Prevalence of Adverse Drug Reactions among Pediatric Patients on Antiretroviral Therapy in Selected Hospitals in Eastern Ethiopia: 8-Year Retrospective Cross-Sectional Study.

J Int Assoc Provid AIDS Care. 2019 Jan-Dec;18:2325958218823208

Authors: Abdela J, Assefa A, Shamele S

Abstract
BACKGROUND: Antiretroviral-related adverse drug reactions (ADRs) are one of the leading causes of drug changes, poor adherence, and treatment failure. Therefore, this study was designed to assess the magnitude of ADR and associated factors among pediatric patients on antiretroviral therapy (ART).
METHODS: A retrospective cross-sectional study was conducted by reviewing the medical records of pediatric patients on ART at Hiwot Fana Specialized University Hospital and Jugal Hospital ART clinics. The collected data were coded, entered, and analyzed using SPSS, IBM version 16. The associations of selected categorical variables were done using binary logistic and multivariate logistic regression.
RESULTS: Of 186 medical records of pediatric patients on ART, 153 (82.25%) were reviewed. From the total medical records assessed, ADRs were observed in 23 (15.03%) of pediatric patients on ART, of which the most commonly encountered ADRs were anemia (34.8%) and followed by rash (17.4%). Most of ADRs were ranked as grade 3 (39.13%) and followed by grade 2 (30.4%) based on the degree of their severity. The likelihood of developing ADR was significantly associated with the regimen AZT/3TC/NVP (adjusted odds ratio: 6.420; 95% confidence interval: 1.056-39.018) relative to pediatric patients on D4T/3TC/NVP regimen.
CONCLUSION: This study indicated that few pediatric patients on ART experienced ADRs. Most of the observed ADRs were ranked as grade 2 and 3 in terms of their severity. Drug out of stock and ADRs were the 2 most common reasons for antiretroviral (ARV) drug regimen change that could affect patient's treatment outcome and limited future option.

PMID: 30798673 [PubMed - indexed for MEDLINE]

A Comparison of Pediatric and Adult Safety Studies for Antipsychotic and Antidepressant Drugs Submitted to the United States Food and Drug Administration.

J Pediatr. 2019 05;208:236-242.e3

Authors: Liu XI, Schuette P, Burckart GJ, Green DJ, La J, Burnham JM, Rakhmanina N, Robb A, Huang SM, van den Anker JN

Abstract
OBJECTIVE: To examine the differences in the adverse drug reaction (ADR) profile of antipsychotic and antidepressant agents between pediatric and adult patients in studies submitted to the Food and Drug Administration (FDA) during the drug development process.
STUDY DESIGN: Clinical trials in adult and pediatric patients were conducted by sponsors as part of the drug development programs for antipsychotic and antidepressant agents, and ADR information was collected as part of those trials and submitted to the FDA. Data collection was conducted by reviewing publicly available FDA-authored reviews and FDA-approved product labels for 10 drugs with an antipsychotic or an antidepressant indication from 2007 to 2017.
RESULTS: There were 308 drug and ADR combinations for the 10 drugs and drug combinations with 113 (36.7%) having a significantly different incidence in pediatric patients compared with adults. Sixty-eight (60.2%) of these ADRs had a significantly higher incidence in pediatric patients than in adults. Sedation was higher in 6 of the 10 drugs and drug combinations with risk differences ranging from 9.6 to 36.6%.
CONCLUSIONS: This analysis indicates that there were significant differences between the pediatric and adult safety profiles of antipsychotic and antidepressant drugs. Sedation was the major ADR associated with the use of atypical antipsychotic drugs in pediatric patients. Clinicians caring for children should consider the ADR profile when prescribing antipsychotics and antidepressants in pediatric patients.

PMID: 30679050 [PubMed - indexed for MEDLINE]

The others: characterizing "other" therapeutic errors reported to a poison center.

