Exploration of baseline patient-reported side effect bother from cancer therapy.

Clin Trials. 2020 06;17(3):332-337

Authors: Roydhouse JK, King-Kallimanis BL, Roy P, Weinstock C, Krol D, Daniels SR, Suzman DL, Beaver JA, Kluetz PG

Abstract
BACKGROUND: Patient reports of expected treatment side effects are increasingly collected as part of the assessment of patient experience in clinical trials. A global side effect item that is patient-reported has the potential to inform overall tolerability. Therefore, the aim of this study was to examine the completion and distribution of such a global single-item measure of side effect burden in five cancer clinical trials.
METHODS: Data from five trials from internal Food and Drug Administration databases that included the Functional Assessment of Cancer Therapy-General single-item measure of overall side effect burden (i.e. impact on degree of bother) were analyzed. Completion rates for the side effect bother item, items adjacent to this item, and two non-adjacent items on the Functional Assessment of Cancer Therapy-General that are related to health-related quality of life were calculated at the baseline assessment and at the 3-month assessment. To evaluate the distribution, the percentage of patients reporting high levels (quite a bit or very much bother) of side effect bother at baseline and 3 months was assessed.
RESULTS: Completion rates for all items were at least 80% regardless of time point or trial population. However, in three of the five trials, completion rates for the side effect bother item were lower at baseline compared to adjacent and non-adjacent items. This difference was not observed at 3 months. Up to 9.4% of patients reported high levels of side effect bother at baseline.
CONCLUSION: Patients may enter trials already reporting some bother from side effects. This can make interpretation of results with respect to the investigational agent under study challenging. Patients may skip an item evaluating side effect bother at baseline, suggesting some difficulty with interpretation of what is being asked. Further study of the wording and utility of a baseline side effect bother assessment is warranted.

PMID: 32153216 [PubMed - indexed for MEDLINE]

Temozolomide is effective and well tolerated in patients with primary vitreoretinal lymphoma.

Blood. 2020 05 14;135(20):1811-1815

Authors: Baron M, Belin L, Cassoux N, Fardeau C, Blaizeau M, Soussain C, Houillier C, Hoang-Xuan K, Gyan E, Le Lez ML, Lavaud A, Soubeyran P, Bodaghi B, Costopoulos M, Leblond V, Touitou V, Maloum K, Errera MH, Roos-Weil D, Le Garff-Tavernier M, Choquet S

PMID: 32125361 [PubMed - indexed for MEDLINE]

Development of novel in silico prediction model for drug-induced ototoxicity by using naïve Bayes classifier approach.

Toxicol In Vitro. 2020 Jun;65:104812

Authors: Zhang H, Liu CT, Mao J, Shen C, Xie RL, Mu B

Abstract
Some drugs have the potential to cause cellular degeneration of cochlear and/or vestibular system, leading to temporary or permanent hearing loss, innitus, ataxia, dizziness, ear infections, hyperacusis, vertigo, nystagmus and other ear problems. Thus, precise assessment of ototoxicity has become a strong urge task for the toxicologist. In this research, the in silico prediction model of ototoxicity was developed based on 2612 diverse chemicals by using naïve Bayes classifier approach. A set of 7 molecular descriptors considered as important for ototoxicity was selected by genetic algorithm method, and some structural alerts for ototoxicity were identified. The established naïve Bayes prediction model produced 90.2% overall prediction accuracy for the training set and 88.7% for the external test set. We hope the established naïve Bayes prediction model should be employed as precise and convenient computational tool for assessing and screening the chemical-induced ototoxicity in drug development, and these important information of ototoxic chemical structures could provide theoretical guidance for hit and lead optimization in drug design.

PMID: 32109528 [PubMed - indexed for MEDLINE]

Comparing Potentially Inappropriate Prescribing Tools and Their Association With Patient Outcomes.

