This was a phase 1, open-label, multicenter clinical study of patients aged ≥2 months to <18 years. Patients received daily administration of travoprost 0.004% preserved with Polyquad in both eyes for 7 days. Plasma samples were collected 30 min before the final dose and at 10, 20, 40, and 80 min postdose. The main outcome measure was maximum concentration of travoprost free acid in plasma (Cmax).
RESULTS: Included in the PK analysis were 24 patients (average age 9.6 ± 4.9 years). At least 1 sample with quantifiable levels of travoprost free acid was collected for 11 patients. The mean Cmax was 0.0471 ± 0.0105 ng/mL for patients aged 2 months to <3 years; 0.0258 ± 0.0128 ng/mL for ages 3 to <12 years; and 0.0109 ± 0.0005 ng/mL for ages 12 to <18 years. Travoprost was undetectable in samples collected predose from pediatric patients. Treatment-related adverse events (AEs) included hyperemia, eye pain, and eye pruritus (n = 1 each). There were no discontinuations or drug-related serious AEs.
CONCLUSIONS: Travoprost free acid concentration in plasma was low in pediatric patients, detectable in only 11 of 24 patients. There was no accumulation of travoprost over the course of treatment. No clear relationship was observed between age/body surface area and Cmax. No increased risk was identified for the use of travoprost 0.004% preserved with Polyquad in patients <18 years of age.

PMID: 28437175 [PubMed - as supplied by publisher]

Management of skin adverse events associated with immune checkpoint inhibitors in patients with melanoma: A nursing perspective.

J Am Assoc Nurse Pract. 2017 Apr 24;:

Authors: Thebeau M, Rubin K, Hofmann M, Grimm J, Weinstein A, Choi JN

Abstract
PURPOSE: Immune checkpoint inhibitors are associated with a unique immune-related side effect profile that requires prompt recognition and management. Skin toxicities are the most common, and often earliest occurring, drug-related adverse events (AEs) of any grade observed upon treatment with these agents. The purpose of this review is to provide practical guidance on the identification and treatment of skin AEs associated with the immune checkpoint inhibitors (ipilimumab, nivolumab, and pembrolizumab) from a nursing perspective, and demonstrate hands-on application of the guidance using relevant patient case studies.
DATA SOURCES: Data for drug-related skin AEs were summarized from phase 3 nivolumab and nivolumab + ipilimumab trials and phase 2 and 3 pembrolizumab trials. Patient case studies were provided by the lead (M.T.) and senior (J.N.C.) authors.
CONCLUSIONS: The recommendations presented here, based on accumulated clinical trial and clinical practice experience are consistent with established treatment guidelines and reach beyond established guidelines and recommendations for the management of AEs associated with immune checkpoint inhibitors.
IMPLICATIONS FOR PRACTICE: The practical treatment guidance presented here may help familiarize medical teams with the recognition and management of skin AEs associated with these recently approved agents. The enclosed recommendations may contribute to optimized treatment through awareness of typical time to onset and clinical presentation, knowledge of management options, and appropriate application of treatment.

PMID: 28436601 [PubMed - as supplied by publisher]

Posttreatment Reactions After Single-Dose Diethylcarbamazine or Ivermectin in Subjects With Loa loa Infection.

Clin Infect Dis. 2017 Apr 15;64(8):1017-1025

Authors: Herrick JA, Legrand F, Gounoue R, Nchinda G, Montavon C, Bopda J, Tchana SM, Ondigui BE, Nguluwe K, Fay MP, Makiya M, Metenou S, Nutman TB, Kamgno J, Klion AD

Abstract
Background.: Severe adverse reactions have been observed in individuals with Loa loa infection treated with either diethylcarbamazine (DEC), the drug of choice for loiasis, or ivermectin (IVM), which is used in mass drug administration programs for control of onchocerciasis and lymphatic filariasis in Africa. In this study, posttreatment clinical and immunologic reactions were compared following single-dose therapy with DEC or IVM to assess whether these reactions have the same underlying pathophysiology.
Methods.: Twelve patients with loiasis and microfilarial counts <2000 mf/mL were randomized to receive single-dose DEC (8 mg/kg) or IVM (200 µg/kg). Clinical and laboratory assessments were performed at 4, 8, 24, 48, and 72 hours and 5, 7, 9, and 14 days posttreatment.
Results.: Posttreatment adverse events were similar following DEC or IVM, but peaked earlier in subjects who received DEC, consistent with a trend toward more rapid and complete microfilarial clearance in the DEC group. After a transient rise (post-IVM) or fall (post-DEC) in the first 24 hours posttreatment, the eosinophil count rose significantly in both groups, peaking at day 5 in the DEC group and day 9 in the IVM group. Serum interleukin 5 levels and eosinophil activation, as assessed by surface expression of CD69 and serum levels of eosinophil granule proteins, were increased posttreatment in both groups.
Conclusions.: Despite differences in eosinophil and lymphocyte counts during the first 24 hours posttreatment, the overall pattern of hematologic and immunologic changes suggest that posttreatment reactions following DEC and IVM share a common pathophysiology.
Clinical Trials Registration.: NCT01593722.

