Safety and tolerability of intravenous regadenoson in healthy subjects: A randomized, repeat-dose, placebo-controlled study.

J Nucl Cardiol. 2017 Feb;24(1):57-65

Authors: Townsend R, Desai A, Rammelsberg D, Kowalski D, Simmons N, Kitt TM

Abstract
BACKGROUND: Regadenoson is a selective A2A adenosine receptor agonist indicated for radionuclide myocardial perfusion imaging in patients unable to undergo adequate exercise stress. However, the safety, tolerability, and plasma concentrations associated with repeated doses have not previously been assessed.
METHOD AND RESULTS: Healthy males and females were randomized to receive intravenous regadenoson [100 μg (3 doses), 200 μg (3 doses), or 400 μg (2 doses)], or placebo (2 or 3 doses; 0.9% sodium chloride); all doses 10 minutes apart. The primary endpoint was vital sign measurements (blood pressure and heart rate). Secondary endpoints included 12-lead electrocardiogram measurements, clinical laboratory evaluations (hematology, chemistry, and urinalysis), and adverse events. Thirty-six subjects were randomized and completed the study. Plasma concentrations of regadenoson increased in a dose-related manner and with successive doses. No consistent effect was observed for systolic blood pressure, although diastolic blood pressure was slightly lower than placebo for all regadenoson groups. Transient, dose-dependent increases in heart rate were observed in all regadenoson groups. There were no serious adverse events; 27 adverse events occurred in 14 regadenoson-treated subjects vs two events in two placebo-treated subjects.
CONCLUSION: Repeated doses of regadenoson appeared to be safe and well tolerated in healthy subjects.

PMID: 26607361 [PubMed - indexed for MEDLINE]

Preventable ADRs leading to hospitalization - results of a long-term prospective safety study with 6,427 ADR cases focusing on elderly patients.

Expert Opin Drug Saf. 2018 Feb;17(2):125-137

Authors: Schmiedl S, Rottenkolber M, Szymanski J, Drewelow B, Siegmund W, Hippius M, Farker K, Guenther IR, Hasford J, Thuermann PA, German Net of Regional Pharmacovigilance Centers (NRPC)

Abstract
BACKGROUND: Studies evaluating the impact of age and potentially inappropriate medication (PIM) on avoidable adverse drug reactions (ADRs) are scarce.
METHODS: In this prospective, multi-center, long-term (8.5 years) observational study, we analysed ADRs leading to hospitalization in departments of internal medicine. ADRs causality and preventability were assessed using standardised algorithms. PIM was defined based on the PRISCUS-list. Multivariate analyses and estimation of ADR incidence rates were conducted.
RESULTS: Of all 6,427 ADR patients, a preventable ADR was present in 1,253 (19.5%) patients (elderly patients ≥70 years: 828). Risk factors for preventable ADRs in elderly patients were multimorbidity, two to four ADR-causative drugs, and intake of particular compounds (e.g. spironolactone) but not sex, PIM usage, or the total number of drugs. Regarding particular compounds associated with preventable ADRs, highest incidence rates for preventable ADRs were found for patients aged ≥70 years for spironolactone (3.3 per 1,000 exposed persons (95% CI: 1.4-6.6)) and intermediate-acting insulin (3.3 per 1,000 exposed persons (95% CI: 1.6-6.1)).
CONCLUSION: Avoiding PIM usage seems to be of limited value in increasing safety in elderly patients whereas our results underline the importance of an individualized medication review of the most commonly implicated drugs in preventable ADRs (supported by BfArM FoNr: V-11337/68605/2008-2010).

PMID: 29258401 [PubMed - indexed for MEDLINE]

New and incremental FDA black box warnings from 2008 to 2015.

Expert Opin Drug Saf. 2018 Feb;17(2):117-123

Authors: Solotke MT, Dhruva SS, Downing NS, Shah ND, Ross JS

Abstract
BACKGROUND: The boxed warning (also known as 'black box warning [BBW]') is one of the strongest drug safety actions that the U.S. Food & Drug Administration (FDA) can implement, and often warns of serious risks. The objective of this study was to comprehensively characterize BBWs issued for drugs after FDA approval.
METHODS: We identified all post-marketing BBWs from January 2008 through June 2015 listed on FDA's MedWatch and Drug Safety Communications websites. We used each drug's prescribing information to classify its BBW as new, major update to a preexisting BBW, or minor update. We then characterized these BBWs with respect to pre-specified BBW-specific and drug-specific features.
RESULTS: There were 111 BBWs issued to drugs on the US market, of which 29% (n = 32) were new BBWs, 32% (n = 35) were major updates, and 40% (n = 44) were minor updates. New BBWs and major updates were most commonly issued for death (51%) and cardiovascular risk (27%). The new BBWs and major updates impacted 200 drug formulations over the study period, of which 64% were expected to be used chronically and 58% had available alternatives without a BBW.
CONCLUSIONS: New BBWs and incremental updates to existing BBWs are frequently added to drug labels after regulatory approval.

PMID: 29215916 [PubMed - indexed for MEDLINE]

First experiences with a tool to measure the level of clinical information present in adverse drug reaction reports.