J Am Geriatr Soc. 2020 03;68(3):526-534

Authors: Moriarty F, Bennett K, Kenny RA, Fahey T, Cahir C

Abstract
OBJECTIVE: To assess the agreement of several different measures of potentially inappropriate prescribing (PIP) in older people and compare their relationship with patient-reported outcomes.
DESIGN: Prospective cohort study including participants in The Irish Longitudinal Study on Ageing (TILDA).
SETTING: Waves 1 and 2 of TILDA, a nationally representative aging cohort study.
PARTICIPANTS: A total of 1753 community-dwelling TILDA participants with linked administrative pharmacy claims data on medications.
MEASUREMENTS: Potentially inappropriate medications were assessed using the Screening Tool of Older Persons' Potentially Inappropriate Prescriptions (STOPP) v1, American Geriatrics Society (AGS) Beers Criteria® 2012, and relevant Assessing Care of Vulnerable Elders (ACOVE) v3 indicators. Potential prescribing omissions were assessed using the Screening Tool to Alert Doctors to the Right Treatment (START) v1 and ACOVE v3 indicators. Their agreement was assessed via κ statistics, and multivariate regression was used to assess relationships with emergency department visits, general practitioner (GP) visits, quality of life, and functional decline (increased assistance needed for activities of daily living).
RESULTS: There was slight agreement between STOPP and AGS Beers Criteria® (κ = 0.20) and ACOVE indicators (κ = 0.15), while agreement between AGS Beers Criteria® and ACOVE indicators was fair (κ = 0.31). Agreement was fair between START and ACOVE indicators (κ = 0.34). All measures of inappropriate medications were significantly associated with increased GP visits. Only exposure to two or more START indicators was associated with reduced quality of life (adjusted mean difference = -1.12; 95% confidence interval [CI] = -1.92 to -0.33), and only two or more AGS Beers Criteria® were associated with functional decline (adjusted odds ratio = 2.11; 95% CI = 1.37-3.28). For omissions, both measures were associated with functional decline, but only ACOVE indicators were associated with increased GP visits.
CONCLUSION: Prevalence of PIP and relationships with outcomes can differ substantially between tools with little agreement. Choice of PIP measure for research or practice should be considered in light of the circumstances and requirements in each case. J Am Geriatr Soc 68:526-534, 2020.

PMID: 31675114 [PubMed - indexed for MEDLINE]

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Drug reactions affecting hair and nails.

Clin Dermatol. 2020 Nov - Dec;38(6):693-701

Authors: Wollina U, Abdel-Naser MB

Abstract
Drug-induced changes of hair and nails have been observed with a variety of different pharmaceutical agents, both topical and systemic. These compounds or their metabolites may interfere with hair cycling and texture, nail matrix, nail bed, nail folds, and microvasculature. Phototoxic reactions may also occur. Before initiating treatment, physicians and patients should be aware of possible adverse events to hair and nails and should be aware of the preventive measures, if available, as quality of life can be reduced, and adherence and compliance to treatment may be impaired.

PMID: 33341202 [PubMed - as supplied by publisher]

Drug-induced cutaneous vasculitis and anticoagulant-related cutaneous adverse reactions: insights in pathogenesis, clinical presentation, and treatment.

Clin Dermatol. 2020 Nov - Dec;38(6):613-628

Authors: Guzman AK, Balagula Y

Abstract
Drug-induced vasculitis and anticoagulant-related skin reactions are commonly encountered in the inpatient and outpatient settings. The spectrum of clinical presentation is broad and ranges from focal, skin-limited disease, to more extensive cutaneous and soft tissue necrosis, to potentially fatal systemic involvement. The prompt recognition of these adverse events can have a significant impact on patient morbidity and mortality. We highlight the key features of the clinical presentation with an emphasis on primary lesion morphology, distribution, and epidemiology of purpuric drug reactions. The proposed pathophysiology, histologic findings, and therapeutic interventions of these potentially life-threatening diseases are discussed.

PMID: 33341196 [PubMed - as supplied by publisher]

Ulipristal acetate: How to value safety in a new drug?

