Pharmacoepigenetics and Pharmacoepigenomics: An Overview.

Curr Drug Discov Technol. 2019;16(4):392-399

Authors: Peedicayil J

Abstract
BACKGROUND: The rapid and major advances being made in epigenetics are impacting pharmacology, giving rise to new sub-disciplines in pharmacology, pharmacoepigenetics, the study of the epigenetic basis of variation in response to drugs; and pharmacoepigenomics, the application of pharmacoepigenetics on a genome-wide scale.
METHODS: This article highlights the following aspects of pharmacoepigenetics and pharmacoepigenomics: epigenetic therapy, the role of epigenetics in pharmacokinetics, the relevance of epigenetics to adverse drug reactions, personalized medicine, drug addiction, and drug resistance, and the use of epigenetic biomarkers in drug therapy.
RESULTS: Epigenetics is having an increasing impact on several areas of pharmacology.
CONCLUSION: Pharmacoepigenetics and pharmacoepigenomics are new sub-disciplines in pharmacology and are likely to have an increasing impact on the use of drugs in clinical practice.

PMID: 29676232 [PubMed - indexed for MEDLINE]

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

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These pubmed results were generated on 2020/08/28

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Efficacy and Safety of Sitagliptin Compared with Dapagliflozin in People ≥ 65 Years Old with Type 2 Diabetes and Mild Renal Insufficiency.

Diabetes Ther. 2020 Aug 27;:

Authors: Raji A, Xu ZJ, Lam RLH, O'Neill EA, Kaufman KD, Engel SS

Abstract
INTRODUCTION: Older patients with type 2 diabetes (T2D) are at increased risk of diabetic nephropathy and mild renal insufficiency. This analysis compared the anti-hyperglycemic efficacy and safety of sitagliptin with dapagliflozin in patients ≥ 65 years of age with T2D and mild renal insufficiency.
METHODS: This was a post hoc analysis of data from 410 patients ≥ 65 years old who participated in a 24-week, randomized, double-blind clinical trial (CompoSIT-R [comparison of sitagliptin with dapagliflozin in mild renal impairment]; NCT02532855) in T2D patients with mild renal insufficiency and on metformin ± a sulfonylurea; the primary efficacy end point was change in HbA1c at week 24.
RESULTS: Treatment groups were well balanced at baseline (mean HbA1c = 7.7/7.7% and eGFR = 79/76 ml/min/1.73 m2 for sitagliptin/dapagliflozin). At week 24, LS mean (95% CI) change in HbA1c and percentage of patients with HbA1c < 7% were greater with sitagliptin, - 0.48% and 41%, respectively, compared with dapagliflozin, - 0.36% and 28%; between-group differences = - 0.12% (- 0.36, 0.01) and 12.8% (3.3, 22.2) for change in HbA1c and percentage with HbA1c < 7%, respectively. The sitagliptin group had greater reductions in PPG end points, while the dapagliflozin group had greater reductions in FPG. Treatments were generally well tolerated. There were fewer drug-related adverse events (AEs) with sitagliptin than with dapagliflozin but AE profiles were otherwise similar.
CONCLUSIONS: In patients ≥ 65 years of age with T2D and mild renal insufficiency with inadequate glycemic control on metformin ± sulfonylurea, treatment with sitagliptin for 24 weeks resulted in improvement in HbA1c relative to treatment with dapagliflozin that is consistent with that previously observed in the overall population. Both treatments were generally well tolerated.

PMID: 32852696 [PubMed - as supplied by publisher]

TREK-1 channel activation as a new analgesic strategy devoid of opioid adverse effects.

