The role of extended-release amantadine for the treatment of dyskinesia in Parkinson's disease patients.

Neurodegener Dis Manag. 2018 04;8(2):73-80

Authors: Elkurd MT, Bahroo LB, Pahwa R

Abstract
Levodopa is the most efficacious treatment for Parkinson's disease (PD). Long-term treatment with levodopa is limited due to dyskinesia. Dyskinesia in PD can be socially and functionally disabling. Extended-release amantadine (amantadine ER) is the first approved medication for the treatment of dyskinesia. When it is given at bedtime, it reaches plasma concentration approximately twice the level achieved by amantadine immediate release. Amantadine ER reduces the severity and duration of dyskinesia during the day, reduces OFF time and increases ON time without troublesome dyskinesia. The most common side effects are hallucination, dizziness, orthostatic hypotension and pedal edema. This review discusses the safety and efficacy of amantadine ER in dyskinesia in PD patients.

PMID: 29564954 [PubMed - indexed for MEDLINE]

Relationship between number of drugs and duration of hospital stay in older patients with neuromuscular diseases.

Geriatr Gerontol Int. 2018 Jul;18(7):1018-1024

Authors: Nishida S, Hayashi Y, Suzuki A, Kobayashi R, Inuzuka T, Itoh Y

Abstract
AIM: Older patients are considered to be at high risk for developing adverse drug reactions (ADR), because they commonly receive multidrug therapy despite changes in pharmacokinetic function with age. In the present study, we assessed the relationship between the number of prescribed drugs and the incidence of ADR or the time to discharge in older patients with neuromuscular disease.
METHODS: A retrospective study was carried out among 135 older patients (aged ≥65 years) who were admitted to the neurology ward from October 2007 through December 2011. Drugs that possess a high risk for initiation of grade ≥2 ADR were determined using logistic regression analysis.
RESULTS: A total of 38 patients (28.1%) experienced grade ≥2 ADR. Multivariate logistic regression analysis showed that corticosteroids, antibiotics, enteric nutrients and insulin were significant risks for grade ≥2 ADR. Notably, the time to discharge extended as the grade of ADR increased, with mean values of 24.4 days for grade 0, 38.3 days for grade 1, 47.5 days for grade 2 and 73.1 days for grade 3-4 events. Furthermore, the number of high-risk drugs for grade ≥2 ADR correlated well with the incidence of grade ≥2 events (R = 0.964, P = 0.008), as well as with the time to discharge (R = 0.473, P < 0.001).
CONCLUSIONS: Older patients receiving multidrug therapy using corticosteroids, antibiotics, enteric nutrients, or insulin were at high risk for grade ≥2 ADR and prolongation of hospital stay. Geriatr Gerontol Int 2018; 18: 1018-1024.

PMID: 29512265 [PubMed - indexed for MEDLINE]

Assessment of adverse events in clinical drug trials: Identifying amitriptyline's placebo- and baseline-controlled side effects.

Exp Clin Psychopharmacol. 2018 06;26(3):320-326

Authors: Rheker J, Rief W, Doering BK, Winkler A

Abstract
Adverse events in clinical drug trials are often poorly assessed and reported. The absence of baseline assessment and structured symptom lists, as well as the fact that most drug trials are industry-sponsored are common sources of bias. In addition, adverse events are usually assessed in patient samples, which can bias results because of the misattribution of symptoms that are part of the illness to medication intake. We aimed to identify amitriptyline's placebo- and baseline-controlled side effects by examining a sample of healthy adults, using structured assessments via a symptom list. Forty healthy individuals were randomized equally to either a group taking 50 mg amitriptyline on four consecutive days or to a placebo control group. Complaints were assessed via the Generic Assessment of Side Effects Scale prior to and after four days of medication intake. Frequency of complaints and their intensity were compared after medication intake between the two groups while controlling for complaints at baseline. The amitriptyline group's participants reported having suffered from "dry mouth," "dizziness," "subjective blood circulation-associated problems," and "constipation" significantly more often. When taking into account the complaint's intensity, the amitriptyline group also reported higher intensities for "dry mouth," "dizziness," and "subjective blood circulation-associated problems." Our results emphasize the importance of a structured and well-controlled harm assessment. Future drug trials should report the placebo- and baseline-controlled side effects with a clear causal relationship to the intake of the drug under investigation, in addition to the frequency of complaints and their odds ratios. (PsycINFO Database Record

PMID: 29863388 [PubMed - indexed for MEDLINE]

Large-Scale Variability of Inpatient Tacrolimus Therapeutic Drug Monitoring at an Academic Transplant Center: A Retrospective Study.