Br J Clin Pharmacol. 2020 Dec 19;:

Authors: Middelkoop MA, Bet PM, Drenth JPH, Huirne JAF, Hehenkamp WJK

Abstract
BACKGROUND AND PURPOSE: Uterine fibroids are benign tumours that cause various complaints. These complaints may significantly compromise quality of life, necessitating a clinical intervention in 25-50% of the affected women. Hysterectomy, myomectomy or embolization may offer symptomatic relief, but are costly, include a recovery period, can cause serious side-effects, sometimes fail to treat symptoms completely and are not always desired by patients. Ulipristal is a conservative long-term treatment that has a fibroid-volume decreasing effect, acceptable side-effects while preserving fertility and may be an alternative to surgical alternatives. Currently, ulipristal is investigated by the European Medicine Agency and suspended from marketing authorization because it may cause drug induced liver injury (DILI). However, many drugs can cause severe DILI and prospective studies estimate 14-19 DILI cases/100,000 people. This overview will discuss the risk-benefit balance between ulipristal and DILI, describe the safety - efficacy balance of ulipristal and its alternative treatments and the arguments that led to the suspension of its marketing authorization.
CONCLUSION AND IMPLICATIONS: Ulipristal may be associated with DILI resulting in a risk of severe liver injury in 1.5:100,000 patients and fatal liver injury in 0.1:100,000 patients. This risk needs to be weighed against the higher mortality risk of >1:1000 and higher incidence of severe complications after surgery. The DILI risk of ulipristal is considerably lower than that of other medicines that are not suspended, nor need additional safety measures. When valuing drugs and drug safety, risks that apply to the alternative non-pharmacological treatment options should be taken into consideration.

PMID: 33341097 [PubMed - as supplied by publisher]

New Associations between Drug-Induced Adverse Events in Animal Models and Humans Reveal Novel Candidate Safety Targets.

Chem Res Toxicol. 2020 Dec 18;:

Authors: Giblin KA, Basili D, Afzal AM, Rosenbrier-Ribeiro L, Greene N, Barrett I, Hughes SJ, Bender A

Abstract
To improve our ability to extrapolate preclinical toxicity to humans, there is a need to understand and quantify the concordance of adverse events (AEs) between animal models and clinical studies. In the present work, we discovered 3011 statistically significant associations between preclinical and clinical AEs caused by drugs reported in the PharmaPendium database of which 2952 were new associations between toxicities encoded by different Medical Dictionary for Regulatory Activities terms across species. To find plausible and testable candidate off-target drug activities for the derived associations, we investigated the genetic overlap between the genes linked to both a preclinical and a clinical AE and the protein targets found to interact with one or more drugs causing both AEs. We discuss three associations from the analysis in more detail for which novel candidate off-target drug activities could be identified, namely, the association of preclinical mutagenicity readouts with clinical teratospermia and ovarian failure, the association of preclinical reflexes abnormal with clinical poor-quality sleep, and the association of preclinical psychomotor hyperactivity with clinical drug withdrawal syndrome. Our analysis successfully identified a total of 77% of known safety targets currently tested in in vitro screening panels plus an additional 431 genes which were proposed for investigation as future safety targets for different clinical toxicities. This work provides new translational toxicity relationships beyond AE term-matching, the results of which can be used for risk profiling of future new chemical entities for clinical studies and for the development of future in vitro safety panels.

PMID: 33338378 [PubMed - as supplied by publisher]

Complex sleep-disordered breathing after vagus nerve stimulation: broadening the spectrum of adverse events of special interest.