Clin Toxicol (Phila). 2019 07;57(7):652-656

Authors: Leonard JB, Klein-Schwartz W

Abstract
Background: Therapeutic errors are costly and result in unplanned hospital visits. Recent poison center studies on therapeutic errors have focused on coded data from either the National Poison Data System (NPDS) or individual poison centers. Approximately 21% of therapeutic errors reported to NPDS are coded as "other incorrect dose" (OI) or "other/unknown therapeutic error" (OU). The purpose of this study was to characterize errors coded as OI or OU reported to a single poison center. Methods: Retrospective, single poison center chart review was conducted of therapeutic error exposures with at least one scenario coded as OI or OU seen in or referred to hospitals from 1/1/2000 to 9/30/2017. Cases were reviewed and re-coded to predefined or newly created scenarios. Results: A total of 3413 cases were identified. There were 726 cases assessed as not therapeutic errors and re-coded as either intentional misuse (430), adverse reaction drug (204), or other non-therapeutic errors (82). Of the remaining cases, 1726 cases were re-coded to one of the 16 existing therapeutic error scenarios. After re-coding, there remained 971 coded as OI or OU. Most were due to double, triple, quadruple, or higher than recommended dose (477/971); an additional common error was mistaken strength (81/971). The remaining scenarios occurred in fewer than 50 cases each with greater than 40 different scenarios such that additional coded scenarios would not be feasible. Conclusions: Most cases coded as OI or OU could be recoded as one of the NPDS predefined therapeutic error scenarios or non-error reasons for exposure. Considering the large proportion of double dose cases and the unique errors associated with mistaken strengths of tablets, these scenarios could be appropriate to add as new predefined coding scenarios, which would aid in future research and patient counseling.

PMID: 30600728 [PubMed - indexed for MEDLINE]

Real-world use of emicizumab in patients with haemophilia A: Bleeding outcomes and surgical procedures.

Haemophilia. 2020 Apr 20;:

Authors: McCary I, Guelcher C, Kuhn J, Butler R, Massey G, Guerrera MF, Ballester L, Raffini L

Abstract
INTRODUCTION: Emicizumab is a recombinant humanized bispecific antibody that bridges factor IXa and factor X to mimic the cofactor function of factor VIII. It is approved to prevent bleeding in patients with haemophilia A (HA). Outside of clinical trials, there is limited data on outcomes of patients treated with emicizumab, particularly in children without inhibitors.
AIM: To report our experience treating patients with emicizumab, including (a) bleeding rates pre and postemicizumab, (b) peri-procedural management and outcomes and (c) serious drug-related adverse events.
METHODS: Multicentre observational study in patients with HA who started emicizumab prior to 15 May 2019. Data collection continued until 15 October 2019 and included demographics, disease history, bleeding events, invasive procedures, thrombotic events and death. Annualized bleeding rates (ABR) prior to emicizumab were compared to postemicizumab.
RESULTS: Ninety-three patients (including three females) met inclusion criteria, 19 with an active inhibitor. Median age was 8.6 years; patients <12 years without inhibitors (n = 49) accounted for the majority. ABR dropped from 4.4 (inhibitors) and 1.6 (non-inhibitors) to 0.4 (both groups) on emicizumab, P = .0012 and .0025, respectively. There were 28 minor (21 port removals) and two major procedures. Three patients received 1-2 doses of unplanned factor postoperatively to treat minor bleeding events. No patient discontinued therapy, and there were no thrombotic events or deaths.
DISCUSSION: Our favourable clinical experience with emicizumab is similar to that reported in the clinical trials. Notably, this is the largest cohort of patients <12 years without inhibitors treated with emicizumab.

PMID: 32311809 [PubMed - as supplied by publisher]

[Mouth and medication].

Rev Prat. 2019 Oct;69(8):861-867

Authors: Ben Slama L

Abstract
Mouth and medication. Medication holds a prominent place for better comfort and increased life expectancy. Adverse effects and drug interactions are frequently observed and reported. Many of the drug-related complications - unrelated to excessive pharmacological activity - which we describe occur in the mouth.

