Chemotherapy-related damage to ovarian reserve in childhood cancer survivors: interpreting the evidence.

J Assist Reprod Genet. 2019 Feb;36(2):341-348

Authors: Somigliana E, Terenziani M, Filippi F, Bergamini A, Martinelli F, Mangili G, Peccatori F, Vercellini P

Abstract
Chemotherapy during childhood damages ovarian reserve and can affect future fertility. However, recent large epidemiological studies showed that the detrimental impact on fertility is less severe if women seek for pregnancy at a younger age. To explain this observation, we hypothesize that the detrimental effects of previous chemotherapy on the ovarian reserve may be attenuated in young adults for two main reasons. Firstly, recent evidence showed that the amount of ovarian reserve is not a critical factor for effective natural conceptions. Provided that the residual ovarian reserve allows regular ovulatory cycles, the chances of pregnancy are similar in women with intact or reduced ovarian reserve. Secondly, ovarian reserve depletion appears to be a phenomenon that is inversely related to the residual ovarian reserve rather than to age. From a mathematical perspective, this kind of regulation intrinsically attenuates the effects of an early loss of a significant amount of primordial follicles. In conclusion, the detrimental effects of chemotherapy on natural fertility may be less severe if women with a history of chemotherapy during childhood seek for pregnancy early. This information should be part of the counseling.

PMID: 30362055 [PubMed - indexed for MEDLINE]

What occurs in the other 20% of cancer patients with chemotherapy-induced nausea and vomiting (CINV)? A single-institution qualitative study.

Support Care Cancer. 2019 Jan;27(1):249-255

Authors: Childs DS, Looker S, Le-Rademacher J, Ridgeway JL, Breitkopf CR, Jatoi A

Abstract
PURPOSE: Despite recent advances in prophylaxis and management, 20% of patients who receive moderately to severely emetogenic chemotherapy continue to experience nausea and vomiting. Relying on patients' own words, this study sought to capture and characterize the lived experience with chemotherapy-induced nausea and vomiting (CINV) for this important subgroup of patients.
METHODS: Solid tumor patients with a history of poorly controlled CINV provided informed consent and participated in a semi-structured interview, which was audio-recorded and transcribed. After data saturation, enrollment ceased, and inductive, qualitative analytic methods were employed.
RESULTS: The median age of the 20 enrolled patients was 56 years (range 27-83) with an equal gender split; half had gastrointestinal cancers. Two themes emerged. First, CINV is severe and multidimensional: "It's like shredding your muscles… It's doing it over and over again." This symptom complex has psychosocial implications: "Isolation is a big thing." Financial toxicity is also implicated: "I use [an antiemetic] when I feel like it is absolutely necessary because it is so expensive I cannot afford it anyway." The second theme is underreporting of symptoms. Patients seemed to accept N/V as part of treatment and were therefore less forthcoming: "God, if you're pumping poison in your system, you gotta expect some side effects."
CONCLUSIONS: These vivid data should motivate investigators to continue conducting clinical trials CINV and should remind healthcare providers about the importance of patient education on the availability of therapy for breakthrough symptomatology.

PMID: 29938306 [PubMed - indexed for MEDLINE]

Patient-reported treatment-related symptom burden for patients with advanced melanoma in Canada.

Support Care Cancer. 2019 Jan;27(1):219-227

Authors: Cheung WY, White MK, Bayliss MS, Stroupe A, Lovley A, King-Kallimanis BL, Lasch K

Abstract
BACKGROUND: Little is known on the impact of emerging treatments for advanced melanoma (stages III and IV) on patients' functioning and well-being. The objective of this study was to describe the patient-reported treatment-related symptom (TRS) burden in advanced melanoma.
METHOD: Twenty-nine in-depth, qualitative interviews were conducted among adult patients with advanced melanoma in Canada using a semi-structured interview method. Interviews were transcribed verbatim, and key concepts were identified using a grounded theory analytic approach.
RESULTS: The 29 patients reported 13 unique treatment journeys involving the following drug therapy categories: cytotoxic chemotherapies, CTLA-4 inhibitors, BRAF or MEK inhibitors, and PD-1 inhibitors. Patients typically underwent multiple treatment episodes over time. Common TRSs included nausea, fatigue, diarrhea or constipation, and skin rashes. Patients described these as impacting their physical functioning, ability to perform activities of daily living, social functioning, and overall quality of life.
CONCLUSION: Our findings provide a description of the patient's experience with treatment for advanced melanoma. Our sample included patients typically diagnosed in mid-life, facing an urgent sequence of medical procedures and a pharmacological treatment journey that was burdensome. There is a need for less toxic and more efficacious treatments earlier in the patient journey to alleviate the impact of advanced melanoma treatment on patients' health-related quality of life.