PMID: 28329346 [PubMed - indexed for MEDLINE]

Applying mixture toxicity modelling to predict bacterial bioluminescence inhibition by non-specifically acting pharmaceuticals and specifically acting antibiotics.

Chemosphere. 2017 Apr;173:387-394

Authors: Neale PA, Leusch FD, Escher BI

Abstract
Pharmaceuticals and antibiotics co-occur in the aquatic environment but mixture studies to date have mainly focused on pharmaceuticals alone or antibiotics alone, although differences in mode of action may lead to different effects in mixtures. In this study we used the Bacterial Luminescence Toxicity Screen (BLT-Screen) after acute (0.5 h) and chronic (16 h) exposure to evaluate how non-specifically acting pharmaceuticals and specifically acting antibiotics act together in mixtures. Three models were applied to predict mixture toxicity including concentration addition, independent action and the two-step prediction (TSP) model, which groups similarly acting chemicals together using concentration addition, followed by independent action to combine the two groups. All non-antibiotic pharmaceuticals had similar EC50 values at both 0.5 and 16 h, indicating together with a QSAR (Quantitative Structure-Activity Relationship) analysis that they act as baseline toxicants. In contrast, the antibiotics' EC50 values decreased by up to three orders of magnitude after 16 h, which can be explained by their specific effect on bacteria. Equipotent mixtures of non-antibiotic pharmaceuticals only, antibiotics only and both non-antibiotic pharmaceuticals and antibiotics were prepared based on the single chemical results. The mixture toxicity models were all in close agreement with the experimental results, with predicted EC50 values within a factor of two of the experimental results. This suggests that concentration addition can be applied to bacterial assays to model the mixture effects of environmental samples containing both specifically and non-specifically acting chemicals.

PMID: 28129616 [PubMed - indexed for MEDLINE]

Safety and immunogenicity of a recombinant Staphylococcus aureus α-toxoid and a recombinant Panton-Valentine leukocidin subunit, in healthy adults.

Hum Vaccin Immunother. 2017 Apr 03;13(4):791-801

Authors: Landrum ML, Lalani T, Niknian M, Maguire JD, Hospenthal DR, Fattom A, Taylor K, Fraser J, Wilkins K, Ellis MW, Kessler PD, Fahim RE, Tribble DR

Abstract
We conducted a randomized, double-blind, placebo-controlled dose-escalation study in healthy adults to evaluate the safety and immunogenicity of recombinant Staphylococcus aureus candidate vaccine antigens, recombinant α-toxoid (rAT) and a sub-unit of Panton-Valentine leukocidin (rLukS-PV). 176 subjects were enrolled and randomized within 1 of 11 treatment cohorts: monovalent rAT or rLukS-PV dosages of 10, 25, 50, and 100 μg; bivalent rAT:rLukS dosages of 10:10, 25:25, and 50:50 μg; and alum or saline placebo. All subjects were assessed at Days 0, 7, 14, 28, and 84. Subjects in the 50:50 μg bivalent cohort received a second injection on Day 84 and were assessed on Days 98 and 112. Incidence and severity of reactogenicity and adverse events (AEs) were compared. Geometric mean serum concentrations (GMC) and neutralizing activity of anti-rAT and anti-rLukS-PV IgG were assessed. Reactogenicity incidence was significantly higher in vaccine than placebo recipients (77% versus 55%, respectively; p = 0.006). However, 77% of reactogenicity events were mild and 19% were moderate in severity. The AE incidence and severity were similar between the cohorts. All monovalent and bivalent rAT dosages resulted in a significant increase in the anti-rAT IgG and anti- rLukS-PV GMCs between day 0 and 28 compared with placebo, and persisted through Day 84. Exploratory subgroup analyses suggested a higher GMC and neutralizing antibody titers for the 50 μg monovalent or bivalent rAT and rLukS-PV dose as compared to the other doses. No booster effect was observed after administration of the second dose. We conclude that the rAT and rLukS-PV vaccine formulations were well-tolerated and had a favorable immunogenicity profile, producing antibody with neutralizing activity through day 84. There was no benefit observed with a booster dose of the vaccine.

PMID: 28010246 [PubMed - indexed for MEDLINE]

Rapid safety assessment of a seasonal intradermal trivalent influenza vaccine.