Epileptic Disord. 2020 Dec 18;:

Authors: Santos MO, Bentes C, Teodoro T, Moreira S, Marques M, Tomé D, Peralta AR

Abstract
Two young males with refractory epilepsy of unknown aetiology were referred for vagus nerve stimulation (VNS). Sleep disturbances emerged following VNS parameter changes. In Patient 1, video-polysomnogram (PSG) disclosed snoring and catathrenia in non-REM sleep. Central apnoea also occurred, but more rarely. In Patient 2, video-PSG showed mixed apnoea with desaturation and episodes of stridor followed by a catathrenia-like sound. A drug-induced sleep endoscopy (DISE) revealed, during VNS OFF time, glossoptosis, "trap door" of the epiglottis, and paresis of the left side of the larynx and ipsilateral vocal cords. During ON time, there were periods of pharyngeal collapse, in which video-PSG revealed patterns suggestive of both obstructive and central sleep apnoea. All these sleep-related phenomena were coincident with VNS ON time. In the first patient, VNS parameter adjustment was sufficient to successfully reverse all the symptoms, whereas the other patient required concomitant treatment with continuous positive airway pressure. The data broaden our knowledge about sleep disorders related to VNS, in particular stridor and catathrenia. We suggest that central sleep apnoea may be associated with laryngeal occlusion. DISE may be considered in selected cases as a valuable clinical tool to evaluate, in a single session, the effectiveness of multiple VNS parameter changes on respiration and laryngeal side effects. [Published with video sequences].

PMID: 33337335 [PubMed - as supplied by publisher]

Clinician vs Patient Reporting of Baseline and Postbaseline Symptoms for Adverse Event Assessment in Cancer Clinical Trials.

JAMA Oncol. 2020 03 01;6(3):437-439

Authors: Atkinson TM, Dueck AC, Satele DV, Thanarajasingam G, Lafky JM, Sloan JA, Basch E

PMID: 31876902 [PubMed - indexed for MEDLINE]

Assessment of Adverse Events From the Patient Perspective in a Phase 3 Metastatic Castration-Resistant Prostate Cancer Clinical Trial.

JAMA Oncol. 2020 02 01;6(2):e193332

Authors: Dueck AC, Scher HI, Bennett AV, Mazza GL, Thanarajasingam G, Schwab G, Weitzman AL, Rogak LJ, Basch E

Abstract
Importance: Standard adverse event (AE) reporting in oncology clinical trials has historically relied on clinician grading, which prior research has shown can lead to underestimation of rates of symptomatic AEs. Industry sponsors are beginning to implement in trials the National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), which was developed to allow patients to self-report symptomatic AEs and improve the quality of symptomatic AE detection.
Objectives: To evaluate the feasibility of implementing PRO-CTCAE in a prespecified correlative analysis of the phase 3 COMET-2 trial and enumerate statistically significant between-group differences in symptomatic AEs using PRO-CTCAE and the CTCAE.
Design, Setting, and Participants: This correlative study of 119 men in the randomized, double-blind, placebo-controlled phase 3 COMET-2 trial with metastatic castration-resistant prostate cancer who had undergone at least 2 prior lines of systemic treatment was conducted from March 2012 to July 2014. Participants completed PRO-CTCAE items using an automated telephone system from home prior to treatment and every 3 weeks during treatment. Statistical analysis was performed from May 2018 to June 2019.
Main Outcomes and Measures: The proportion of patients who completed expected PRO-CTCAE self-reports was computed as a measure of feasibility.
Results: Among the 119 men in the study (median age, 65 years [range, 44-80 years]), 534 of 587 (91.0%) expected PRO-CTCAE self-reports were completed, with consistently high rates of completion throughout participation. Rates of self-report adherence were similar between groups (cabozantinib s-maleate, 286 of 317 [90.2%]; and mitoxantrone hydrochloride-prednisone, 248 of 270 [91.9%]). Of 12 measured, patient-reported PRO-CTCAE symptomatic AEs, 4 reached statistical significance when comparing the proportion of patients with at least 1 postbaseline score greater than 0 between groups (differences ranged from 20.1% to 34.1% with higher proportions in the cabozantinib group; all P < .05), and use of a method for accounting for preexisting symptoms at baseline yielded 7 AEs with statistically significant differences between groups (differences ranged from 20.5% to 41.2% with higher proportions in the cabozantinib group; all P < .05). In the same analysis using investigator-reported CTCAE data, no statistically significant differences were found between groups for any symptomatic AEs.
Conclusions and Relevance: PRO-CTCAE data collection was feasible and improved the accuracy of symptomatic AE detection in a phase 3 cancer trial. This analysis adds to mounting evidence of the feasibility and value of patient-reported AEs in oncology, which should be considered for inclusion in cancer trials that incorporate AE evaluation.
Trial Registration: ClinicalTrials.gov identifier: NCT01522443.