Ther Drug Monit. 2018 08;40(4):394-400

Authors: Strohbehn GW, Pan WW, Petrilli CM, Heidemann L, Larson S, Aaronson KD, Johnson M, Ellies T, Heung M

Abstract
BACKGROUND: Inpatient tacrolimus therapeutic drug monitoring (TDM) lacks standardized guidelines. In this study, the authors analyzed variability in the preanalytical phase of the inpatient tacrolimus TDM process at their institution.
METHODS: Patients receiving tacrolimus (twice-daily formulation) and tacrolimus laboratory analysis were included in the study. Times of tacrolimus administration and laboratory study collection were extracted, and time distribution plots for each step in the inpatient TDM process were generated.
RESULTS: Trough levels were drawn appropriately in 25.9% of the cases. Timing between doses was consistent, with 91.9% of the following dose administrations occurring 12 ± 2 hours after the previous dose. Only 38.1% of the drug administrations occurred within 1 hour of laboratory study collection. Tacrolimus-related patient safety events were reported at a rate of 1.9 events per month while incorrect timing of TDM sample collection occurred approximately 200 times per month. Root cause analysis identified a TDM process marked by a lack of communication and coordination of drug administration and TDM sample collection. Extrapolating findings nationwide, we estimate $22 million in laboratory costs wasted annually.
CONCLUSIONS: Based on this large single-center study, the authors concluded that the inpatient TDM process is prone to timing errors, thus is financially wasteful, and at its worst harmful to patients due to clinical decisions being made on the basis of unreliable data. Further work is needed on systems solutions to better align the laboratory study collection and drug administration processes.

PMID: 29750738 [PubMed - indexed for MEDLINE]

Latent tuberculosis in childhood: tolerability of two different therapeutic approaches.

Expert Rev Anti Infect Ther. 2018 04;16(4):359-365

Authors: Tersigni C, Venturini E, Cordola C, Piccini P, Bianchi L, Montagnani C, Sollai S, Chiappini E, de Martino M, Galli L

Abstract
BACKGROUND: Isoniazid monotherapy for six or nine months and the combination of isoniazid and rifampicin for three or four months are the most used regimens for treating latent tuberculosis. The main aim of this retrospective study is to evaluate the safety of latent tuberculosis treatment by analysing side effects in both regimens.
RESEARCH DESIGN AND METHODS: Children with latent tuberculosis and treated with isoniazid or isoniazid and rifampicin were included. Periodic evaluations with clinical assessment and blood exams were carried out to detect any adverse reaction, including elevated serum transaminases.
RESULTS: 441 children were included, 14.5% treated with isoniazid and 85.5% with isoniazid and rifampicin. Five patients under combined treatment developed hepatotoxicity within the first month. None of the patients under isoniazid monotherapy presented hepatotoxicity. A slight increase of transaminases level was found in both groups (18.7% in isoniazid and 10.3% in isoniazid/rifampicin groups, respectively) without causing discontinuation of treatment, with values normalization at the subsequent checks.
CONCLUSIONS: Both regimens resulted safe. Hepatotoxicity occurred rarely and within the first month. For this reason, it may be appropriate to perform liver function tests after about one month from the beginning of therapy to avoid diagnostic delays.

PMID: 29465259 [PubMed - indexed for MEDLINE]

Real-world chart review study of adverse events management in patients taking tyrosine kinase inhibitors to treat metastatic renal cell carcinoma.