Hum Vaccin Immunother. 2017 Apr 03;13(4):889-894

Authors: Demeulemeester M, Lavis N, Balthazar Y, Lechien P, Heijmans S

Abstract
Seasonal influenza vaccine formulations must be updated annually to correspond to the influenza viruses in circulation. This was an uncontrolled, open-label, multi-center phase IV study conducted in Belgium to comply with interim European Medicines Agency (EMA) guidelines for rapidly evaluating the safety of newly formulated seasonal influenza vaccines. Adult volunteers received one dose of the 2014-2015 Northern Hemisphere formulation of licensed intradermal trivalent influenza vaccine at either the standard dose (9µg hemagglutinin/strain for 18-59 year-olds) or the high dose (15µg hemagglutinin/strain for ≥ 60 year-olds). Vaccinees recorded their solicited reactions and unsolicited adverse events for 7 d after vaccination. Solicited reaction frequencies were compared to historical reference values obtained from previous clinical trials to determine if the new formulations were excessively reactogenic or allergenic. A total of 210 participants (105 per age group) were included and vaccinated in October 2014. In both groups, pain, erythema, and pruritus were the most common solicited injection site reactions, and headache and myalgia were the most common solicited systemic reactions. Although the frequencies of shivering in 18-59 year-olds and malaise in ≥ 60 year-olds were higher than historical reference values, they were not considered indicative of excessive reactogenicity because almost all of these reactions were mild. The study design was endorsed by the EMA and permitted the reactogenicity of both vaccine formulations to be assessed within one month by collecting adverse events for 7 d. Both formulations exhibited acceptable safety profiles although this should be confirmed through forthcoming enhanced post-marketing safety surveillance systems.

PMID: 27960593 [PubMed - indexed for MEDLINE]

Systematic Review of Adverse Effects from Herbal Drugs Reported in Randomized Controlled Trials.

Phytother Res. 2016 Sep;30(9):1412-9

Authors: Lee JY, Jun SA, Hong SS, Ahn YC, Lee DS, Son CG

Abstract
Herbal drugs have become a popular form of healthcare, raising concerns about their safety. This study aimed to characterize the adverse effects of herbal drugs through a systematic review of results reported in randomized controlled trials (RCTs). Using eight electronic databases including PubMed, the Cochrane library and six Korean medical databases, the frequency of reported toxicity was recorded based on drug composition and indication. Among 4957 potentially relevant articles, 242 papers comprised of 244 studies met our inclusion criteria; these included 111 studies of a single herb and 133 of multiple herbs. These studies accounted for a total 15 441 participants (male = 5590; female = 9851; 7383 for single and 8058 for multiple herb studies). There were 480 cases (3.1%) of adverse events (344 for single, 136 for multiple herb studies; p < 0.01). A total of 259 cases reported blood test abnormalities, including five cases of abnormality in hepatic functional enzymes. The most frequently reported adverse event was digestive symptoms (44.3%), followed by nervous system symptoms (17.3%) and behaviors such as loss of appetite (16.3%). This is the first systematic review of adverse effects of herbal drugs among clinical studies, and the results indicate that herbal drugs are relatively safe. Copyright © 2016 John Wiley & Sons, Ltd.

PMID: 27196988 [PubMed - indexed for MEDLINE]

Solithromycin: A novel ketolide antibiotic.

Am J Health Syst Pharm. 2017 Apr 21;:

Authors: Buege MJ, Brown JE, Aitken SL

Abstract
PURPOSE: The pharmacology, pharmacokinetics, pharmacodynamics, antimicrobial activity, clinical safety, and current regulatory status of solithromycin are reviewed.
SUMMARY: Solithromycin is a novel ketolide antibiotic developed for the treatment of community-acquired bacterial pneumonia (CABP). Its pharmacologic, pharmacokinetic, and pharmacodynamic properties provide activity against a broad range of intracellular organisms, including retained activity against pathogens displaying various mechanisms of macrolide resistance. Phase III clinical trials of solithromycin demonstrated noninferiority of both oral and i.v.-to-oral regimens of 5-7 days' duration compared with moxifloxacin for patients with moderately severe CABP. Nearly one third of patients receiving i.v. solithromycin experienced infusion-site reactions. Although no liver-related adverse events were reported in patients receiving oral solithromycin, more patients receiving i.v.-to-oral solithromycin experienced asymptomatic, transient transaminitis, with alanine transaminase levels of >3 to >5 times the upper limit, compared with those treated with moxifloxacin. These results led the Food and Drug Administration to conclude that the solithromycin new drug application was not approvable as filed, adding that the risk of hepatotoxicity had not yet been adequately characterized. The agency further recommended a comparative study of patients with CABP to include approximately 9,000 patients exposed to solithromycin in order to exclude drug-induced liver injury events occurring at a rate of 1 in 3,000 with 95% probability.
CONCLUSION: Solithromycin is a novel ketolide antibiotic with activity against a broad spectrum of intracellular organisms, including those displaying macrolide resistance. While demonstrating noninferiority to a current first-line agent in the treatment of CABP, concerns for drug-induced liver injury and infusion-site reactions have placed its regulatory future in doubt.