PMID: 32237648 [PubMed - indexed for MEDLINE]

Molecular Events Behind Adverse Effects.

Adv Exp Med Biol. 2020;1248:119-141

Authors: Sun S, Wang F

Abstract
Immune checkpoint blockade (ICB) therapy has become a promising way of overcoming cancers, whereas the therapy can induce immunopathology due to the disruption of the immune homeostasis. These adverse events caused by ICB are named as immune-related adverse events (irAEs), which can be severe and life-threaten. Understanding the mechanisms and managements of irAEs is critical for improving the efficacy of immune checkpoint therapy. Immune-related adverse events can occur on various organs, and gastrointestinal tract has the highest rate for severe irAEs. Accumulated evidences indicate the ability of the gut microbiota in regulating the response to immune checkpoint therapy, but the function of microbiota in irAEs remains unclear. T cells, including functional subsets: Th17 T cells and regulatory T (Treg) cells, play significant roles in determining the inflammatory microenvironment. The gut immune tolerance toward dietary antigens and commensals, and anti-inflammatory function in intestines are maintained mainly by Treg cells. Furthermore, tissue residency of functional T cells depends on the homing/trafficking to the locations of inflammation. Here, we review the role of microbiota and the interaction between microbiota and intestinal Treg cells in irAEs, and discuss the function of gut-trafficking blockade antibodies in the context of ICB therapy.

PMID: 32185709 [PubMed - indexed for MEDLINE]

Viscerotropic disease and acute uveitis following yellow fever vaccination: a case report.

BMC Infect Dis. 2020 Feb 10;20(1):116

Authors: Volkov L, Grard G, Bollaert PE, Durand GA, Cravoisy A, Conrad M, Nace L, Courte G, Marnai R, Leparc-Goffart I, Gibot S

Abstract
BACKGROUND: Yellow fever vaccine exists for over 80 years and is considered to be relatively safe. However, in rare cases it can produce serious neurotropic and viscerotropic complications. We report a case of a patient who presented both viscerotropic and neurological manifestations after yellow fever vaccination.
CASE PRESENTATION: We describe the case of a 37 years old man who developed after the yellow fever vaccination a yellow fever vaccine-associated viscerotropic disease followed by acute uveitis. Prolonged detection of yellow fever RNA in blood and urine was consistent with yellow fever vaccine-associated adverse event. The final outcome was good, although with persistent fatigue over a few months.
CONCLUSIONS: Even if the yellow fever vaccine is relatively safe, physicians should be aware of its possible serious adverse effects.

PMID: 32041533 [PubMed - indexed for MEDLINE]

Clinical medication review type III of polypharmacy reduced unplanned hospitalizations in older adults: A meta-analysis of randomized clinical trials.

Geriatr Gerontol Int. 2019 Dec;19(12):1275-1281

Authors: Mizokami F, Mizuno T, Kanamori K, Oyama S, Nagamatsu T, Lee JK, Kobayashi T

Abstract
AIM: To analyze the impact of clinical medication reviews (CMR) on reducing unplanned hospitalizations owing to polypharmacy among older adults using an intervention.
METHODS: Our meta-analysis complied with PRISMA guidelines. The literature review comprised a search for articles published between January 1972 and March 2017 on MEDLINE and Google Scholar. We identified randomized controlled trials focusing on CMR that evaluated unplanned hospitalization and re-hospitalization among older adults as a primary outcome. The keywords used were "CMR" or "medication review" in their titles, and the phrases "elderly" or "older adults" or "geriatric" and "polypharmacy." The randomized controlled trials selected were divided according to the three types of CMR to analyze the characteristics of each review.
RESULTS: We included nine randomized controlled trials that examined the impact of CMR of polypharmacy in older patients. Five trials corresponded to CMR type I (prescription only review) or II (adherence review), whereas four corresponded to type III (comprehensive clinical evaluation for disease management). Type I/II increased the number of unplanned hospitalizations (RR 1.22, 95% CI 1.07-1.38, P = 0.002), whereas type III decreased hospital admissions (RR 0.86, 95% CI 0.79-0.95, P = 0.001).
CONCLUSIONS: The present findings show the need for an intervention standardization for CMR, particularly for type III in older adults with polypharmacy, to decrease hospitalizations. Geriatr Gerontol Int 2019; 19: 1275-1281.