PMID: 31556911 [PubMed - indexed for MEDLINE]

Efficacy and safety of fumaric acid esters in young patients aged 10 to 17 years with moderate-to-severe plaque psoriasis - A randomised, double-blinded, placebo-controlled trial.

Br J Dermatol. 2020 Dec 17;:

Authors: Hamm H, Wilsmann-Theis D, Tsianakas A, Gambichler T, Taipale K, Lauterbach J, Freudensprung U, Makepeace C, KIFUderm study investigators

Abstract
BACKGROUND: Apart from three biologics, no systemic drugs are approved in Europe for children with moderate-to-severe psoriasis. Retrospective observational studies showed promising results for fumaric acid esters (FAE) in this setting.
OBJECTIVES: To show superiority of FAE over placebo in terms of treatment response after 20 weeks in children and adolescents aged 10-17 years.
METHODS: In a multicentre, randomised, double-blind, placebo-controlled phase 3b study patients aged 10-17 years with moderate-to-severe plaque psoriasis requiring systemic therapy were randomised 2:1 to receive FAE (N=91) or placebo (N=43) over 20 weeks, followed by an open-label FAE treatment phase. The co-primary endpoints were Psoriasis Area and Severity Index (PASI) 75 and/or Physician's Global Assessment (PGA) 0,1 (clear or almost clear) responder rate at week 20.
RESULTS: At week 20, 55% (95% CI 0.44-0.65) of FAE-treated patients achieved a PASI 75 response vs. 19% (95% CI 0.08-0.33) in the placebo group (absolute difference: 36%; 95% CI 0.20-0.53; p<0.001). 42% (95% CI 0.32-0.53) in the FAE group vs. 7% (95% CI 0.01-0.19) in the placebo group achieved a PGA (0,1) response at week 20 (absolute difference: 35%; 95% CI 0.21-0.49; p<0.001). During the double-blind period, drug-related adverse events occurred more frequently in patients receiving FAE compared to placebo (75.8% vs. 46.5%). Gastro-intestinal disorders were the most common adverse events.
CONCLUSIONS: FAE administered over a period of 20 weeks demonstrated a response that was statistically significant and clinically meaningful better to placebo. Application up to 40 weeks was generally well tolerated. However, further studies are required.

PMID: 33332574 [PubMed - as supplied by publisher]

Effect of Once-Weekly Azithromycin vs Placebo in Children With HIV-Associated Chronic Lung Disease: The BREATHE Randomized Clinical Trial.

JAMA Netw Open. 2020 Dec 01;3(12):e2028484

Authors: Ferrand RA, McHugh G, Rehman AM, Mujuru H, Simms V, Majonga ED, Nicol MP, Flaegstad T, Gutteberg TJ, Gonzalez-Martinez C, Corbett EL, Rowland-Jones SL, Kranzer K, Weiss HA, Odland JO, BREATHE Trial Group