Br J Pharmacol. 2020 Aug 27;:

Authors: Busserolles J, Soussia IB, Pouchol L, Marie N, Meleine M, Devilliers M, Judon C, Schopp J, Clémenceau L, Poupon L, Chapuy E, Richard S, Noble F, Lesage F, Ducki S, Eschalier A, Lolignier S

Abstract
BACKGROUND AND PURPOSE: Opioids are effective painkillers. However, their risk-benefit ratio is dampened by numerous adverse effects and opioid misuse has led to a public health crisis. Safer alternatives are required but isolating the antinociceptive effect of opioids from their adverse effects is a pharmacological challenge because activation of the mu opioid receptor triggers both the antinociceptive and adverse effects of opioids.
EXPERIMENTAL APPROACH: The TREK-1 potassium channel is activated down-stream of mu and involved in the antinociceptive activity of morphine but not in its adverse effects. Bypassing the mu opioid receptor to directly activate TREK-1 could therefore be a safer analgesic strategy.
KEY RESULTS: We developed a selective TREK-1 activator, RNE28, with antinociceptive activity in naive rodents and in models of inflammatory and neuropathic pain. This activity was lost in TREK-1 knock-out mice or wild-type mice treated with the TREK-1 blocker spadin, showing that TREK-1 is required for the antinociceptive activity of RNE28. RNE28 did not induce respiratory depression, constipation, rewarding effects or sedation at the analgesic doses tested.
CONCLUSIONS AND IMPLICATIONS: This proof-of-concept study shows that TREK-1 activators could constitute a novel class of painkillers, inspired by the mechanism of action of opioids but devoid of their adverse effects.

PMID: 32851651 [PubMed - as supplied by publisher]

Efficacy of Selpercatinib in RET-Altered Thyroid Cancers.

N Engl J Med. 2020 08 27;383(9):825-835

Authors: Wirth LJ, Sherman E, Robinson B, Solomon B, Kang H, Lorch J, Worden F, Brose M, Patel J, Leboulleux S, Godbert Y, Barlesi F, Morris JC, Owonikoko TK, Tan DSW, Gautschi O, Weiss J, de la Fouchardière C, Burkard ME, Laskin J, Taylor MH, Kroiss M, Medioni J, Goldman JW, Bauer TM, Levy B, Zhu VW, Lakhani N, Moreno V, Ebata K, Nguyen M, Heirich D, Zhu EY, Huang X, Yang L, Kherani J, Rothenberg SM, Drilon A, Subbiah V, Shah MH, Cabanillas ME

Abstract
BACKGROUND: RET mutations occur in 70% of medullary thyroid cancers, and RET fusions occur rarely in other thyroid cancers. In patients with RET-altered thyroid cancers, the efficacy and safety of selective RET inhibition are unknown.
METHODS: We enrolled patients with RET-mutant medullary thyroid cancer with or without previous vandetanib or cabozantinib treatment, as well as those with previously treated RET fusion-positive thyroid cancer, in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response), as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety.
RESULTS: In the first 55 consecutively enrolled patients with RET-mutant medullary thyroid cancer who had previously received vandetanib, cabozantinib, or both, the percentage who had a response was 69% (95% confidence interval [CI], 55 to 81), and 1-year progression-free survival was 82% (95% CI, 69 to 90). In 88 patients with RET-mutant medullary thyroid cancer who had not previously received vandetanib or cabozantinib, the percentage who had a response was 73% (95% CI, 62 to 82), and 1-year progression-free survival was 92% (95% CI, 82 to 97). In 19 patients with previously treated RET fusion-positive thyroid cancer, the percentage who had a response was 79% (95% CI, 54 to 94), and 1-year progression-free survival was 64% (95% CI, 37 to 82). The most common adverse events of grade 3 or higher were hypertension (in 21% of the patients), increased alanine aminotransferase level (in 11%), increased aspartate aminotransferase level (in 9%), hyponatremia (in 8%), and diarrhea (in 6%). Of all 531 patients treated, 12 (2%) discontinued selpercatinib owing to drug-related adverse events.
CONCLUSIONS: In this phase 1-2 trial, selpercatinib showed durable efficacy with mainly low-grade toxic effects in patients with medullary thyroid cancer with and without previous vandetanib or cabozantinib treatment. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).

PMID: 32846061 [PubMed - in process]

Efficacy of Selpercatinib in RET Fusion-Positive Non-Small-Cell Lung Cancer.