PMID: 31758656 [PubMed - indexed for MEDLINE]

Intensive monitoring of adverse drug reactions in nephrology unit of tertiary care teaching hospital.

Saudi J Kidney Dis Transpl. 2019 Sep-Oct;30(5):1075-1083

Authors: Kareem SA, Sridhar SB, Shetty MS

Abstract
Adverse drug reactions (ADRs) are one of the common causes of morbidity and mortality. Renal insufficiency is considered as one of the risk factors for the development of ADR. The study determined the occurrence of ADRs in patients with renal failure and their incidence of hospital admission. The study also evaluated the nature and severity of ADRs. This was a prospective study conducted in the nephrology unit at a tertiary care teaching hospital for a period of nine months. Patients receiving regular hemodialysis and those either referred or admitted to the nephrology ward were included. ADRs were intensively monitored throughout the study. The causality of suspected ADRs was assessed with the WHO probability scale, Naranjo algorithm, and Karch and Lasagna's scale. The predictability and preventability of ADRs were also determined. A total of 45 ADRs were identified in 369 patients; incidence was 12.19%. Nine ADRs (20%) needed hospitalization. A total of 27 (60%) and 17 (37.8%) ADRs were found to be probable and possible, respectively when assessed by the WHO probability scale. On the contrary, 33 (73.3%) and 26 (57.8%) ADRs were possible in causality when assessed by Karch and Lasagna's scale and Naranjo scale, respectively. Most of the ADRs [26 (57.8%)] were predictable in nature. A wide range of ADRs was noticed in patients with renal impairment, and our study has systematically assessed the nature and severity of ADRs.

PMID: 31696846 [PubMed - indexed for MEDLINE]

Montelukast modifies simvastatin-induced myopathy and hepatotoxicity.

Drug Dev Res. 2019 11;80(7):1000-1009

Authors: Hareedy MS, Ahmed EA, Ali MF

Abstract
Montelukast (MNK) has prominent anti-inflammatory and antioxidant activities. It can protect the liver in different hepatotoxic models in animals. Simvastatin (SMV) is one of commonly used lipid lowering drugs for treatment of dyslipidemia in order to reduce cardiovascular disease. It has severe side effects such as myopathy and hepatotoxicity. The aim of the present study is to investigate the possible effect of MNK on SMV-induced myopathy and hepatotoxicity. Four groups of male rats: control group which received saline via stomach tube, MNK treated group (received 10 mg/kg/day MNK via stomach tube), SMV treated group (received 30 mg/kg/day SMV via stomach tube), and MNK + SMV (combination) group which received both MNK and SMV. All animals were treated for 14 days before obtaining blood and tissue samples. SMV has both hepatotoxic effects and myopathy. SMV caused a significant increase in myoglobin, creatinine kinase, ALT, AST, ALP, and bilirubin but, it decreased total proteins, globulin and albumin levels. Co-treatment of SMV and MNK increased the antioxidant activity significantly. MNK modifies partially the myopathic changes and hepatotoxic effect of SMV. Co-administration of MNK and SMV decreased their toxic potentials on the liver, skeletal muscles, and kidney. They have antioxidant activities when given together that produce muscle and hepatic protective effects.

PMID: 31389048 [PubMed - indexed for MEDLINE]

Associations Between Potentially Inappropriate Medications and Adverse Health Outcomes in the Elderly: A Systematic Review and Meta-analysis.