J Oncol Pharm Pract. 2018 Dec;24(8):574-583

Authors: Srinivas S, Stein D, Teltsch DY, Tao S, Cisar L, Ramaswamy K

Abstract
PURPOSE: The purpose is to describe management of adverse events of special interest across tyrosine kinase inhibitors approved for metastatic renal cell carcinoma.
METHODS: We conducted a retrospective chart review in metastatic renal cell carcinoma patients initiating tyrosine kinase inhibitor monotherapy between 15 November 2010 and 15 November 2013, and experiencing ≥ 1 adverse events of special interest (diarrhea, fatigue, hand-foot syndrome, hypertension, or stomatitis/mucositis) within 3 months of initiation. Demographics, medical history, treatment regimens, and adverse events of special interest management data for 3.5 months postonset were collected.
RESULTS: In 220 charts from 27 centers, tyrosine kinase inhibitors prescribed included sunitinib (55%), pazopanib (27%), axitinib (9%), and sorafenib (8%). During the study period, patients experienced 376 adverse events of special interest (13% serious). Fatigue was most common (62% of patients), followed by hypertension (37%), diarrhea (30%), stomatitis/mucositis (29%), and hand-foot syndrome (12%). Over half (56%) the adverse events of special interest were resolved or resolving. Treatment discontinuation due to adverse events of special interest occurred in 15% of patients. Prophylaxis was rarely provided (8%), whereas 59% of patients received adverse events of special interest treatment (pharmacologic (55%) and/or nonpharmacologic (7%)), 27% received tyrosine kinase inhibitor dose management, 23% received both adverse events of special interest treatment and dose management, and 31% received neither. Hypertension was the most treated (72% of all events), and fatigue was the least treated (9%); only 4% of patients received pharmacologic treatment for fatigue.
CONCLUSIONS: Most adverse events of special interest were nonserious and more than half of the patients received pharmacologic and/or nonpharmacologic treatment. Fatigue was the most common yet least frequently treated adverse event of special interest, and few patients received prophylaxis or nonpharmacologic treatment. More emphasis on treatment and prophylaxis options for bothersome adverse events is warranted.

PMID: 28732453 [PubMed - indexed for MEDLINE]

Anesthesia Adverse Events Voluntarily Reported in the Veterans Health Administration and Lessons Learned.

Anesth Analg. 2018 02;126(2):471-477

Authors: Neily J, Silla ES, Sum-Ping SJT, Reedy R, Paull DE, Mazzia L, Mills PD, Hemphill RR

Abstract
BACKGROUND: Anesthesia providers have long been pioneers in patient safety. Despite remarkable efforts, anesthesia errors still occur, resulting in complications, injuries, and even death. The Veterans Health Administration (VHA) National Center of Patient Safety uses root cause analysis (RCA) to examine why system-related adverse events occur and how to prevent future similar events. This study describes the types of anesthesia adverse events reported in VHA hospitals and their root causes and preventative actions.
METHODS: RCA reports from VHA hospitals from May 30, 2012, to May 1, 2015, were reviewed for root causes, severity of patient outcomes, and actions. These elements were coded by consensus and analyzed using descriptive statistics.
RESULTS: During the study period, 3228 RCAs were submitted, of which 292 involved an anesthesia provider. Thirty-six of these were specific to anesthesia care. We reviewed these 36 RCA reports of adverse events specific to anesthesia care. Types of event included medication errors (28%, 10), regional blocks (14%, 5), airway management (14%, 5), skin integrity or position (11%, 4), other (11%, 4), consent issues (8%, 3), equipment (8%, 3), and intravenous access and anesthesia awareness (3%, 1 each). Of the 36 anesthesia events reported, 5 (14%) were identified as being catastrophic, 10 (28%) major, 12 (34%) moderate, and 9 (26%) minor. The majority of root causes identified a need for improved standardization of processes.
CONCLUSIONS: This analysis points to the need for systemwide implementation of human factors engineering-based approaches to work toward further eliminating anesthesia-related adverse events. Such actions include standardization of processes, forcing functions, separating storage of look-alike sound-alike medications, limiting stock of high-risk medication strengths, bar coding medications, use of cognitive aids such as checklists, and high-fidelity simulation.

PMID: 28678068 [PubMed - indexed for MEDLINE]

A Guidance Manual for the Toxicity Assessment of Traditional Herbal Medicines.

Nat Prod Commun. 2016 Nov;11(11):1763-1773

Authors: Aydιn A, Aktay G, Yesilada E

Abstract
Herbal remedies have been used for thousands of years in worldwide traditional medicines for their potential health benefits. Although they are generally presumed safe unless a significant risk has been identified in humans, increasing number of case reports notify acute or chronic intoxications resulting from their use. This study aims to produce a scientific guide for the evaluation of traditional herbal medicines (THMs) in terms of their toxicity risks based on the published regulatory documents. For this purpose recommended in vitro and in vivo toxicity tests on medicinal products for human use issued by the international regulatory bodies are overviewed and they are then adopted to be used for the toxicity assessment of THMs. Accordingly, based on compilation of these issued regulations, the following tests are recommended for the toxicity assessment of THMs; in vitrocytotoxicity, genotoxicity, acute and repeated dose toxicity, carcinogenicity, reproductive and developmental toxicity, local tolerance tests, toxicokinetic studies, and additional toxicity tests including safety pharmacology, immunotoxicity and antigenicity, endocrine system toxicity, gastro-intestinal toxicity, renal and hepatotoxicity, and drug interaction studies. This study describes and discusses the applicability of these tests for the risk assessment in THMs.