N Engl J Med. 2020 08 27;383(9):813-824

Authors: Drilon A, Oxnard GR, Tan DSW, Loong HHF, Johnson M, Gainor J, McCoach CE, Gautschi O, Besse B, Cho BC, Peled N, Weiss J, Kim YJ, Ohe Y, Nishio M, Park K, Patel J, Seto T, Sakamoto T, Rosen E, Shah MH, Barlesi F, Cassier PA, Bazhenova L, De Braud F, Garralda E, Velcheti V, Satouchi M, Ohashi K, Pennell NA, Reckamp KL, Dy GK, Wolf J, Solomon B, Falchook G, Ebata K, Nguyen M, Nair B, Zhu EY, Yang L, Huang X, Olek E, Rothenberg SM, Goto K, Subbiah V

Abstract
BACKGROUND: RET fusions are oncogenic drivers in 1 to 2% of non-small-cell lung cancers (NSCLCs). In patients with RET fusion-positive NSCLC, the efficacy and safety of selective RET inhibition are unknown.
METHODS: We enrolled patients with advanced RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated separately in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response) as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety.
RESULTS: In the first 105 consecutively enrolled patients with RET fusion-positive NSCLC who had previously received at least platinum-based chemotherapy, the percentage with an objective response was 64% (95% confidence interval [CI], 54 to 73). The median duration of response was 17.5 months (95% CI, 12.0 to could not be evaluated), and 63% of the responses were ongoing at a median follow-up of 12.1 months. Among 39 previously untreated patients, the percentage with an objective response was 85% (95% CI, 70 to 94), and 90% of the responses were ongoing at 6 months. Among 11 patients with measurable central nervous system metastasis at enrollment, the percentage with an objective intracranial response was 91% (95% CI, 59 to 100). The most common adverse events of grade 3 or higher were hypertension (in 14% of the patients), an increased alanine aminotransferase level (in 12%), an increased aspartate aminotransferase level (in 10%), hyponatremia (in 6%), and lymphopenia (in 6%). A total of 12 of 531 patients (2%) discontinued selpercatinib because of a drug-related adverse event.
CONCLUSIONS: Selpercatinib had durable efficacy, including intracranial activity, with mainly low-grade toxic effects in patients with RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).

PMID: 32846060 [PubMed - in process]

A Randomized Controlled Trial of Intravenous N-acetylcysteine in the Management of Anti-tuberculosis Drug-Induced Liver Injury.

Clin Infect Dis. 2020 Aug 26;:

Authors: Moosa MS, Maartens G, Gunter H, Allie S, Chughlay MF, Setshedi M, Wasserman S, Hickman N, Stewart A, Sonderup M, Spearman CW, Cohen K

Abstract
BACKGROUND: Liver injury is a common complication of first-line anti-tuberculosis therapy. N-acetylcysteine (NAC) is widely used in patients with paracetamol toxicity with limited evidence of benefit in liver injury due to other causes.
METHODS: We conducted a randomized, double-blind, placebo-controlled trial to assess whether intravenous NAC hastens liver recovery in hospitalized adult patients with anti-tuberculosis drug induced liver injury (AT-DILI). The primary endpoint was the time for serum alanine aminotransferase (ALT) to fall below 100 U/L. Secondary endpoints included length of hospital stay, in-hospital mortality and adverse events.
RESULTS: Fifty-three participants were randomized to NAC and 49 to placebo. Mean age was 38 (SD±10) years, 58 (57%) were female and 89 (87%) were HIV-positive. Median serum ALT and total bilirubin at presentation were 462 U/L (IQR 266-790) and 56 μmol/L (IQR 25-100) respectively. Median time to ALT&100 U/L was 7.5 days (IQR 6 -11) in the NAC arm and 8 days (IQR 5 -13) in the placebo arm. Median time to hospital discharge was shorter in the NAC arm (9 days; IQR 6-15) than in the placebo arm (18 days; IQR 10-25), hazard ratio 1.73 (95% CI 1.13-2.65). Mortality was 14% overall and did not differ by study arm. The study infusion was stopped early due to an adverse reaction in 5 participants receiving NAC [nausea and vomiting (3), anaphylaxis (1), pain at drip site (1)].
CONCLUSION: NAC did not shorten time to ALT&100 U/L in participants with AT-DILI, but significantly reduced length of hospital stay. NAC should be considered in management of AT-DILI.