Ann Pharmacother. 2019 10;53(10):1005-1019

Authors: Xing XX, Zhu C, Liang HY, Wang K, Chu YQ, Zhao LB, Jiang C, Wang YQ, Yan SY

Abstract
Background: Adverse drug outcomes in the elderly have led to the development of lists of potentially inappropriate medications (PIMs), such as the Beers criteria, and these PIMs have been studied widely; however, it is still unclear whether PIM use is predictive of adverse outcomes in older people. Objective: To qualitatively examine the associations between exposure to PIMs from the general Beers criteria and the Screening Tool of Older Persons' Prescriptions list and adverse outcomes, such as adverse drug reactions (ADRs)/adverse drug events (ADEs), hospitalization, and mortality. Methods: Specified databases were searched from inception to February 1, 2018. Two reviewers independently selected studies that met the inclusion criteria, assessed study quality, and extracted data. Data were pooled using Stata 12.0. The outcomes were ADRs/ADEs, hospitalization, and mortality. Results: A total of 33 studies met the inclusion criteria. The combined analysis revealed a statistically significant association between ADRs/hospitalizations and PIMs (odds ratio [OR] = 1.44, 95% CI = 1.33-1.56; OR = 1.27, 95% CI = 1.20-1.35), but no statistically significant association was found between mortality and PIMs (OR = 1.04; 95% CI = 0.75-1.45). It is interesting to note that the results changed when different continents/criteria were used for the analysis. Compared with the elderly individuals exposed to 1 PIM, the risk of adverse health outcomes was much higher for those who took ≥2 PIMs. Conclusion and Relevance: We recommend that clinicians avoid prescribing PIMs for older adults whenever feasible. In addition, the observed associations should be generalized to other countries with different PIM criteria with caution.

PMID: 31129978 [PubMed - indexed for MEDLINE]

Whole-body Imaging of Cell Death Provides a Systemic, Minimally Invasive, Dynamic, and Near-real Time Indicator for Chemotherapeutic Drug Toxicity.

Clin Cancer Res. 2019 02 15;25(4):1331-1342

Authors: Johnson SE, Ugolkov A, Haney CR, Bondarenko G, Li L, Waters EA, Bergan R, Tran A, O'Halloran TV, Mazar A, Zhao M

Abstract
PURPOSE: Response to toxicity in chemotherapies varies considerably from tissue to tissue and from patient to patient. An ability to monitor the tissue damage done by chemotherapy may have a profound impact on treatment and prognosis allowing for a proactive management in understanding and mitigating such events. For the first time, we investigated the feasibility of using whole-body imaging to map chemotherapeutic drug-induced toxicity on an individual basis.
EXPERIMENTAL DESIGN: In a preclinical proof-of-concept, rats were treated with a single clinical dose of cyclophosphamide, methotrexate, or cisplatin. In vivo whole-body imaging data were acquired using 99mTc-duramycin, which identifies dead and dying cells as an unambiguous marker for tissue injury in susceptible organs. Imaging results were cross-validated using quantitative ex vivo measurements and histopathology and compared with standard blood and serum panels for toxicology.
RESULTS: The in vivo whole-body imaging data detected widespread changes, where spatially heterogeneous toxic effects were identified across different tissues, within substructures of organs, as well as among different individuals. The signal changes were consistent with established toxicity profiles of these chemotherapeutic drugs. Apart from generating a map of susceptible tissues, this in vivo imaging approach was more sensitive compared with conventional blood and serum markers used in toxicology. Also, repeated imaging during the acute period after drug treatment captured different kinetics of tissue injury among susceptible organs in males and females.
CONCLUSIONS: This novel and highly translational imaging approach shows promise in optimizing therapeutic decisions by detecting and managing drug toxicity on a personalized basis.Toxicity to normal tissues is a significant limitation in chemotherapies. This work demonstrated an in vivo imaging-based approach for characterizing toxicity-induced tissue injury in a systemic, dynamic, and near-real time fashion. This novel approach shows promise in optimizing therapeutic decisions by monitoring drug toxicity on a personalized basis.