Abstract
Importance: HIV-associated chronic lung disease (HCLD) in children is associated with small airways disease, is common despite antiretroviral therapy (ART), and is associated with substantial morbidity. Azithromycin has antibiotic and immunomodulatory activity and may be effective in treating HCLD through reducing respiratory tract infections and inflammation.
Objective: To determine whether prophylactic azithromycin is effective in preventing worsening of lung function and in reducing acute respiratory exacerbations (AREs) in children with HCLD taking ART.
Design, Setting, and Participants: This double-blind, placebo-controlled, randomized clinical trial (BREATHE) was conducted between 2016 and 2019, including 12 months of follow-up, at outpatient HIV clinics in 2 public sector hospitals in Malawi and Zimbabwe. Participants were randomized 1:1 to intervention or placebo, and participants and study personnel were blinded to treatment allocation. Participants included children aged 6 to 19 years with perinatally acquired HIV and HCLD (defined as forced expiratory volume in 1 second [FEV1] z score < -1) who were taking ART for 6 months or longer. Data analysis was performed from September 2019 to April 2020.
Intervention: Once-weekly oral azithromycin with weight-based dosing, for 48 weeks.
Main Outcomes and Measures: All outcomes were prespecified. The primary outcome was the mean difference in FEV1 z score using intention-to-treat analysis for participants seen at end line. Secondary outcomes included AREs, all-cause hospitalizations, mortality, and weight-for-age z score.
Results: A total of 347 individuals (median [interquartile range] age, 15.3 [12.7-17.7] years; 177 boys [51.0%]) were randomized, 174 to the azithromycin group and 173 to the placebo group; 162 participants in the azithromycin group and 146 placebo group participants had a primary outcome available and were analyzed. The mean difference in FEV1 z score was 0.06 (95% CI, -0.10 to 0.21; P = .48) higher in the azithromycin group than in the placebo group, a nonsignificant difference. The rate of AREs was 12.1 events per 100 person-years in the azithromycin group and 24.7 events per 100 person-years in the placebo groups (hazard ratio, 0.50; 95% CI, 0.27 to 0.93; P = .03). The hospitalization rate was 1.3 events per 100 person-years in the azithromycin group and 7.1 events per 100 person-years in the placebo groups, but the difference was not significant (hazard ratio, 0.24; 95% CI, 0.06 to 1.07; P = .06). Three deaths occurred, all in the placebo group. The mean weight-for-age z score was 0.03 (95% CI, -0.08 to 0.14; P = .56) higher in the azithromycin group than in the placebo group, although the difference was not significant. There were no drug-related severe adverse events.
Conclusions and Relevance: In this randomized clinical trial specifically addressing childhood HCLD, once-weekly azithromycin did not improve lung function or growth but was associated with reduced AREs; the number of hospitalizations was also lower in the azithromycin group but the difference was not significant. Future research should identify patient groups who would benefit most from this intervention and optimum treatment length, to maximize benefits while reducing the risk of antimicrobial resistance.
Trial Registration: ClinicalTrials.gov Identifier: NCT02426112.

PMID: 33331916 [PubMed - as supplied by publisher]

A randomized, active-controlled, multicentre clinical trial to evaluate the efficacy and safety of oral sitafloxacin versus levofloxacin in Chinese adults with acute uncomplicated or complicated urinary tract infection.

Ann Med. 2021 Dec;53(1):217-226

Authors: Li Y, Yin Y, Peng X, Zheng H, Fu F, Liu Z, Wu X, Wu X, Zheng S, Chen N, He L, Ren L, Ni Z, Li D, Liang P, Lv X, Zhang Y

Abstract
PURPOSE: To evaluate the efficacy and safety of oral sitafloxacin versus levofloxacin in Chinese adults with acute uncomplicated urinary tract infection (UTI) or complicated UTI.
METHODS: In this randomized, active-controlled clinical trial, the patients with acute uncomplicated UTI were randomized to receive sitafloxacin 100-mg once-daily (qd) or levofloxacin 500-mg qd orally for 3-5 days. The patients with complicated UTI were randomized to receive sitafloxacin 100-mg twice daily or levofloxacin 500-mg qd orally for 10-14 days. The primary endpoint was the clinical efficacy at test-of-cure (TOC) visit.
RESULTS: At TOC visit, the clinical cure rate was 89.2% (58/65) in sitafloxacin group and 97.1% (68/70) in levofloxacin group for the patients with acute uncomplicated UTI corresponding to the bacterial eradication rate of 97.1% (34/35) and 97.6% (41/42) (all p > .05), respectively. For the patients with complicated UTI, the clinical cure rate was 81.8% (27/33) in sitafloxacin group and 76.9% (20/26) in levofloxacin group corresponding to the bacterial eradication rate of 93.3% (14/15) and 63.6% (7/11) (all p > .05), respectively. Sitafloxacin and levofloxacin showed similar incidence of drug-related adverse events.
CONCLUSIONS: Oral sitafloxacin is as effective and safe as levofloxacin in treating acute uncomplicated and complicated UTI. KEY MESSAGE: Oral sitafloxacin showed similar clinical cure rate and bacterial eradication rate as levofloxacin for treatment of complicated and uncomplicated urinary tract infections (UTIs) in a randomized, active-controlled, multicentre clinical trial. Oral sitafloxacin is safe and well-tolerated in treating acute uncomplicated and complicated UTIs in Chinese adults. Sitafloxacin is a promising alternative treatment option for UTIs in adults.