PMID: 30475523 [PubMed - indexed for MEDLINE]

Cisplatin-induced cardiotoxicity with midrange ejection fraction: A case report and review of the literature.

Medicine (Baltimore). 2018 Dec;97(52):e13807

Authors: Hu Y, Sun B, Zhao B, Mei D, Gu Q, Tian Z

Abstract
RATIONALE: Cisplatin monotherapy-induced cardiotoxicity is rare, and the prevalence remains unknown. It's extremely important to stop cisplatin when cardiotoxicity is considered.
PATIENT CONCERNS: A 53-year-old woman developed cervical cancer. She was administered cisplatin (37 mg/m/wk) for 3 weeks, but the left ventricular ejection fraction (LVEF) declined from 70% to 48%.
DIAGNOSIS: Electrocardiogram showed first-degree atrioventricular block and ST-segment depression by 0.05 mv on leads II, III, and V3-5. Neither cardiac markers nor N-terminal pro-B-type natriuretic peptide (NT-pro BNP) was elevated. After a careful physical examination and laboratory investigation, we confirmed that cervical cancer did not progress and no other cause was evident. So we figured cardiotoxicity might be induced by cisplatin.
INTERVENTIONS: Cisplatin was stopped and cardioprotective therapies were given to the patient.
OUTCOMES: After discontinuing cisplatin and adding cardioprotective therapies, the LVEF increased to 50% and 53%, respectively (M-mode echocardiography) after 17 and 90 days, which further confirmed our diagnosis.
LESSONS: According to this case and literature review, cisplatin-induced cardiotoxicity should be considered for the patient. When necessary, we should discontinue the suspected drug to confirm diagnosis. Cardioprotective therapies would minimize the drug-induced cardiovascular adverse events and improve patients' outcome.

PMID: 30593170 [PubMed - in process]

Potential drug-drug interactions among prescriptionsfor elderly patients in primary health care.

Turk J Med Sci. 2017 Feb 27;47(1):47-54

Authors: Gören Z, J Demirkapu M, Akpinar Acet G, Çali S, Gülçebi Idriz Oğlu M

Abstract
BACKGROUND/AIM: Elderly patients are at high risk from drug-drug interactions (DDIs). This study evaluates the potential DDIs in Turkish elderly patients at a primary health care outpatient clinic.
MATERIALS AND METHODS: Online database systems were used to examine DDIs on the prescriptions of patients (n = 1206). The clinical severity of DDIs was classified by the Lexi-Interact Online database.
RESULTS: Of the 5059 prescriptions, 33% were found to have DDIs. We detected 29 (0.9%) A, 380 (11.8%) B, 2494 (77.7%) C, 289 (9%) D, and 18 (0.6%) X risk rating category DDIs among the prescriptions. Prescriptions of female patients and patients aged between 65 and 72 years showed significantly higher number of DDIs. The frequency of DDIs increased both with the number of drugs and combined preparations per prescription. Acetylsalicylic acid and salbutamol were the most frequently prescribed drugs contributing to clinically important DDIs. Additionally, acetylsalicylic acid and escitalopram, which interact with each other, were found on the list of Beers criteria. The most predicted clinical outcomes of DDIs were increase in therapeutic efficacy and adverse/toxic reactions. Conclusions: Prediction of DDIs in elderly patients will provide better prescribing and drug safety. Use of nonsteroidal anti-inflammatory agents, selective serotonin reuptake inhibitors, and beta-2 adrenergic receptor agonists should be closely monitored.

PMID: 28263519 [PubMed - indexed for MEDLINE]

Evaluating associations between the benefits and risks of drug therapy in type 2 diabetes: a joint modeling approach.