PMID: 30420445 [PubMed - indexed for MEDLINE]

Genetic and Modifiable Risk Factors Contributing to Cisplatin-induced Toxicities.

Clin Cancer Res. 2019 02 15;25(4):1147-1155

Authors: Trendowski MR, El Charif O, Dinh PC, Travis LB, Dolan ME

Abstract
Effective administration of traditional cytotoxic chemotherapy is often limited by off-target toxicities. This clinical dilemma is epitomized by cisplatin, a platinating agent, which has potent antineoplastic activity due to its affinity for DNA and other intracellular nucleophiles. Despite its efficacy against many adult-onset and pediatric malignancies, cisplatin elicits multiple off-target toxicities that can not only severely impact a patient's quality of life but also lead to dose reductions or the selection of alternative therapies that can ultimately affect outcomes. Without an effective therapeutic measure by which to successfully mitigate many of these symptoms, there have been attempts to identify a priori those individuals who are more susceptible to developing these sequelae through studies of genetic and nongenetic risk factors. Older age is associated with cisplatin-induced ototoxicity, neurotoxicity, and nephrotoxicity. Traditional genome-wide association studies have identified single-nucleotide polymorphisms in ACYP2 and WFS1 associated with cisplatin-induced hearing loss. However, validating associations between specific genotypes and cisplatin-induced toxicities with enough stringency to warrant clinical application remains challenging. This review summarizes the current state of knowledge with regard to specific adverse sequelae following cisplatin-based therapy, with a focus on ototoxicity, neurotoxicity, nephrotoxicity, myelosuppression, and nausea/emesis. We discuss variables (genetic and nongenetic) contributing to these detrimental toxicities and currently available means to prevent or treat their occurrence.

PMID: 30305294 [PubMed - indexed for MEDLINE]

Efficacy and Safety of Metformin and Sitagliptin-based Dual and Triple Therapy in Elderly Chinese Patients with Type 2 Diabetes: Subgroup Analysis of STRATEGY Study.

J Diabetes Investig. 2020 Apr 18;:

Authors: Liu X, Wang L, Xing Y, Engel SS, Zeng L, Yao B, Xu W, Chen G, Zhang Y, Zhang R, Liu S, Weng J, Ji Q

Abstract
AIMS: To assess the efficacy and safety of metformin/sitagliptin-based dual/triple therapy in elderly Chinese patients with type 2 diabetes mellitus (T2DM).
MATERIALS AND METHODS: This subgroup analysis included individuals aged ≥65 years from the STRATEGY study, a two-stage study in which T2DM patients with unsatisfactory glycemic control on metformin were first treated with the dual combination of metformin and sitagliptin for 16 weeks (n=681), and then, if glycemic control had not been achieved, treated with a third add-on oral antihyperglycemic drug for another 24 weeks (n=291). The efficacy endpoint was change in HbA1c in each stage, and the safety endpoint was adverse events (AEs) with a focus on hypoglycemia.
RESULTS: At week 16, the change in HbA1c was -0.81% from baseline, and the percentages of patients who achieved HbA1c targets of <7% and <7.5% were 44.9% and 67.2%, respectively. After 24 weeks, a further average HbA1c reduction of -0.60% was observed with specific reductions of -0.70% with glimepiride, -0.63% with gliclazide, -0.51% with repaglinide, and -0.45% with acarbose. The proportions of patients who achieved HbA1c targets of <7% and <7.5% were 65.4% and 81.3%, respectively, over the entire study. The rates of drug-related AEs and hypoglycemia were, respectively, 4.1% and 4.3% in the dual therapy stage and 5.2% and 7.1% in the triple therapy stage, without occurrence of severe hypoglycemia.
CONCLUSIONS: In elderly Chinese T2DM patients, metformin/sitagliptin-based dual and triple oral therapy can provide clinically meaningful glycemic control and is generally well tolerated with a low incidence of hypoglycemia.