PMID: 32845997 [PubMed - as supplied by publisher]

Adverse Drug Events Observed with the Novel Sodium/Glucose Co-Transporter 2 Inhibitor Ipragliflozin for the Treatment of Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-analysis of Randomized Studies.

Adv Ther. 2020 Aug 26;:

Authors: Liu D, Chen H, Song F, Ahmed MA, Wu H

Abstract
INTRODUCTION: Type 2 diabetes mellitus (T2DM) is becoming a major issue worldwide. To effectively control the blood sugar of patients with T2DM, several novel oral hypoglycemic agents (OHAs) are being developed. Sodium/glucose co-transporter 2 (SGLT 2) inhibitors have recently shown beneficial outcomes in patients with T2DM. In this analysis, we aimed to systematically compare the adverse drug events observed with ipragliflozin versus placebo for the treatment of patients with T2DM.
METHODS: http://www.ClinicalTrials.gov , the bibliographic database of life science and biomedical information MEDLINE, EMBASE and the Cochrane Central were searched for English publications satisfying the inclusion and exclusion criteria of this study. Adverse drug events were the end points in this analysis. The latest version (5.4) of the RevMan software was used to analyze the data, and risk ratios (RR) with 95% confidence intervals (CI) were used to represent the data post analysis.
RESULTS: Eight randomized studies with a total of 1519 participants with T2DM were included in this analysis whereby total treatment-emergent adverse events (RR: 1.06, 95% CI: 0.96-1.16; P = 0.26), including mild (RR: 0.95, 95% CI: 0.79-1.13; P = 0.54), moderate (RR: 1.04, 95% CI: 0.72-1.51; P = 0.83) and severe treatment-emergent adverse events (RR: 0.72, 95% CI: 0.26-1.96; P = 0.52), were not significantly different in those patients who were assigned to ipragliflozin versus placebo for the treatment of T2DM. Moreover, drug-related adverse events (RR: 1.04, 95% CI: 0.69-1.58; P = 0.85), adverse events leading to drug discontinuation (RR: 1.09, 95% CI: 0.57-2.10; P = 0.79), urinary tract infection (RR: 1.03, 95% CI: 0.60-1.77; P = 0.91), naso-pharyngitis (RR: 0.54, 95% CI: 0.19-1.52; P = 0.25), constipation (RR: 1.94, 95% CI: 0.90-4.20; P = 0.09), dizziness (RR: 0.81, 95% CI: 0.20-3.23; P = 0.76), gastrointestinal disorders (RR: 0.96, 95% CI: 0.68-1.36; P = 0.82) and dehydration (RR: 2.26, 95% CI: 0.38-13.43; P = 0.37) were also not significantly different. However, genital infection (RR: 4.53, 95% CI: 1.48-13.85; P = 0.008) and hypoglycemia (RR: 1.68, 95% CI: 1.03-2.74; P = 0.04) rates were significantly higher in the ipragliflozin group.
CONCLUSIONS: The current analysis showed ipragliflozin to be associated with significantly higher genital infection rates compared to placebo, whereas no significant difference was observed compared to the other adverse drug events in these patients with T2DM. In addition, hypoglycemia was also not significantly different following sensitivity analysis.

PMID: 32845473 [PubMed - as supplied by publisher]

Quinidine hypersensitivity: a side effect of a forgotten antiarrhythmic.

BMJ Case Rep. 2020 Aug 24;13(8):

Authors: El-Khatib L, Alrayes H, Sallam O, Elbanna A

Abstract
Quinidine is one of the oldest antiarrhythmics known. Over the years, its use has decreased along with its side effects. Our case describes a 69-year-old woman with recurrent resistant ventricular tachycardia on Quinidine and Amiodarone who presented with acute liver toxicity. Drug-induced liver toxicity was at the top of our differential diagnosis list. Taking multiple factors into consideration, a decision was made to discontinue Quinidine, the patient's symptoms and lab abnormalities resolved within 1 week, yielding the diagnosis of Quinidine hypersensitivity.

PMID: 32843415 [PubMed - in process]

[Medicaments and oral healthcare. Adverse effects of medications on the oral mucosa].