PMID: 29934684 [PubMed - indexed for MEDLINE]

What is the epidemiology of medication errors, error-related adverse events and risk factors for errors in adults managed in community care contexts? A systematic review of the international literature.

BMJ Open. 2018 05 05;8(5):e019101

Authors: Assiri GA, Shebl NA, Mahmoud MA, Aloudah N, Grant E, Aljadhey H, Sheikh A

Abstract
OBJECTIVE: To investigate the epidemiology of medication errors and error-related adverse events in adults in primary care, ambulatory care and patients' homes.
DESIGN: Systematic review.
DATA SOURCE: Six international databases were searched for publications between 1 January 2006 and 31 December 2015.
DATA EXTRACTION AND ANALYSIS: Two researchers independently extracted data from eligible studies and assessed the quality of these using established instruments. Synthesis of data was informed by an appreciation of the medicines' management process and the conceptual framework from the International Classification for Patient Safety.
RESULTS: 60 studies met the inclusion criteria, of which 53 studies focused on medication errors, 3 on error-related adverse events and 4 on risk factors only. The prevalence of prescribing errors was reported in 46 studies: prevalence estimates ranged widely from 2% to 94%. Inappropriate prescribing was the most common type of error reported. Only one study reported the prevalence of monitoring errors, finding that incomplete therapeutic/safety laboratory-test monitoring occurred in 73% of patients. The incidence of preventable adverse drug events (ADEs) was estimated as 15/1000 person-years, the prevalence of drug-drug interaction-related adverse drug reactions as 7% and the prevalence of preventable ADE as 0.4%. A number of patient, healthcare professional and medication-related risk factors were identified, including the number of medications used by the patient, increased patient age, the number of comorbidities, use of anticoagulants, cases where more than one physician was involved in patients' care and care being provided by family physicians/general practitioners.
CONCLUSION: A very wide variation in the medication error and error-related adverse events rates is reported in the studies, this reflecting heterogeneity in the populations studied, study designs employed and outcomes evaluated. This review has identified important limitations and discrepancies in the methodologies used and gaps in the literature on the epidemiology and outcomes of medication errors in community settings.

PMID: 29730617 [PubMed - indexed for MEDLINE]

Usability of mepolizumab single-use prefilled syringe for patient self-administration.

J Asthma. 2019 Apr 24;:1-10

Authors: Bel EH, Bernstein DI, Bjermer L, Follows R, Bentley JH, Pouliquen I, Bradford E

Abstract
OBJECTIVE: A liquid mepolizumab formulation in a single-use prefilled syringe (PFS) is under development. We evaluated the usability of mepolizumab self-injected via PFS by patients with severe eosinophilic asthma (SEA), or their caregivers, in clinic and at home.
METHODS: This open-label, single-arm, Phase IIIa study included patients with SEA, aged ≥12 years, and receiving mepolizumab (100 mg subcutaneously) every 4 weeks for ≥12 weeks prior to screening. Patients with SEA not receiving mepolizumab at screening who met additional criteria were also included. Patients/caregivers self-administered mepolizumab (100 mg subcutaneously) via PFS every 4 weeks for 12 weeks. The first (Week 0) and third (Week 8) dose were observed in clinic; the second dose (Week 4) was unobserved at home. Primary and secondary endpoints were the proportion of patients who successfully self-administered their third and second doses, respectively. Injection success was determined by investigator/site staff. Patient experience, mepolizumab trough concentrations, blood eosinophil counts, and safety were also assessed.
RESULTS: Of the 56 patients/caregivers who self-administered ≥1 dose of mepolizumab, 55 completed the study. All patients were reported to have successfully self-administered their third mepolizumab dose in clinic (N = 55, 100%); this was further evidenced by trough concentrations/blood eosinophil counts. Most patients/caregivers found the PFS easy and convenient to use with 75% (n = 42) expressing little/no anxiety about using the device at home. Incidence of on-treatment drug-related adverse events was low (4%); none were fatal.
CONCLUSIONS: Patients/caregivers successfully self-administered mepolizumab via the PFS both in clinic and at home, with no new safety concerns identified.

PMID: 31017022 [PubMed - as supplied by publisher]

Anaemia in heart failure patients: the prevalence of haematinic deficiencies and the role of ACE inhibitors and aspirin doses as risk factors.