PMID: 32304283 [PubMed - as supplied by publisher]

Phase II Study of Ensituximab, a Novel Chimeric Monoclonal Antibody, in Adults with Unresectable, Metastatic Colorectal Cancer.

Clin Cancer Res. 2020 Apr 17;:

Authors: Kim RD, Azad NS, Morse MA, Poplin E, Mahipal A, Tan B, Mavroukakis SA, Fantini M, Tsang KY, Zaki A, Torrealba J, Arlen PM, Beg MS

Abstract
PURPOSE: Patients with metastatic colorectal cancer (CRC) refractory to chemotherapy have limited treatment options. Ensituximab (NEO-102) is a novel chimeric monoclonal antibody targeting a variant of MUC5AC with specificity to CRC.
PATIENTS AND METHODS: Single arm, phase II trial assessed the efficacy and safety of ensituximab in patients with advanced, refractory cancer who expressed MUC5AC antigen in tumor tissue. Ensituximab was administered intravenously every 2 weeks with 3 mg/kg as recommended phase II dose (RP2D). A minimum sample size of 43 patients was required based on the assumption that ensituximab would improve median overall survival by 7 months using a one-sided significance level of 10% and 80% power. Written informed consent was obtained from all patients.
RESULTS: Sixty-three patients with advanced, refractory CRC were enrolled and 53 subjects were treated in phase 2 arm. Median age was 58 years and 46% of the patients were female. Among 57 evaluable patients, median OS was 6.8 months. No responses were observed, and stable disease was achieved in 21% of the patients. The most common treatment related adverse events at RP2D included fatigue (38%), anemia (30%), nausea (15%), vomiting (11%), increased bilirubin (9%), constipation (8%), decreased appetite (6%) and diarrhea (6%). Serious adverse events at least possibly related to ensituximab occurred in 4 patients and included anemia, nausea, increased bilirubin and hypoxia. No patients discontinued treatment due to drug related adverse events.
CONCLUSIONS: Ensituximab was well tolerated and demonstrated modest antitumor activity in patients with heavily pretreated refractory CRC.

PMID: 32303539 [PubMed - as supplied by publisher]

Response to inhibition of receptor-interacting protein kinase 1 (RIPK1) in active plaque psoriasis: a randomized placebo-controlled study.

Clin Pharmacol Ther. 2020 Apr 17;:

Authors: Weisel K, Berger S, Papp K, Maari C, Krueger JG, Scott N, Tompson D, Wang S, Simeoni M, Bertin J, Tak PP

Abstract
Receptor-interacting protein kinase 1 (RIPK1), a regulator of inflammation and cell death, is a potential therapeutic target in immune-mediated inflammatory diseases (IMIDs). The objective of this phase 2a multicenter, randomized, double-blind, placebo-controlled study was to evaluate safety, tolerability pharmacokinetics, pharmacodynamics and preliminary efficacy of GSK2982772, a RIPK1 inhibitor, in plaque-type psoriasis. Psoriasis patients (N=65) were randomized to 60 mg twice daily (BID) or three times daily (TID), or placebo for 84 days. .Most adverse events (AEs) were mild with no severe drug-related AEs reported. Plaque Lesion Severity Sum improved with BID treatment compared with placebo; interpretation of TID treatment results was complicated by a high placebo response. Reductions in epidermal thickness and infiltration by CD3+ T cells in epidermis and dermis were observed compared with placebo. Results support the rationale for additional studies on RIPK1 inhibition in IMIDs.

PMID: 32301501 [PubMed - as supplied by publisher]

[Algorithms for systemic therapy of prostate cancer, transitional cell carcinoma and renal cell carcinoma].

Urologe A. 2020 Apr 16;:

Authors: Eisenhardt A, Ohlmann CH, Doehn C

Abstract
Systemic therapy in uro-oncology is currently undergoing major changes. In the past, drug therapies only showed good treatment results in metastasized testicular tumors. New developments indicate that an improved understanding of tumor biology will lead to targeted treatment strategies for metastatic prostate, urothelial and renal cell carcinoma. In the following article, we summarize the practice-relevant innovations in systemic therapy in the guidelines on prostate cancer, transitional cell carcinoma of the bladder and renal cell carcinoma.