Clin Epidemiol. 2018;10:1869-1877

Authors: Dennis JM, Shields BM, Jones AG, Pearson ER, Hattersley AT, Henley WE, MASTERMIND consortium

Abstract
Objective: Precision medicine drug therapy seeks to maximize efficacy and minimize harm for individual patients. This will be difficult if drug response and side effects are positively associated, meaning that patients likely to respond best are at increased risk of side effects. We applied joint longitudinal-survival models to evaluate associations between drug response (longitudinal outcome) and the risk of side effects (survival outcome) for patients initiating type 2 diabetes therapy.
Study design and setting: Participants were randomized to metformin (MFN), sulfonylurea (SU), or thiazolidinedione (TZD) therapy in the A Diabetes Outcome Progression Trial (ADOPT) drug efficacy trial (n=4,351). Joint models were parameterized for 1) current HbA1c response (change from baseline in HbA1c) and 2) cumulative HbA1c response (total HbA1c change).
Results: With MFN, greater HbA1c response did not increase the risk of gastrointestinal events (HR per 1% absolute greater current response 0.82 [95% CI 0.67, 1.01]; HR per 1% higher cumulative response 0.90 [95% CI 0.81, 1.00]). With SU, greater current response was associated with an increased risk of hypoglycemia (HR 1.41 [95% CI 1.04, 1.91]). With TZD, greater response was associated with an increased risk of edema (current HR 1.45 [95% CI 1.05, 2.01]; cumulative 1.22 [95% CI 1.07, 1.38]) but not fracture.
Conclusion: Joint modeling provides a useful framework to evaluate the association between response to a drug and the risk of developing side effects. There may be great potential for widespread application of joint modeling to evaluate the risks and benefits of both new and established medications.

PMID: 30588118 [PubMed]

Carbamazepine-Mediated Adverse Drug Reactions: CBZ-10,11-epoxide but Not Carbamazepine Induces the Alteration of Peptides Presented by HLA-B∗15:02.

J Immunol Res. 2018;2018:5086503

Authors: Simper GS, Hò GT, Celik AA, Huyton T, Kuhn J, Kunze-Schumacher H, Blasczyk R, Bade-Döding C

Abstract
Among patients treated with the anticonvulsive and psychotropic drug carbamazepine (CBZ), approximately 10% develop severe and life-threatening adverse drug reactions. These immunological conditions are resolved upon withdrawal of the medicament, suggesting that the drug does not manifest in the body in long term. The HLA allele B∗15:02 has been described to be a genomic biomarker for CBZ-mediated immune reactions. It is not well understood if the immune reactions are triggered by the original drug or by its metabolite carbamazepine-10,11-epoxide (EPX) and how the interaction between the drug and the distinct HLA molecule occurs. Genetically engineered human B-lymphoblastoid cells expressing soluble HLA-B∗15:02 molecules were treated with the drug or its metabolite. Functional pHLA complexes were purified; peptides were eluted and sequenced. Applying mass spectrometric analysis, CBZ and EPX were monitored by analyzing the heavy chain and peptide fractions separately for the presence of the drug. This method enabled the detection of the drug in a biological situation post-pHLA assembly. Both drugs were bound to the HLA-B∗15:02 heavy chain; however, solely EPX altered the peptide-binding motif of B∗15:02-restricted peptides. This observation could be explained through structural insight; EPX binds to the peptide-binding region and alters the biochemical features of the F pocket and thus the peptide motif. Understanding the nature of immunogenic interactions between CBZ and EPX with the HLA immune complex will guide towards effective and safe medications.

PMID: 30302345 [PubMed - indexed for MEDLINE]

Phloretin cytoprotection and toxicity.

Chem Biol Interact. 2018 Dec 25;296:117-123

Authors: Geohagen BC, Korsharskyy B, Vydyanatha A, Nordstroem L, LoPachin RM

Abstract
Phloretin (Phl) is a dihydrochalcone flavonoid with significant cytoprotective properties; e.g., free radical trapping, electrophile scavenging. Based on this, it has been suggested that Phl might be useful in the treatment of pathogenic processes and prevention of drug toxicities. Therefore, we determined the ability of Phl to provide route- and dose-dependent hepatoprotection in a mouse model of acetaminophen (APAP) overdose. Intraperitoneal (i.p.) administration of Phl produced a bimodal effect; i.e., the highest dose (2.40 mmol/kg) did not prevent APAP-induced lethality, whereas lower doses (0.2-0.4 mmol/kg) afforded modest hepatoprotection. When given alone, the highest i.p. Phl dose was lethal within 24 h, whereas the lower doses were not toxic. Oral Phl (0.40-2.40 mmol/kg) did not prevent APAP-induced hepatotoxicity. The highest oral dose given alone (2.4 mmol/kg) produced 64% lethality, whereas lower doses were not lethal. This toxicity profile was reflected in a study using APAP-exposed isolated mouse hepatocytes, which showed that the Phl pharmacophores, 1,3,5-trihydroxyacetophenone (PG) and 2',4',6'-trihydroxyacetophenone (THA) where protective. Corroborative cell free studies showed that polyphenol protectants prevented glutathione loss mediated by the APAP metabolite, N-acetyl-p-benzoquinone imine (NAPQI). Thus, in spite of possessing cytoprotective attributes, Phl was generally toxic in our APAP models. These and earlier findings suggest that Phl is not a candidate for drug design. In contrast, we have found that the enol-forming pharmacophores, THA and PG, are potential platforms for pharmacotherapeutic development.