Pharm Pract (Granada). 2019 Jan-Mar;17(1):1406

Authors: Guirguis K

Abstract
Background: Patients with heart failure often have comorbidities that alter the progression of heart failure and impact on prognosis. One such comorbidity is anaemia, and clinicians have started to appreciate the full gravity of its impact on heart failure patients. Yet, the extent of the problem is not fully understood, particularly the role of heart failure therapy itself as a risk factor for developing anaemia.
Objective: This study aimed to investigate the prevalence of anaemia in a cohort of heart failure patients. The impact of using different ACEIs and different doses of aspirin was also explored, together with the prevalence of haematinic deficiencies.
Methods: Medication lists and pathology results were examined to establish the prevalence of ACEIs use, and the use of aspirin at its most common doses of 100mg and 150mg, together with haematinic deficiencies. Multinomial logistic regression and the Student's t-test were utilised for the analysis of data. Statistical significance was pre-set at p<0.05.
Results: Ninety-six patients were eligible for analysis, with 26% having anaemia. The use of ACEIs had a RR of 17.4 for the presence of anaemia. Perindopril was associated with a RR of 20.8, while the use of ramipril was not significantly associated with such a high RR. Haematinic anaemia occurred only at a rate of 3.3%, but borderline deficiencies were found in more than a third of all patients. An aspirin dose of 150mg was associated with a higher risk for anaemia, compared to a dose of 100mg.
Conclusions: ACEIs are associated with the presence of anaemia, with perindopril posing more risk than ramipril when used in heart failure patients. The dose of aspirin may also be a factor in the development of anaemia, with lower doses being safer. Despite the lack of high prevalence of haematinic anaemia among this cohort of patients, borderline haematinic deficiencies were common.

PMID: 31015880 [PubMed]

Role of epigenetic mechanisms in cisplatin-induced toxicity.

Crit Rev Oncol Hematol. 2019 May;137:131-142

Authors: Quintanilha JCF, Saavedra KF, Visacri MB, Moriel P, Salazar LA

Abstract
Cisplatin (CDDP) is a highly effective antineoplastic agent, widely used in the treatment of various malignant tumors. However, its major problems are side effects associated to toxicity. Considerable inter-individual differences have been reported for CDDP-induced toxicity due to genetic and epigenetic factors. Genetic causes are well described; however, epigenetic modifications are not fully addressed. In the last few years, many evidences were found linking microRNA to the development of CDDP-mediated toxicity, particularly nephrotoxicity. In this review, we described how genetic and epigenetic modifications can be important determinants for the development of toxicity in patients treated with CDDP, and how these alterations may be interesting biomarkers for monitoring toxicity induced by CDDP. Considering the validation in different studies, we suggest that miR-34a, -146b, -378a, -192, and -193 represent an attractive study group to evaluate potential biomarkers to detect CDDP-related nephrotoxicity.

PMID: 31014509 [PubMed - in process]

Gut Reactions: Breaking Down Xenobiotic-Microbiome Interactions.

Pharmacol Rev. 2019 04;71(2):198-224

Authors: Clarke G, Sandhu KV, Griffin BT, Dinan TG, Cryan JF, Hyland NP

Abstract
The microbiome plays a key role in health and disease, and there has been considerable interest in therapeutic targeting of the microbiome as well as mining this rich resource in drug discovery efforts. However, a growing body of evidence suggests that the gut microbiota can itself influence the actions of a range of xenobiotics, in both beneficial and potentially harmful ways. Traditionally, clinical studies evaluating the pharmacokinetics of new drugs have mostly ignored the important direct and indirect effects of the gut microbiome on drug metabolism and efficacy. Despite some important observations from xenobiotic metabolism in general, there is only an incomplete understanding of the scope of influence of the microbiome specifically on drug metabolism and absorption, and how this might influence systemic concentrations of parent compounds and toxic metabolites. The significance of both microbial metabolism of xenobiotics and the impact of the gut microbiome on host hepatic enzyme systems is nonetheless gaining traction and presents a further challenge in drug discovery efforts, with implications for improving treatment outcomes or counteracting adverse drug reactions. Microbial factors must now be considered when determining drug pharmacokinetics and the impact that an evolving and dynamic microbiome could have in this regard. In this review, we aim to integrate the contribution of the gut microbiome in health and disease to xenobiotic metabolism focusing on therapeutic interventions, pharmacological drug action, and chemical biotransformations that collectively will have implications for the future practice of precision medicine.