Ned Tijdschr Tandheelkd. 2020 Jul-Aug;127(7-08):434-440

Authors: Rooijers W, Rademacher WHM, Raber-Durlacher JE, Aziz Y, Hielema AP, Rozema FR

Abstract
Many medications prescribed in the Netherlands have adverse effects on the oral mucosa. Adverse events often described are stomatitis, white lesions, abnormal pigmentation and sensibility disorders. Stomatitis is frequently observed in patients using medications for the treatment of malignancies or auto-immune diseases. Important causative classes of medicines are alkylating agents, anthracyclines, monoclonal antibodies, protein kinase inhibitors, purine derivatives, pyrimidine antagonists, taxanes and vinca alkaloids. White oral lesions often concern candidiasis and are frequently seen in patients using certain immunosuppressants and antibiotics. Abnormal pigmentation is frequently seen in patients using hydroxycarbamide, an antineoplastic agent. Sensibility disorders of the oral mucosa are described in several classes of medications, including protein kinase inhibitors. It is very important oral healthcare professionals can recognise possible adverse effects of medications on the oral mucosa. When it is probable an anomaly of the oral mucosa is caused by medication, the oral healthcare professional should contact the prescribing physician to discuss the possibility of adjusting or discontinuing the medication.

PMID: 32840499 [PubMed - indexed for MEDLINE]

Targeting gap junctional intercellular communication by hepatocarcinogenic compounds.

J Toxicol Environ Health B Crit Rev. 2020 08 17;23(6):255-275

Authors: Leroy K, Pieters A, Tabernilla A, Cooreman A, Van Campenhout R, Cogliati B, Vinken M

Abstract
Gap junctions in liver, as in other organs, play a critical role in tissue homeostasis. Inherently, these cellular constituents are major targets for systemic toxicity and diseases, including cancer. This review provides an overview of chemicals that compromise liver gap junctions, in particular biological toxins, organic solvents, pesticides, pharmaceuticals, peroxides, metals and phthalates. The focus in this review is placed upon the mechanistic scenarios that underlie these adverse effects. Further, the potential use of gap junctional activity as an in vitro biomarker to identify non-genotoxic hepatocarcinogenic chemicals is discussed.

PMID: 32568623 [PubMed - indexed for MEDLINE]

Long-Term Evaluation of Low-Dose Betamethasone for Ataxia Telangiectasia.

Pediatr Neurol. 2019 11;100:60-66

Authors: Hasegawa S, Kumada S, Tanuma N, Tsuji-Hosokawa A, Kashimada A, Mizuno T, Moriyama K, Sugawara Y, Shirai I, Miyata Y, Nishida H, Mashimo H, Hasegawa T, Hosokawa T, Hisakawa H, Uematsu M, Fujine A, Miyata R, Sakuma H, Kashimada K, Imai K, Morio T, Hayashi M, Mizutani S, Takagi M

Abstract
BACKGROUND: Ataxia telangiectasia is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectases, immune defects, and a predisposition to malignancy. Quality of life is severely impaired by neurological symptoms. However, curative options for the neurological symptoms are limited. Recent studies have demonstrated short-term improvement in neurological symptoms with betamethasone therapy. However, the long-term and adverse effects of betamethasone are unclear. The aim of this study was to evaluate the long-term effects, benefits, and adverse effects of low-dose betamethasone in ataxia telangiectasia.
METHODS: Six patients with ataxia telangiectasia received betamethasone at 0.02 mg/kg/day for two years. After cessation of betamethasone, the patients were observed for two additional years. Neurological assessments were performed, and adverse effects were monitored every three months throughout the four-year study period.
RESULTS: Transient improvement of neurological symptom was observed in five of the six patients. However, after two years betamethasone treatment, only one of the six patients showed a slight improvement in the neurological score, one patient showed no change, and the neurological scores of the remaining four patients deteriorated. After the cessation of betamethasone treatment, neurological symptoms worsened in all patients. As an adverse effect of betamethasone, transient adrenal dysfunction was observed in all cases.
CONCLUSIONS: Although these findings are in agreement with previous studies suggesting that short-term betamethasone treatment transiently benefits patients with ataxia telangiectasia, the long-term benefits and risks should be carefully considered.