PMID: 30287234 [PubMed - indexed for MEDLINE]

Evaluation of safety and immunogenicity of a group A streptococcus vaccine candidate (MJ8VAX) in a randomized clinical trial.

PLoS One. 2018;13(7):e0198658

Authors: Sekuloski S, Batzloff MR, Griffin P, Parsonage W, Elliott S, Hartas J, O'Rourke P, Marquart L, Pandey M, Rubin FA, Carapetis J, McCarthy J, Good MF

Abstract
BACKGROUND: Group A streptococcus (GAS) is a serious human pathogen that affects people of different ages and socio-economic levels. Although vaccination is potentially one of the most effective methods to control GAS infection and its sequelae, few prototype vaccines have been investigated in humans. In this study, we report the safety and immunogenicity of a novel acetylated peptide-protein conjugate vaccine candidate MJ8VAX (J8-DT), when delivered intramuscularly to healthy adults.
METHODS: A randomized, double-blinded, controlled Phase I clinical trial was conducted in 10 healthy adult participants. Participants were randomized 4:1 to receive the vaccine candidate (N = 8) or placebo (N = 2). A single dose of the vaccine candidate (MJ8VAX), contained 50 μg of peptide conjugate (J8-DT) adsorbed onto aluminium hydroxide and re-suspended in PBS in a total volume of 0.5 mL. Safety of the vaccine candidate was assessed by monitoring local and systemic adverse reactions following intramuscular administration. The immunogenicity of the vaccine was assessed by measuring the levels of peptide (anti-J8) and toxoid carrier (anti-DT)-specific antibodies in serum samples.
RESULTS: No serious adverse events were reported over 12 months of study. A total of 13 adverse events (AEs) were recorded, two of which were assessed to be associated with the vaccine. Both were mild in severity. No local reactogenicity was recorded in any of the participants. MJ8VAX was shown to be immunogenic, with increase in vaccine-specific antibodies in the participants who received the vaccine. The maximum level of vaccine-specific antibodies was detected at 28 days post immunization. The level of these antibodies decreased with time during follow-up. Participants who received the vaccine also had a corresponding increase in anti-DT serum antibodies.
CONCLUSIONS: Intramuscular administration of MJ8VAX was demonstrated to be safe and immunogenic. The presence of DT in the vaccine formulation resulted in a boost in the level of anti-DT antibodies.
TRIAL REGISTRATION: ACTRN12613000030774.

PMID: 29965967 [PubMed - indexed for MEDLINE]

The FDA Sentinel Initiative - An Evolving National Resource.

N Engl J Med. 2018 Nov 29;379(22):2091-2093

Authors: Platt R, Brown JS, Robb M, McClellan M, Ball R, Nguyen MD, Sherman RE

PMID: 30485777 [PubMed - indexed for MEDLINE]

Short-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): 10-year results from a randomised, phase 3, factorial trial.

Lancet Oncol. 2018 Dec 19;:

Authors: Denham JW, Joseph D, Lamb DS, Spry NA, Duchesne G, Matthews J, Atkinson C, Tai KH, Christie D, Kenny L, Turner S, Gogna NK, Diamond T, Delahunt B, Oldmeadow C, Attia J, Steigler A