PMID: 30890566 [PubMed - indexed for MEDLINE]

Management of adverse effects/toxicity of ibrutinib.

Crit Rev Oncol Hematol. 2019 Apr;136:56-63

Authors: Paydas S

Abstract
Bruton tyrosine kinase signaling (BTK) is critical step for B-cell development and immunoglobulin synthesis. Ibrutinib is an orally bioavailable bruton tyrosine kinase inhibitor (BTKi) and forms an irreversible covalent bound to BTK at the Cysteine-481 residue. Ibrutinib has been approved by FDA for the treatment of mantle cell lymphoma, chronic lymphocytic leukemia, Waldenstrom's macroglobulinemia, marginal zone lymphoma and chronic graft-versus-host disease in allogeneic stem cell transplantation. Ibrutinib is generally well tolerated drug with rapid and durable responses but has some side events. The most common side effects are diarrhea, upper respiratory tract infection, bleeding, fatigue and cardiac side effects. These events are generally mild (grade I-II). However atrial fibrillation (AF) and bleeding are important and may be grade III or higher side effects require strict monitoring. Here side effects of ibrutinib have been summarized and important considerations in the management of these adverse events have been reviewed.

PMID: 30878129 [PubMed - indexed for MEDLINE]

Immunogenicity and Immune Complex Disease in Preclinical Safety Studies.

Toxicol Pathol. 2018 12;46(8):1013-1019

Authors: Vahle JL

Abstract
This article summarizes a continuing education presentation on immunogenicity that was part of a continuing education course entitled, "Clinical Pathology of Biotherapeutics." Immunogenicity of a biotherapeutic can have diverse impacts including altered systemic exposure and pharmacologic responses and, in a fraction of the cases, safety concerns including cross-reactive neutralization of endogenous proteins or sequela related to immune complex disease (ICD). In most cases, immune complexes are readily cleared from circulation; however, based on physiochemical properties, insoluble complexes form, activate complement, and deposit in tissues. Using published information and personal experience, a set of repeat-dose monkey toxicity studies with manifestations suggestive of ICD was reviewed to summarize the spectrum of clinical and pathology findings. The most common live-phase observation linked to ICD was an acute postdosing reaction following multiple dose administrations characterized by generalized collapse and attributed to acute complement activation. Less common live-phase observations were related to syndromes such as a consumptive coagulopathy or a protein losing nephropathy. The most common histologic change attributed to ICD was multi-organ vascular/perivascular inflammation followed by glomerulonephritis. The presentation concluded with a description of the challenges in assessing the relevance of immunogenicity-related reaction in monkey to human clinical use.

PMID: 30157708 [PubMed - indexed for MEDLINE]

Adjunctive Treatments for the Prevention of Chemotherapy- and Radiotherapy-Induced Mucositis.

Integr Cancer Ther. 2018 12;17(4):1027-1047

Authors: Thomsen M, Vitetta L

Abstract
BACKGROUND: Chemoradiotherapy-associated mucositis can manifest as pain, inflammation, dysphagia, diarrhea, weight loss, rectal bleeding, and infection. Mucositis is a major dose-limiting side effect of chemotherapy, affecting nutritional intake and oral and intestinal function. Despite several interventions being available, there is a need for safe and effective preventative and treatment options for treatment-induced mucositis. The goals of this review are to discuss interventions based on foods and natural products and present the research to date.
METHODS: A narrative literature review identified 60 clinical studies examining various nutritional compounds and 20 examining probiotics. 9 studies on probiotics for the prevention of diarrhea were also assessed on methodological quality and limitations identified.
RESULTS: Several compounds have been posited as useful adjuvants for cancer treatment-related mucositis. Probiotics demonstrate efficacy for the prevention and treatment of chemoradiotherapy-induced gastrointestinal toxicity without significant side effects. Glutamine and activated charcoal were reported to reduce chemotherapy-induced diarrhea but not radiation-induced intestinal mucositis. Honey has been reported to decrease treatment interruptions, weight loss, and delays the onset of oral mucositis. Zinc, glutamine, and topical vitamin E were demonstrated efficacy for oral mucositis.
CONCLUSION: There is plausible clinical evidence for the administration of several adjunctive treatments for the prevention and treatment of mucositis. Probiotics were reported to reduce the burden of intestinal mucositis and treatment-induced diarrhea. Activated charcoal and glutamine are beneficial for chemotherapy-induced diarrhea, whereas the administration of honey, zinc, and glutamine reduce the risk of developing oral mucositis during chemotherapy or radiotherapy.