PMID: 31272782 [PubMed - indexed for MEDLINE]

Combined Therapy for Alzheimer's Disease: Tacrine and PAMAM Dendrimers Co-Administration Reduces the Side Effects of the Drug without Modifying its Activity.

AAPS PharmSciTech. 2020 Mar 25;21(3):110

Authors: Igartúa DE, Martinez CS, Del V Alonso S, Prieto MJ

Abstract
Alzheimer's disease has become a public health priority, so an investigation of new therapies is required. Tacrine (TAC) was licensed for treatments; however, its oral administration caused hepatotoxicity, so it is essential to reduce the side effects. PAMAM dendrimer generation 4.0 and 4.5 (DG4.0 and DG4.5) can be used as drug delivery systems and as nanodrugs per se. Our work aims to propose a combined therapy based on TAC and PAMAM dendrimer co-administration. TAC and dendrimer interactions were studied by in vitro drug release, drug stability, and FTIR. The toxicity profile of co-administration was evaluated in human red blood cells, in Neuro-2a cell culture, and in zebrafish larvae. Also, the anti-acetylcholinesterase activity was studied in cell culture. It was possible to obtain DG4.0-TAC and DG4.5-TAC suspensions, without reducing the drug solubility and stability. FTIR and in vitro release studies confirmed that interaction between TAC and DG4.5 was of the electrostatic type. No toxicity effects on human red blood cells were observed, whereas the co-administration with DG4.5 reduced cytotoxicity of TAC on the Neuro-2a cell line. Moreover, in vivo co-administration of both DG4.0-TAC and DG4.5-TAC reduced the morphological and hepatotoxic effects of TAC in zebrafish larvae. The reduction of TAC toxicity was not accompanied by a reduction in its activity since the anti-acetylcholinesterase activity remains when it is co-administrated with dendrimers. In conclusion, the co-administration of TAC with both DG4.0 and DG4.5 is a novel therapy since it was less-toxic, was more biocompatible, and has the same effectiveness than the free drug. Graphical abstract.

PMID: 32215751 [PubMed - indexed for MEDLINE]

Update on penicillin allergy delabeling.

Curr Opin Pediatr. 2020 04;32(2):321-327

Authors: Shaker M, McWilliams S, Greenhawt M

Abstract
PURPOSE OF REVIEW: To review phenotyping and risk classification of penicillin allergy and provide an update on penicillin allergy delabeling strategies for primary care.
RECENT FINDINGS: Beta-lactams are considered the treatment of choice for a wide range of bacterial pathogens; however, many patients receive second-line agents due to being labeled as having an allergy to penicillin. This approach can lead to antibiotic resistance and inferior health outcomes. While 10% of the population is labeled as penicillin allergic, penicillin anaphylaxis occurs in less than 1% of patients. For patients with delayed benign skin rashes (e.g., urticaria or maculopapular exanthem >1 h after administration) attributable to beta-lactam administration occurring more than 12 months ago, direct oral challenge (rechallenge with antibiotic in the clinical setting) can be a safe and effective strategy, with immediate reactions occurring in less than 5% of such low-risk patients and delayed reactions appearing infrequently. In patients with penicillin-associated immediate urticaria, other IgE-mediated features, or anaphylaxis, further allergy evaluation and penicillin skin testing is warranted. Any severe idiosyncratic cutaneous adverse reaction is rare, but can be dangerous so prompt removal of the inciting agent is required.
SUMMARY: Penicillin allergy delabeling is a high-value service that can be effectively delivered through a multidisciplinary collaborative approach.

PMID: 32068593 [PubMed - indexed for MEDLINE]

Management of toxicity to isoform α-specific PI3K inhibitors.