Abstract
BACKGROUND: The optimal duration of androgen suppression for men with locally advanced prostate cancer receiving radiotherapy with curative intent is yet to be defined. Zoledronic acid is effective in preventing androgen suppression-induced bone loss, but its role in preventing castration-sensitive bone metastases in locally advanced prostate cancer is unclear. The RADAR trial assessed whether the addition of 12 months of adjuvant androgen suppression, 18 months of zoledronic acid, or both, can improve outcomes in men with locally advanced prostate cancer who receive 6 months of androgen suppression and prostatic radiotherapy. This report presents 10-year outcomes from this trial.
METHODS: For this randomised, phase 3, 2 × 2 factorial trial, eligible men were 18 years or older with locally advanced prostate cancer (either T2b-4, N0 M0 tumours or T2a, N0 M0 tumours provided Gleason score was ≥7 and baseline prostate-specific antigen [PSA] concentration was ≥10 μg/L). We randomly allocated participants in a 2 × 2 factorial design by computer-generated randomisation (using the minimisation technique, and stratified by centre, baseline PSA concentration, clinical tumour stage, Gleason score, and use of a brachytherapy boost) in a 1:1:1:1 ratio to four treatment groups. Patients in the control group received 6 months of neoadjuvant androgen suppression with leuprorelin (22·5 mg every 3 months, intramuscularly) and radiotherapy alone (short-term androgen suppression [STAS]); this treatment was either followed by another 12 months of adjuvant androgen suppression with leuprorelin (22·5 mg every 3 months, intramuscularly; intermediate-term androgen suppression [ITAS]), or accompanied by 18 months of zoledronic acid (4 mg every 3 months, intravenously) starting at randomisation (STAS plus zoledronic acid), or both (ITAS plus zoledronic acid). All patients received radiotherapy to the prostate and seminal vesicles, starting from the end of the fifth month of androgen suppression; dosing options were 66, 70, and 74 Gy in 2-Gy fractions per day, or 46 Gy in 2-Gy fractions followed by a high-dose-rate brachytherapy boost dose of 19·5 Gy in 6·5-Gy fractions. Treatment allocation was open label. The primary endpoint was prostate cancer-specific mortality and was analysed according to intention-to-treat using competing-risks methods. The trial is closed to follow-up and this is the final report of the main endpoints. This trial is registered with ClinicalTrials.gov, number NCT00193856.
FINDINGS: Between Oct 20, 2003, and Aug 15, 2007, 1071 men were enrolled and randomly assigned to STAS (n=268), ITAS (n=268), STAS plus zoledronic acid (n=268), and ITAS plus zoledronic acid (n=267). Median follow-up was 10·4 years (IQR 7·9-11·7). At this 10-year follow-up, no interactions were observed between androgen suppression and zoledronic acid so the treatment groups were collapsed to compare treatments according to duration of androgen suppression: 6 months of androgen suppression plus radiotherapy (6AS+RT) versus 18 months of androgen suppression plus radiotherapy (18AS+RT) and to compare treatments according to whether or not patients received zoledronic acid. The total number of deaths was 375 (200 men receiving 6AS+RT and 175 men receiving 18AS+RT), of which 143 (38%) were attributable to prostate cancer (81 men receiving 6AS+RT and 62 men receiving 18AS+RT). When analysed by duration of androgen suppression, the adjusted cumulative incidence of prostate cancer-specific mortality was 13·3% (95% CI 10·3-16·0) for 6AS+RT versus 9·7% (7·3-12·0) for 18AS+RT, representing an absolute difference of 3·7% (95% CI 0·3-7·1; sub-hazard ratio [sHR] 0·70 [95% CI 0·50-0·98], adjusted p=0·035). The addition of zoledronic acid did not affect prostate cancer-specific mortality; the adjusted cumulative incidence of prostate cancer-specific mortality was 11·2% (95% CI 8·7-13·7) with zoledronic acid vs 11·7% (9·2-14·1) without, representing an absolute difference of -0·5% (95% CI -3·8 to 2·9; sHR 0·95 [95% CI 0·69-1·32], adjusted p=0·78). Although safety analysis was not prespecified for this 10-year analysis, one new serious adverse event (osteonecrosis of the mandible, in a patient who received 18 months of androgen suppression plus zoledronic acid) occurred since our previous report, bringing the total number of cases of this serious adverse event to three (<1% out of 530 patients who received zoledronic acid evaluated for safety) and the total number of drug-related serious adverse events to 12 (1% out of all 1065 patients evaluable for safety). No treatment-related deaths occurred during the study.
INTERPRETATION: 18 months of androgen suppression plus radiotherapy is a more effective treatment option for locally advanced prostate cancer than 6 months of androgen suppression plus radiotherapy, but the addition of zoledronic acid to this treatment regimen is not beneficial. Evidence from the RADAR and French Canadian Prostate Cancer Study IV trials suggests that 18 months of androgen suppression with moderate radiation dose escalation is an effective but more tolerable option than longer durations of androgen suppression for men with locally advanced prostate cancer including intermediate and high risk elements.
FUNDING: National Health and Medical Research Council of Australia, Novartis Pharmaceuticals Australia, AbbVie Pharmaceuticals Australia, New Zealand Health Research Council, New Zealand Cancer Society, Cancer Standards Institute New Zealand, University of Newcastle (Australia), Hunter Medical Research Institute, Calvary Mater Newcastle Radiation Oncology Fund, and Maitland Cancer Appeal.