PMID: 30136590 [PubMed - indexed for MEDLINE]

Compatibility of medication with PRISCUS criteria and identification of drug interactions in a large cohort of patients with COPD.

Pulm Pharmacol Ther. 2018 04;49:123-129

Authors: Graf J, Lucke T, Herrera R, Watz H, Holle R, Vogelmeier C, Ficker JH, Jörres RA

Abstract
Patients with COPD are often of advanced age and have a high number of medications due to their lung disease and comorbidities. Thus they are at risk for unwanted effects from drugs, either due to age or due to interactions between drugs. These issues are not clarified. We therefore assessed the number of medications and potential adverse effects in a large cohort of patients with COPD. The analysis was performed in 2741 patients of the German COPD cohort COSYCONET, using baseline data (visit 1) and follow-up data after about 1.5 years (visit 3). Spirometric GOLD grades 1-4 were found in 8/35/32/9% of patients and GOLD groups ABCD in 7/25/4/48% of patients, while the remaining patients (n = 450, 16.4%) could not be classified according to GOLD criteria. The compatibility of medication with age was evaluated via the PRISCUS list, drug interactions via the AiD clinic system, whereby only drug combinations occurring in at least 10 patients were considered (nine unwanted interactions, one wanted interaction). The median numbers of medications were 5 or more in all patient categories, among them 3 or more non-respiratory medications. In the total population there were 153 patients (10.2%) aged ≥65 years who had any medication of the PRISCUS list with intermediate or low risk. Serious adverse combinations of drugs according to AiD occurred in 114 patients (4.2%), while the number of unwanted but only potentially clinically relevant combinations was 175 (6.4%). The number of wanted combinations was 219 (8.0%). These numbers did not markedly change when restricting the analysis to patients of GOLD grades 1-4. Moreover, the results were similar for visit 1 and visit 3. We conclude that in a large cohort of COPD patients about 10% of patients aged at least 65 years had medications that could interfere with their age and that the proportions of patients with either unwanted or wanted drug interactions were both in the range of 8-10%. These results suggest that problems arising from the high number of medications were not very frequent in the COPD cohort analysed.

PMID: 29421666 [PubMed - indexed for MEDLINE]

Long-term safety of a weekly and monthly subcutaneous buprenorphine depot (CAM2038) in the treatment of adult outpatients with opioid use disorder.

Addiction. 2019 Apr 23;:

Authors: Frost M, Bailey GL, Lintzeris N, Strang J, Dunlop A, Nunes EV, Jansen JB, Frey LC, Weber B, Haber P, Oosman S, Kim S, Tiberg F

Abstract
AIMS: To assess long-term safety of subcutaneous buprenorphine (CAM2038) weekly and monthly depots.
DESIGN: Phase 3, open-label, observational, multicentre 48-week trial (ClinicalTrials.gov NCT02672111).
SETTING: Twenty-six outpatient sites (US, UK, Hungary, Denmark, Sweden, Germany, Australia) between December 14, 2015, and April 12, 2017.
PARTICIPANTS: Two hundred and twenty-eight adults with opioid use disorder, 227 received CAM2038 (37 initiated onto CAM2038 and 190 converted from sublingual buprenorphine).
INTERVENTIONS: CAM2038 weekly (8, 16, 24, or 32 mg) or monthly (64, 96, 128, or 160 mg) with flexible dosing and individualised titration utilising multiple CAM2038 weekly and monthly doses.
MEASUREMENTS: Safety variables, urine toxicology samples, and self-reported illicit opioid use were collected at each visit. Participants were administered a patient satisfaction survey at months 6 and 12 completed by 162/227 (71.4%) of participants.
FINDINGS: The study treatment period was completed by 167/227 (73.6%) participants. At least 1 treatment emergent adverse event (TEAE) was reported by 143/227 (63.0%) participants of which 60/227 (26.4%) reported as drug-related. Most of the TEAEs, reported by 128/227 (56.4%) of participants, were mild or moderate in intensity. Injection site reactions were reported by 46/227 (20.3%) participants, with most (45/46 [97.8%]) reported as mild to moderate. Five participants (2.2%) discontinued study drug due to a TEAE, of which 2 cases (0.9%) were injection site related. No serious adverse events were attributed to study drug. At end of study, the percentage of opioid-negative urine tests combined with self-reports was 63.0% (17/37) in new-to-treatment participants and 82.8% (111/190) for participants converted from sublingual buprenorphine. Participants reported high levels of satisfaction with CAM2038.
CONCLUSIONS: Subcutaneous buprenorphine delivered weekly or monthly (CAM2038) was well-tolerated with a systemic safety profile consistent with the known profile of sublingual buprenorphine. CAM2038 weekly and monthly was associated with high retention rates and low levels of illicit opioid use throughout this study.