PMID: 33331182 [PubMed - in process]

Treatment of Sarcoidosis: A Multidisciplinary Approach.

Front Immunol. 2020;11:545413

Authors: Gerke AK

Abstract
Sarcoidosis is a systemic disease of unknown etiology defined by the presence of noncaseating granulomatous inflammation that can cause organ damage and diminished quality of life. Treatment is indicated to protect organ function and decrease symptomatic burden. Current treatment options focus on interruption of granuloma formation and propagation. Clinical trials guiding evidence for treatment are lacking due to the rarity of disease, heterogeneous clinical course, and lack of prognostic biomarkers, all of which contribute to difficulty in clinical trial design and implementation. In this review, a multidisciplinary treatment approach is summarized, addressing immunuosuppressive drugs, managing complications of chronic granulomatous inflammation, and assessing treatment toxicity. Discovery of new therapies will depend on research into pathogenesis of antigen presentation and granulomatous inflammation. Future treatment approaches may also include personalized decisions based on pharmacogenomics and sarcoidosis phenotype, as well as patient-centered approaches to manage immunosuppression, symptom control, and treatment of comorbid conditions.

PMID: 33329511 [PubMed - in process]

Allopurinol shows no benefit in slowing decline in renal function.

Drug Ther Bull. 2020 Dec 16;:

Authors:

Abstract
Every month, DTB scans sources of information on treatments, disease management and other healthcare topics for key items to bring to our readers' attention and help them keep up to date. To do this, we produce succinct, contextualised summaries of the information concerned.

PMID: 33328219 [PubMed - as supplied by publisher]

Landscape of immune checkpoint inhibitor-related adverse events in Chinese population.

Sci Rep. 2020 09 23;10(1):15567

Authors: Li L, Li G, Rao B, Dong AH, Liang W, Zhu JX, Qin MP, Huang WW, Lu JM, Li ZF, Wu YZ

Abstract
This study aimed to describe the landscape of Immune checkpoint inhibitors (ICIs)-related adverse events (AEs) in a predominantly Chinese cohort. We searched electronic datasets including PubMed, Web of Science and Embase to identify and recruit relevant trials up to September 2, 2019. Clinical trials focusing on ICIs in Chinese patients or a predominantly Chinese population were included. Incidences of treatment-related AEs (TRAEs) and immune-related AEs (irAEs) were pooled and compared. In total, we recruited 13 trials consisting of 1063 patients, with 922 (86.7%) receiving ICI monotherapy and 141 (13.3%) receiving combination of ICI with chemotherapy or anti-angiogenesis. The pooled incidence of any grade TRAEs, grade 1-2, grade 3-5 TRAEs, any grade irAEs, grade 1-2 irAEs and grade 3-5 irAEs in all 1063 patients were 84.1%, 63.3%, 20.9%, 43.3%, 40.0% and 3.0%, respectively. Moreover, 4.3% (44/1018) of patients experienced treatment discontinuation and only 8 (0.8%) patients experienced treatment-related death. Compared to ICI monotherapy, combination significantly increased grade 3-5 TRAEs (46.1% vs. 17.0%, P < 0.001) and grade 3-5 irAEs (7.1% vs. 2.0%, P = 0.015). By comparing the toxicity profiles between different ICIs, we found some drug-specific AEs such as reactive capillary haemangiomas for camrelizumab (58.6%), hyperglycemia for toripalimab (55.6%) and pyrexia for tislelizumab (54.3%). Additionally, nivolumab has the lowest incidence of any grade (64.1%) and grade 3-5 (11.8%) TRAEs. ICI-related AEs were generally mild and tolerable for a predominantly Chinese cohort. However, we should pay attention to the combination of ICI with chemotherapy as it could increase grade 3-5 TRAEs and irAEs.