PMID: 30579763 [PubMed - as supplied by publisher]

Drug-related Dysgeusia: A Systematic Review.

Oral Health Prev Dent. 2018;16(6):499-507

Authors: Mortazavi H, Shafiei S, Sadr S, Safiaghdam H

Abstract
PURPOSE: Dysgeusia is an unpleasant alteration in taste. It can affect the nutritional and psychological status and decrease the quality of life of patients. It may be caused by nerve injury, head and neck trauma or surgery, infections, radiotherapy and drugs, but certain aetiological factors have not yet been identified. Understanding dysgeusia as a drug side effect is important for practitioners. The aim of this systematic review was to provide detailed information about dysgeusia in patients receiving different common medications.
MATERIALS AND METHODS: An electronic search was conducted in MEDLINE, Google Scholar and Scopus databases, and studies were selected according to our inclusion criteria. We included studies on human subjects that reported dysgeusia as a drug side effect.
RESULTS: Thirty-four eligible studies were included in the systematic review. Thirty-five drugs were found in the literature to be correlated to dysgeusia. The most commonly reported offending drugs were from keratolytic agents, chemotherapeutic and cancer medication, antihistamine, antibiotics and angiotensin-converting enzyme inhibitors.
CONCLUSION: The quality of evidence was low in most reviewed studies. More studies with standard methodology are needed in this field. However, physicians and dental practitioners must consider the probability of dysgeusia as an adverse side effect when prescribing certain medications.

PMID: 30574604 [PubMed - in process]

Oral manifestation of systemic diseases-a perspective from an oral pathology diagnostic service.

Oral Dis. 2018 03;24(1-2):219-223

Authors: Bradley G, Magalhaes MA

PMID: 29480619 [PubMed - indexed for MEDLINE]

Assessing the safety of new drugs during pregnancy.

Br J Dermatol. 2018 01;178(1):18-19

Authors: Hyrich KL

PMID: 29357613 [PubMed - indexed for MEDLINE]

Favorable adverse effect profile of brivaracetam vs levetiracetam in a preclinical model.

Epilepsy Behav. 2018 02;79:117-125

Authors: Sanon NT, Gagné J, Wolf DC, Aboulamer S, Bosoi CM, Simard A, Messiet E, Desgent S, Carmant L

Abstract
Levetiracetam (LEV), and its newer selective analog brivaracetam (BRV), are two seizure medications that share an innovative mechanism of action targeting the Synaptic Vesicle Protein 2A (SV2A), altering neurotransmitter release and decreasing seizure frequency. Behavioral changes are the most significant adverse effects reported by patients taking LEV. We hypothesize that BRV, the more potent SV2A analog, could exert less behavioral side effects, as it requires lower doses than LEV. Using Kainic Acid (KA)-treated and control rats, we measured adverse behavioral effect profiles of LEV, BRV, or Saline, on social and nonsocial behaviors. Our data indicate that both tested drugs had no effect on locomotion, anxiety levels, fear learning, depression-like behavior, and memory retention in rats. However, when considering social interactions, we first confirmed the epilepsy-induced strong increase in aggressive behaviors and specific hippocampal neuronal loss. We furthermore observed, in Sham rats, that LEV-treated animals were 2 times faster to attack at first encounter, had 5 times more aggressive behaviors, and had significantly less social behaviors than control rats. In all circumstances, BRV rats behaved like Saline rats, suggesting that BRV treatment in rats leads to significantly less aggressive behaviors than LEV treatment at the doses used, while there are limited differential effects between these two drugs on other types of behaviors. Since increased aggressiveness has been reported in patients well controlled on LEV, this study indicates based on our findings, that BRV could represent an effective alternative to LEV to limit aggressiveness problems due to this antiepileptic drug (AED) therapy.

PMID: 29287214 [PubMed - indexed for MEDLINE]