PMID: 31013390 [PubMed - as supplied by publisher]

Targeted Tumour Therapy Induced Papulopustular Rash and Other Dermatologic Side Effects: A Retrospective Study.

Cutan Ocul Toxicol. 2019 Apr 22;:1-27

Authors: Yalıcı-Armagan B, Tugrul Ayanoglu B, Demırdag HG

Abstract
BACKGROUND: Papulopustular rash is the most common cutaneous adverse effect during targeted tumour therapy particularly with epidermal growth factor receptor inhibitors (EGFRIs).
OBJECTIVE: To evaluate the adverse skin reactions, mainly papulopustular rash, caused by targeted tumour therapy.
MATERIALS AND METHODS: We retrospectively analyzed the data of patients who were diagnosed papulopustular rash due to targeted chemotherapeutic agents between January-2016 and August-2018. Demographic characteristics of the patients, the type of malignancy, chemotherapeutic agents causing papulopustular rash, clinical features and grade of the rash, treatment modalities used for the rash, other associated cutaneous adverse reactions and the need for dose-modification or discontinuation of the chemotherapy were recorded.
RESULTS: A total of 39 patients (26 males, 13 females) with a median age of 60 (range 32-86) years were included the study. EGFRIs such as erlotinib, lapatinib, cetuximab, and panitimumab were the main drugs causing papulopustular rash in 2 (5.1%), 3 (7.6%), 18 (46.1%), and 13 (33.3%) patients, respectively. Imatinib, bevacizumab in combination with oxaliplatin, and everolimus in combination with exemestan and goserelin were responsible in 3 patients. The most commonly affected area was the face (87.1%) followed by the trunk (56.4%), scalp (25.6%), and extremities (23%). The rash was recorded as grade 1, 2, and 3 in 18, 13, and 6 of the patients, respectively. Grade 3 rash was lead to dose interruptions in 5 (12.8%) patients with subsequent reintroduction at a lower dose in 4 (10.2%) of them and discontinuation of the therapy in one (2.5%) patient. Pruritus, xerosis, paronychia, increased growth of the eyelashes, mucositis, hand-foot syndrome, and symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) are the other skin toxicities associated with the targeted tumour therapy.
CONCLUSION: With the increasing use of targeted therapies, dermatologists are now confronted with the extensive spectrum of skin toxicities. Therefore, it is critical for dermatologists to be aware of these toxicities so as to develop the best approach without discontinuation of cancer therapy.

PMID: 31010330 [PubMed - as supplied by publisher]

Polypharmacy and drug-related problems among people living with HIV/AIDS: a single-center experience

Turk J Med Sci. 2019 Feb 11;49(1):222-229

Authors: Kara E, İnkaya AÇ, Aydın Haklı D, Demirkan K, Ünal S

Abstract
Background/aim: The HIV-infected population is aging, and the concomitant comorbidities increase the likelihood of polypharmacy. There is a scarcity of data for determining drug-related problems in people living with HIV/AIDS (PLWHA).
Materials and methods: This cross-sectional study was carried out between 1 September 2015 and 1 July 2016. All patients underwent a face-to-face interview with a clinical pharmacist. PCNE Classification V 7.0 was used classify incident drug-related problems (DRPs).
Results: The mean age of the patients was 40.4 ± 13.06 years. The rate of polypharmacy was 66.1% in patients with comorbidities and 12.3% in those without comorbidities (P < 0.001). DRPs were more prominent in older patients (46 vs. 37 years, P < 0.001), those with longer durations of antiretroviral therapy (ART) (45 vs. 27 months, P = 0.014), and those with lower education levels (P = 0.013). Receiving >3 ART drugs was associated with more DRPs in the logistic regression model (odds ratio: 8.299, 95% confidence interval: 1.924–35.803). Fifty-eight interventions were performed in 45 (24.9%) patients. Clinical pharmacist interventions were performed in 18.9% of patients without polypharmacy and in 38.9% of patients with polypharmacy (P < 0.001).
Conclusion: DRPs and polypharmacy are common among elderly PLWHA. More interventions are warranted to boost the quality of life in aging PLWHA.