Ann Oncol. 2019 12;30 Suppl 10:x21-x26

Authors: Nunnery SE, Mayer IA

Abstract
Alterations in the phosphoinositide 3-kinase (PI3K)/AKT pathway are frequently found in cancer and are especially common in breast cancer, where it is estimated that 70% of tumors have some type of genetic alteration that could lead to pathway hyperactivation. A variety of PI3K pathway inhibitors have been developed in an attempt to target this pathway and improve cancer control. One of the challenges in treating patients with PI3K/AKT pathway inhibitors is the associated toxicity from on-target and off-target effects. Such side-effects are common, but reversible, and include hyperglycemia, rash, stomatitis, diarrhea, nausea, and fatigue. As a result, dose reductions, treatment delays, and treatment discontinuation are frequently reported. This impairs not only patients' quality of life but also treatment efficacy. Most side-effects are reversible with drug interruption, since these drugs typically have a short half-life and are manageable with early intervention. An interdisciplinary approach with proactive management of patients receiving PI3K pathway inhibitors should include comprehensive education of patients about the range of toxicities, frequent monitoring, early toxicity recognition, active intervention, as well as prophylactic strategies.

PMID: 31928691 [PubMed - indexed for MEDLINE]

HLADQA1*05 genotype predicts anti-drug antibody formation and loss of response during infliximab therapy for inflammatory bowel disease.

Aliment Pharmacol Ther. 2020 02;51(3):356-363

Authors: Wilson A, Peel C, Wang Q, Pananos AD, Kim RB

Abstract
BACKGROUND: Anti-drug antibodies (ADAs) are a leading contributor to infliximab loss of response and adverse drug events. It is not feasible to identify patients at risk of antibody formation before initiating infliximab. The genetic variation HLADQA1*05 (rs2097432) has been linked to infliximab antibody formation in Crohn's disease (CD).
AIMS: To evaluate the association between HLADQA1*05 and infliximab antibody formation, infliximab loss of response, treatment discontinuation and adverse drug events in patients with inflammatory bowel disease (IBD) METHODS: In a retrospective cohort study, infliximab-exposed patients with IBD (n = 262) were screened for the genetic variation, HLADQA1*05A>G (rs2097432). Risk of infliximab ADA formation, infliximab loss of response, adverse events and discontinuation were assessed in wild-type (GG) and variant-carrying (AG or AA) individuals.
RESULTS: Forty per cent of all participants were HLADQA1*05A>G variant carriers, with 79% of participants with infliximab antibodies carrying at least one variant allele. The risk of infliximab antibody formation was higher in HLADQA1*05A>G variant carriers (adjusted HR = 7.29, 95% confidence interval (CI) = 2.97-17.191, P = 1.46 × 10-5 ) independent of age, sex, weight, dose and co-immunosuppression with an immunomodulator. Variant carrier status was associated with an increased risk of infliximab loss of response (adjusted HR = 2.34, 95% CI = 1.41-3.88, P = .001) and discontinuation (adjusted HR = 2.27, 95% CI = 1.46-3.43, P = 2.53 × 10-4 ) although not with infliximab-associated adverse drug events.
CONCLUSIONS: HLADQA1*05 is independently associated with a high risk of infliximab antibody formation in addition to infliximab loss of response and treatment discontinuation. There may be a role for genotype-guided application of combination therapy in IBD.

PMID: 31650614 [PubMed - indexed for MEDLINE]

Drug-related problems with targeted/immunotherapies at an oncology outpatient clinic.

J Oncol Pharm Pract. 2020 Apr;26(3):595-602

Authors: Kucuk E, Bayraktar-Ekincioglu A, Erman M, Kilickap S

Abstract
BACKGROUND: Some studies in the literature describe drug-related problems in patients with cancer, although few studies focused on patients receiving targeted chemotherapy and/or immunotherapy. To identify the incidence of drug-related problems in patients receiving targeted chemotherapy and/or immunotherapy, and demonstrate the impact of a clinical pharmacist in an outpatient oncology care setting.
METHODS: Prospective study was conducted in a hospital outpatient oncology clinic between October 2015 and March 2016. Patients greater than 18 years old receiving cetuximab, nivolumab, ipilimumab, or pembrolizumab were included in the study and monitored over a three-month period by a clinical pharmacist. Drug-related problems were analyzed using the Pharmaceutical Care Network Europe classification system. The main outcome measures were the frequency and causes of drug-related problems and the degree of resolution achieved through the involvement of a clinical pharmacist.
RESULTS: A total of 54 patients (mean age: 57 ± 12 years) were included. There were 105 drug-related problems and 159 associated causes. Among the planned interventions (n = 149), 92 interventions were at the patient-level with 88 (96%) being accepted by the doctors. This resulted in 68 (65%) drug-related problems being completely resolved and 9 (8.6%) being partially resolved. The most common drug-related problem identified was "adverse drug event" (n = 38, 36%). Of the 105 drug-related problems, 63 (60%) related to targeted chemotherapy and/or immunotherapy with 34 (54%) classified as an "adverse drug event."
CONCLUSION: Adverse drug events were the most common drug-related problems in patients with cancer. The involvement of a clinical pharmacist improved the identification of drug-related problems and helped optimize treatment outcomes in patients receiving targeted chemotherapy/immunotherapy.