PMID: 32300817 [PubMed - as supplied by publisher]

Drug selection for sedation and general anesthesia in children undergoing ambulatory magnetic resonance imaging.

Yeungnam Univ J Med. 2020 Apr 17;:

Authors: Jung SM

Abstract
The demand for drug-induced sedation for magnetic resonance imaging (MRI) scans have substantially increased in response to increases in MRI utilization and growing interest in anxiety in children. Understanding the pharmacologic options for deep sedation and general anesthesia in an MRI environment is essential to achieve immobility for the successful completion of the procedure and ensure rapid and safe discharge of children undergoing ambulatory MRI. For painless diagnostic MRI, a single sedative/anesthetic agent without analgesia is safer than a combination of multiple sedatives. The traditional drugs, such as chloral hydrate, pentobarbital, midazolam, and ketamine, are still used due to the ease of administration despite low sedation success rate, prolonged recovery, and significant adverse events. Currently, dexmedetomidine, with respiratory drive preservation, and propofol, with high effectiveness and rapid recovery, are preferred for children undergoing ambulatory MRI. General anesthesia using propofol or sevoflurane can also provide predictable rapid time to readiness and scan times in infant or children with comorbidities. The selection of appropriate drugs as well as sufficient monitoring equipment are vital for effective and safe sedation and anesthesia for ambulatory pediatric MRI.

PMID: 32299181 [PubMed - as supplied by publisher]

Monitoring adverse drug reactions in the community settings.

Bull World Health Organ. 2019 Nov 01;97(11):730

Authors: Ab Rahman AF

PMID: 31673185 [PubMed - indexed for MEDLINE]

Enzyme replacement therapy initiated in adulthood: Findings from the mucopolysaccharidosis VI Clinical Surveillance Program.

Mol Genet Metab. 2019 08;127(4):355-360

Authors: Lampe C, Harmatz PR, Parini R, Sharma R, Teles EL, Johnson J, Sivam D, Sisic Z

Abstract
OBJECTIVE: To evaluate the impact of galsulfase enzyme replacement therapy (ERT) when initiated in adulthood for patients with mucopolysaccharidosis (MPS) VI.
METHODS: In 2005, the multi-national, MPS VI Clinical Surveillance Program (CSP) was established to collect long-term observational data from routine clinical and laboratory assessments. A sub-analysis was performed in patients who started ERT at ≥16 years of age and had received galsulfase for ≥6 months. Urinary glycosaminoglycans (uGAG), 6-min walk test (6MWT), 3-min stair climb test (3MSCT), pulmonary function measures, cardiac function, ophthalmology measures, liver and spleen sizes, and safety were evaluated.
RESULTS: Of 223 patients enrolled in the CSP, 51 were included in the sub-analysis. Patients were between 16 and 63 years of age at first infusion. From pre-treatment baseline, uGAG level decreased by a mean (±standard deviation [SD]) of 66 (±45)% (N = 29) after a median follow-up of 7.2 years. 6MWT distance decreased slightly by a mean of 17 (±107) meters (N = 23) after 6.6 years. Stairs/min in the 3MSCT increased by a mean of 26 (±33) (N = 14) after 2.8 years. Pulmonary function measures, forced expiratory volume in 1 second and forced vital capacity, increased by a mean of 0.06 (±0.21) L after 7.3 years and 0.05 (±0.28) L after 7.2 years, respectively (N = 19 for both measures). Overall, galsulfase was well tolerated, with most adverse events reported being MPS-related clinical manifestations and not related to galsulfase.
CONCLUSIONS: Results of this sub-analysis of the CSP suggest that initiation of galsulfase in adulthood is well tolerated and can possibly stabilize MPS VI in the long term.

PMID: 31324526 [PubMed - indexed for MEDLINE]