PMID: 28432048 [PubMed - as supplied by publisher]

Multicenter observational study of abobotulinumtoxinA neurotoxin in cervical dystonia: The ANCHOR-CD registry.

J Neurol Sci. 2017 May 15;376:84-90

Authors: Trosch RM, Espay AJ, Truong D, Gil R, Singer C, LeWitt PA, Lew MF, Tagliati M, Adler CH, Chen JJ, Marchese D, Comella CL

Abstract
BACKGROUND: The ANCHOR-CD prospective observational registry study evaluated the effectiveness of abobotulinumtoxinA in adult idiopathic cervical dystonia (CD) in clinical practice.
METHODS: Adults with CD were eligible. Treating physicians determined abobotulinumtoxinA dose and treatment interval. The primary endpoint was patient response rate (Toronto Western Spasmodic Torticollis Rating Scale [TWSTRS] score reduction≥25% and Patient Global Impression of Change [PGIC] score of +2 or +3 at Week 4 of Cycle 1).
RESULTS: 350 patients enrolled (75% women; mean age 59±13.6years; 27.4% botulinum neurotoxin-naive) and 347 received at least 1 treatment. The median abobotulinumtoxinA dose for Cycle 1 was 500 Units. At Week 4, the responder rate was 30.6% (n=304) and the TWSTRS total score decreased 27.4% from baseline. PGIC of at least "Much improved" was documented in 43.6% of patients and maintained in Cycles 2 through 4 (43.3%, 48.9%, and 52.8%, respectively). A total of 39 adverse events (31 study drug-related) were reported in 17 patients (5%); the most common were dysphagia (n=6), muscle weakness (n=4), and neck pain (n=3).
CONCLUSION: This study confirmed the beneficial effect of abobotulinumtoxinA on CD in routine clinical practice as measured by improvements in TWSTRS and PGIC. No new safety concerns were identified.

PMID: 28431634 [PubMed - in process]

Comparative histological analysis of drug-induced maculopapular exanthema and DRESS.

J Eur Acad Dermatol Venereol. 2016 Dec;30(12):2085-2090

Authors: Skowron F, Bensaid B, Balme B, Depaepe L, Kanitakis J, Nosbaum A, Maucort-Boulch D, Bérard F, D'Incan M, Kardaun SH, Nicolas JF

Abstract
BACKGROUND: Cutaneous adverse drug reactions frequently present as a benign maculopapular exanthema (MPE) with a rapid healing. Sometimes systemic signs are present, which could represent a more severe or systemic MPE (sMPE) or even be the initial phase of a drug reaction with eosinophilia and systemic symptoms (DRESS). Histopathology associated with MPE, sMPE and DRESS has not been well characterized.
OBJECTIVES: To study the cutaneous histopathological changes associated with MPE, sMPE and DRESS.
METHODS: A retrospective clinicopathological analysis of 13 cases of MPE, 13 of sMPE and 45 of DRESS, collected in one centre from 2005 to 2013.
RESULTS: The number of histopathological changes per section increased gradually from MPE to sMPE and DRESS. Prevalence of spongiosis, dermal lymphocytes, eosinophils and neutrophils did not differ between MPE, sMPE and DRESS. Keratinocyte damage, rare in MPE, was regularly found in sMPE and frequent in DRESS. The density of the inflammatory infiltrate increased progressively from MPE to sMPE and DRESS. Atypical lymphocytes were absent in MPE, present in sMPE and more frequent in DRESS. Deep dermal involvement and leukocytoclastic vasculitis were only observed in DRESS.
LIMITATIONS: This was a retrospective study.
CONCLUSIONS: Numerous histopathological changes per section in drug-induced exanthema should alert for a more severe form of cutaneous adverse drug reactions, i.e. DRESS.

PMID: 27422093 [PubMed - indexed for MEDLINE]

Pharmaceutical strategies towards optimising polypharmacy in older people.

Int J Pharm. 2016 Oct 30;512(2):360-365

Authors: Hughes CM, Cadogan CA, Patton D, Ryan CA

Abstract
This paper focuses on the issue of polypharmacy in older people and potential pharmaceutical strategies to optimize the use of multiple medicines. Although polypharmacy has long been viewed negatively, increasing emphasis is being placed on the difference between appropriate and inappropriate polypharmacy. This is largely being driven by the increasing prevalence of multimorbidity and the use of evidence-based guidelines. In this paper, we outline a number of key considerations that are pertinent to optimizing polypharmacy, notably prescribing appropriate polypharmacy, pharmaceutical formulations, the involvement of older people in clinical trials and patient adherence.

PMID: 26921516 [PubMed - indexed for MEDLINE]