PMID: 31342849 [PubMed - indexed for MEDLINE]

Pharmacologic Management of Common Ailments in Women Who Are Breastfeeding.

J Midwifery Womens Health. 2019 Nov;64(6):703-712

Authors: Dogruluk AA

Abstract
According to the Centers for Disease Control and Prevention, the rate of breastfeeding in the United States has increased 34% between 2005 and 2015. Women who breastfeed can require treatment of various common illnesses. When caring for women who are breastfeeding, health care providers may unnecessarily discourage them from breastfeeding during treatment. Choosing the appropriate medications for these individuals is critical to ensure the woman is effectively treated, infant exposure to medication is minimized, and the breastfeeding relationship is preserved. This article provides an overview of essential principles for prescribing medications for women who are lactating. Recommendations for the management of common illnesses seen in the outpatient setting are suggested and resources that can help guide therapeutic decision making are offered.

PMID: 31287225 [PubMed - indexed for MEDLINE]

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("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

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PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

A pilot study of lenalidomide maintenance therapy after autologous transplantation in relapsed or refractory classical Hodgkin lymphoma.

Biol Blood Marrow Transplant. 2020 Aug 20;:

Authors: Shea L, Watkins MP, Wan F, Cashen A, Wagner-Johnston N, Jacoby M, Abboud C, Dipersio J, Hurd D, Jaglowski S, Bartlett NL, Fehniger T

Abstract
For patients with relapsed or refractory classical Hodgkin lymphoma (cHL), salvage chemotherapy followed by consolidation with autologous stem cell transplant (ASCT) remains the standard of care. Even with this aggressive treatment strategy, 5-year progression-free survival is ≤ 50%, and there remains interest in maintenance strategies to improve long-term disease-free survival. Lenalidomide is an immunomodulatory agent with demonstrated activity in multiple subtypes of lymphoma including cHL, and has also been shown to improve both progression free and overall survival as maintenance therapy after ASCT in multiple myeloma. This multicenter study evaluated maintenance lenalidomide after ASCT for patients with cHL. Patients were enrolled 60-90 days post-transplant and received oral lenalidomide on days 1-28 of 28-day cycles for a maximum of 18 cycles. Lenalidomide was started at 15 mg daily and increased to maximum of 25 mg daily if tolerated. The primary objective of this study was to assess the feasibility of this regimen, with a goal < 30% rate of discontinuation at or before cycle 12 for drug-related reasons. Twenty-seven patients were enrolled and 26 received at least one dose of lenalidomide. With a median follow-up of 51.3 months (range 12.2 - 76.2 months), 23 of 26 patients were alive. Median event-free survival was 9.4 months and median progression free survival had not been reached, with 17 of 26 patients (65.4%) remaining in remission at last follow-up. Excluding four patients who discontinued therapy for progression and two who discontinued due to non-compliance, the discontinuation rate at or before cycle 12 was 52%. Treatment was complicated by a high frequency of hematologic adverse events, with 15 patients (58%) experiencing grade 3-4 hematologic toxicity and 5 (19%) experiencing grade 4 hematologic toxicity. We conclude that the regimen of maintenance lenalidomide explored in this study is not feasible for cHL patients immediately following ASCT. An alternative lenalidomide dose or schedule may be better tolerated following ASCT for patients with rel/ref cHL.

PMID: 32829079 [PubMed - as supplied by publisher]