PMID: 30761883 [PubMed - indexed for MEDLINE]

Does obtaining CYP2D6 and CYP2C19 pharmacogenetic testing predict antidepressant response or adverse drug reactions?

Psychiatry Res. 2019 01;271:604-613

Authors: Solomon HV, Cates KW, Li KJ

Abstract
Treatment non-response and adverse reactions are common in patients receiving antidepressants. Personalizing psychiatric treatment based on pharmacogenetic testing has been proposed to help clinicians guide antidepressant selection and dosing. This systematic literature review assesses the two most robustly studied drug-metabolizing enzymes, CYP2D6 and CYP2C19, and examines whether obtaining CYP2D6 and CYP2C19 testing can be used to predict antidepressant response or adverse drug reactions in order to improve clinical outcomes. In general, literature reviews published prior to 2013 indicated that results have been inconsistent linking CYP2D6 and CYP2C19 to antidepressant treatment outcomes, suggesting that more evidence is required to support the clinical implementation of genotyping to predict outcomes. We thus performed an extensive and systematic literature review, focusing on studies published from 2013 through 2018. Sixteen studies were found to be relevant. The results yielded inconsistent findings, suggesting that CYP2D6 and CYP2C19 testing may predict response in certain individuals, but it remains unclear if this will translate to improved clinical outcomes. Further research is required to determine when pharmacogenetic testing should be utilized and in which populations it is indicated. Randomized, controlled, prospective trials with adequate sample sizes would best clarify whether genotype-guided antidepressant selection will ultimately improve clinical outcomes.

PMID: 30554109 [PubMed - indexed for MEDLINE]

In Silico Pharmacoepidemiologic Evaluation of Drug-Induced Cardiovascular Complications Using Combined Classifiers.

J Chem Inf Model. 2018 05 29;58(5):943-956

Authors: Cai C, Fang J, Guo P, Wang Q, Hong H, Moslehi J, Cheng F

Abstract
Drug-induced cardiovascular complications are the most common adverse drug events and account for the withdrawal or severe restrictions on the use of multitudinous postmarketed drugs. In this study, we developed new in silico models for systematic identification of drug-induced cardiovascular complications in drug discovery and postmarketing surveillance. Specifically, we collected drug-induced cardiovascular complications covering the five most common types of cardiovascular outcomes (hypertension, heart block, arrhythmia, cardiac failure, and myocardial infarction) from four publicly available data resources: Comparative Toxicogenomics Database, SIDER, Offsides, and MetaADEDB. Using these databases, we developed a combined classifier framework through integration of five machine-learning algorithms: logistic regression, random forest, k-nearest neighbors, support vector machine, and neural network. The totality of models included 180 single classifiers with area under receiver operating characteristic curves (AUC) ranging from 0.647 to 0.809 on 5-fold cross-validations. To develop the combined classifiers, we then utilized a neural network algorithm to integrate the best four single classifiers for each cardiovascular outcome. The combined classifiers had higher performance with an AUC range from 0.784 to 0.842 compared to single classifiers. Furthermore, we validated our predicted cardiovascular complications for 63 anticancer agents using experimental data from clinical studies, human pluripotent stem cell-derived cardiomyocyte assays, and literature. The success rate of our combined classifiers reached 87%. In conclusion, this study presents powerful in silico tools for systematic risk assessment of drug-induced cardiovascular complications. This tool is relevant not only in early stages of drug discovery but also throughout the life of a drug including clinical trials and postmarketing surveillance.

PMID: 29712429 [PubMed - indexed for MEDLINE]

A rare case of cefepime-induced cholestatic liver injury.

Ci Ji Yi Xue Za Zhi. 2019 Apr-Jun;31(2):124-128

Authors: Liao PF, Wu YK, Huang KL, Chen HY

Abstract
Cefepime is widely used in the hospital setting, and only a few studies have reported neurotoxicity and nephrotoxicity as side effects of this drug. Herein, we present a 93-year-old man who exhibited features of cholestatic hepatitis including elevated blood transaminases and direct-form predominant bilirubin levels after administration of cefepime. Blood liver tests showed total recovery after discontinuing the offending agent. Cefepime was probable to cause drug-induced cholestatic hepatitis in our patient since the Roussel Uclaf Causality Assessment Method score for cefepime was 7. No drug interactions were likely according to the Drug Interaction Probability Scale for this patient. No similar cases of cholestatic drug-induced liver injury related to cefepime have been reported previously. Hence, this rare condition requires a high degree of clinical suspicion for prompt diagnosis and treatment.