PMID: 32968172 [PubMed - indexed for MEDLINE]

Long-acting reversible contraception side effect management.

Curr Opin Pediatr. 2020 08;32(4):461-470

Authors: Edwards AJ, DiVasta AD, Pitts S

Abstract
PURPOSE OF REVIEW: Long-acting reversible contraception (LARC) is increasingly used by adolescents and young adults (AYAs). Subsequent to LARC insertion, AYAs are presenting to their primary care providers with LARC concerns. This article seeks to equip primary care clinicians with the tools necessary to assess and manage common LARC-associated side effects.
RECENT FINDINGS: Side effects are common with progestin-only LARC, and can precipitate early discontinuation of an otherwise effective, low-maintenance form of contraception. Abnormal uterine bleeding, pelvic pain, acne, and weight change are often cited as progestin-only LARC side effects, yet the causes are poorly understood despite extensive research. While most side effects improve with time, therapeutic interventions are available for patients with undesirable side effects that prefer medical management. Research emphasizes the importance of proper patient counseling and clinical follow-up.
SUMMARY: Counseling remains essential in the management of LARC-associated side effects. However, options are available to temporarily mitigate such side effects and increase LARC satisfaction. While these therapeutic options are prescribed based on expert opinion, such regimens remain inadequately studied in AYA populations.

PMID: 32692045 [PubMed - indexed for MEDLINE]

Drug-induced parkinsonism: Revisiting the epidemiology using the WHO pharmacovigilance database.

Parkinsonism Relat Disord. 2020 01;70:55-59

Authors: de Germay S, Montastruc F, Carvajal A, Lapeyre-Mestre M, Montastruc JL

Abstract
INTRODUCTION: Drug-Induced Parkinsonism (DIP) is the second most common cause of parkinsonism after idiopathic Parkinson's disease. Little is known about DIP epidemiology. Using VigiBase®, the objective of this study was to assess the main characteristics of DIP reporting around the world.
METHODS: We described reports recorded in the WHO pharmacovigilance database, Vigibase® and classified as "Parkinsonism" between 2000 and 2017. Differences of reporting between geographical locations and characteristics of reports were investigated using disproportionality analysis with calculation of Reporting Odds Ratios (ROR) and its 95% confidence interval.
RESULTS: Among the 9,009,107 reports recorded in VigiBase®, 4565 (0.05%) were DIP. Co reported terms were mainly "tremor" (n = 408, 8.9%), "gait disturbance" (n = 209, 4.6%) and "extrapyramidal disorders" (n = 180, 3.9%). DIP reports were significantly more frequent in men (ROR = 1.4; 95% CI 1.3-1.5) and in patients aged 75 and over (ROR = 2.12; 95% CI 1.98-2.26). Compared to all other continents, risk of reporting drug-induced parkinsonism was higher in Europe (ROR = 2.89; 95% CI 2.73-3.07), Africa (ROR = 1.81; 95% CI 1.46-2.25) and Oceania (ROR = 1.50; 95% CI 1.27-1.77). The risk was lower in Asia (ROR = 0.55; 95% CI 0.51-0.59) and America (ROR = 0.55 95% CI 0.51-0.59). The highest risk of DIP reporting was found with sulpiride and haloperidol followed by risperidone, aripiprazole, paliperidone, metoclopramide, olanzapine, quetiapine and clozapine.
CONCLUSION: Risk of DIP reports was higher in men, in people aged 75 and over and in Europe. Main drugs involved are antipsychotics not only drugs from the first generation but also those from the second one.

PMID: 31865063 [PubMed - indexed for MEDLINE]