PMID: 31007494 [PubMed]

A Comparative Analysis of the Safety Profile of Direct Oral Anticoagulants Using the FDA Adverse Event Reporting System.

Eur J Haematol. 2019 Apr 22;:

Authors: DeLoughery EP, Shatzel JJ

Abstract
INTRODUCTIO: Direct oral anticoagulants (DOACs) are being increasingly used. However, unlike warfarin, less is known regarding their long-term side effects. To better evaluate the rates of DOAC-related adverse events (AEs) on a population level we examined AEs reported to the FDA for three commonly used DOACs and warfarin.
METHODS: We evaluated the FDA Adverse Event Reporting System (FAERS) database, which compiles reported drug-related AEs from 1969 onwards. The safety profiles of the included drugs were assessed by comparing AEs per outpatient prescription and with proportional reporting ratios (PRR).
RESULTS: Rivaroxaban had the highest proportion of reported AEs. Most notably the rate for breakthrough venous thromboembolism (VTE) was higher than other DOACs. Dabigatran had the highest reported rated of ischemic stroke. When the DOAC data was analyzed using PRR, reported rates of VTE were again higher with rivaroxaban while dabigatran again showed slightly higher than expected rates of ischemic stroke. Apixaban did not show higher than expected rates in any category.
CONCLUSION: Our analysis found rates of reported breakthrough VTE were significantly higher with rivaroxaban, while apixaban had no higher than expected rates of any studied AEs. This article is protected by copyright. All rights reserved.

PMID: 31009121 [PubMed - as supplied by publisher]

Immunogenicity and safety of the 4CMenB and MenACWY-CRM meningococcal vaccines administered concomitantly in infants: A phase 3b, randomized controlled trial.

Vaccine. 2018 Nov 29;36(50):7609-7617

Authors: Macias Parra M, Gentile A, Vazquez Narvaez JA, Capdevila A, Minguez A, Carrascal M, Willemsen A, Bhusal C, Toneatto D

Abstract
BACKGROUND: Invasive meningococcal disease has its highest incidence in infants. Co-administration of serogroup B (4CMenB) and quadrivalent conjugate (MenACWY-CRM) vaccines could protect against 5 clinically-relevant meningococcal serogroups.
METHODS: This phase 3b, open, multicenter study (NCT02106390), conducted in Mexico and Argentina, enrolled and randomized (1:1:1) 750 healthy infants to receive either 4CMenB co-administered with MenACWY-CRM (4CMenB/MenACWY group), 4CMenB (4CMenB group), or MenACWY-CRM alone (MenACWY group) at ages 3, 5, 7 and 13 months. Non-inferiority of immune responses of co-administration to single administration of vaccines was assessed at 1 month post-booster dose (primary objective). Immunogenicity was evaluated pre- and 1 month post-primary and booster vaccinations using human serum bactericidal assay (hSBA). Safety was assessed.
RESULTS: At 1 month post-booster vaccination, between-group hSBA geometric mean titer (GMT) ratios ranged from 0.89 to 1.03 for serogroup B strains (group 4CMenB/MenACWY over 4CMenB), and from 1.05 to 2.48 for ACWY serogroups (group 4CMenB/MenACWY over MenACWY). The lower limit of the 2-sided 95% confidence intervals for all GMT ratios was >0.5; the primary objective was demonstrated. Across all groups and serogroup B strains, 68-100% and 87-100% of children had hSBA titers ≥5 at 1 month post-primary and booster vaccination, respectively. For serogroups ACWY, ≥96% (post-primary vaccination) and ≥98% (post-booster vaccination) of children in all groups had hSBA titers ≥4. Post-booster vaccination, GMTs increased ≥5.99-fold from pre-booster values for each strain/serogroup. Solicited adverse events (AEs) were more frequent in groups 4CMenB/MenACWY and 4CMenB than in MenACWY; incidence of all other AEs was similar between groups. Serious AEs were reported for 6, 13, and 11 participants in groups 4CMenB/MenACWY, 4CMenB, and MenACWY, respectively; 1 (group 4CMenB) was considered vaccine-related.
CONCLUSION: Immune responses elicited by co-administration of 4CMenB and MenACWY-CRM was non-inferior to single immunization. Co-administration of vaccines was immunogenic and well tolerated in infants. ClinicalTrials.gov: NCT02106390.

PMID: 30414782 [PubMed - indexed for MEDLINE]