Expert Opin Drug Saf. 2018 Feb;17(2):111-115

Authors: Oosterhuis I, Rolfes L, Ekhart C, Muller-Hansma A, Härmark L

Abstract
BACKGROUND: To make a proper causality assessment of an adverse drug reaction (ADR) report, a certain level of clinical information is necessary. A tool was developed to measure the level of clinical information present in ADR reports. The aim of this study was to test the validity and reliability of the clinical documentation tool (ClinDoc) in an international setting.
METHODS: The tool was developed by a panel of pharmacovigilance experts. It includes four domains: ADR, chronology of the ADR, suspected drug and patient characteristics. The final score categorizes reports into: excellent, well, moderately or poorly documented. In two rounds, eight pharmacovigilance assessors of different countries made a total of 224 assessments using the tool, with the expert panels judgement as a standard. Sensitivity and specificity were calculated.
RESULTS: The tool with four outcome-categories demonstrated low sensitivity. A lack of distinctiveness was demonstrated between the categories moderate and well. Results for the second round were re-analysed using three categories. This demonstrated a better validity.
CONCLUSION: This is the first tool to give insight in the level of relevant clinical information present in ADR reports. It can be used internationally to compare reports coming from different reporting methods and different types of reporters in pharmacovigilance.

PMID: 29157026 [PubMed - indexed for MEDLINE]

Immunotherapeutic strategies in non-small-cell lung cancer: the present and the future.

Immunotherapy. 2017 05;9(6):507-520

Authors: Steendam CM, Dammeijer F, Aerts JGJV, Cornelissen R

Abstract
Non-small cell lung cancer (NSCLC) is still the leading cause of cancer death worldwide, with a poor prognosis. In the era of immunotherapies, the field is rapidly changing, and the clinician needs to be aware of the current state and future perspectives of immunotherapeutic strategies. In this review, we discuss the current status of immune checkpoint inhibitors, cancer vaccines and cellular therapies specifically in NSCLC. Last but not least, we will discuss rational combination strategies that are promising for the near future.

PMID: 28472903 [PubMed - indexed for MEDLINE]

Risk Factors for Adverse Drug Reactions in Older Subjects Hospitalized in a Dedicated Dementia Unit.

Am J Geriatr Psychiatry. 2017 Mar;25(3):290-296

Authors: Kanagaratnam L, Dramé M, Novella JL, Trenque T, Joachim C, Nazeyrollas P, Jolly D, Mahmoudi R

Abstract
OBJECTIVE: To identify risk factors for the occurrence of adverse drug reactions (ADRs) based on geriatric evaluation.
DESIGN: Longitudinal prospective study from May 2010 to November 2011.
SETTING: Dedicated acute geriatric care unit specializing in the management of patients with dementia syndrome (Alzheimer disease or related syndromes) at the University Hospital of Reims, France.
PARTICIPANTS: Older patients with dementia syndrome (Alzheimer disease or related syndromes).
MEASUREMENTS: Sociodemographic variables and comprehensive geriatric assessment were recorded. Occurrence of ADRs was noted. Risk factors for ADR were identified by multivariate logistic regression.
RESULTS: During the study period, 293 patients were included; average age was 82 ± 8 years; the majority were women (61.4%). Average Mini-Mental State Examination score was 13 ± 8; average activities of daily living (ADL) score was 3.6 ± 2.1. Independent risk factors for occurrence of at least one ADR were polypharmacy (≥5 drugs/day) (OR: 4.0, 95% CI: 1.1-14.1) and dependence on at least 1 ADL (OR: 2.6, 95% CI: 1.1-6.5).
CONCLUSIONS: Risk factors for ADRs were polypharmacy and dependence on at least one ADL. Our findings underline the importance of taking into consideration the characteristics of the patients when prescribing drugs in this specific population. Prescriptions should be re-evaluated at each follow-up.

PMID: 27742527 [PubMed - indexed for MEDLINE]

Imatinib and polypharmacy in very old patients with chronic myeloid leukemia: effects on response rate, toxicity and outcome.

Oncotarget. 2016 Nov 29;7(48):80083-80090

Authors: Iurlo A, Nobili A, Latagliata R, Bucelli C, Castagnetti F, Breccia M, Abruzzese E, Cattaneo D, Fava C, Ferrero D, Gozzini A, Bonifacio M, Tiribelli M, Pregno P, Stagno F, Vigneri P, Annunziata M, Cavazzini F, Binotto G, Mansueto G, Russo S, Falzetti F, Montefusco E, Gugliotta G, Storti S, D'Addosio AM, Scaffidi L, Cortesi L, Cedrone M, Rossi AR, Avanzini P, Mauro E, Spadea A, Celesti F, Giglio G, Isidori A, Crugnola M, Calistri E, Sorà F, Rege-Cambrin G, Sica S, Luciano L, Galimberti S, Orlandi EM, Bocchia M, Tettamanti M, Alimena G, Saglio G, Rosti G, Mannucci PM, Cortelezzi A

Abstract
BACKGROUND: About 40% of all patients with chronic myeloid leukemia are currently old or very old. They are effectively treated with imatinib, even though underrepresented in clinical studies. Furthermore, as it happens in the general population, they often receive multiple drugs for associated chronic illnesses. Aim of this study was to assess whether or not in imatinib-treated patients aged >75 years the exposure to polypharmacy (5 drugs or more) had an impact on cytogenetic and molecular response rates, event-free and overall survival, as well as on hematological or extra-hematological toxicity.
METHODS: 296 patients at 35 Italian hematological institutions were evaluated.
RESULTS: Polypharmacy was reported in 107 patients (36.1%), and drugs more frequently used were antiplatelets, diuretics, proton pump inhibitors, ACE-inhibitors, beta-blockers, calcium channel blockers, angiotensin II receptors blockers, statins, oral hypoglycemic drugs and alpha blockers. Complete cytogenetic response was obtained in 174 patients (58.8%), 78 (26.4%) within 6 month, 63 (21.3%) between 7 and 12 months. Major molecular response was obtained in 153 patients (51.7%), 64 (21.6%) within the 12 month. One hundred and twenty-eight cases (43.2%) of hematological toxicity were recorded, together with 167 cases (56.4%) of extra-hematological toxicity. Comparing patients exposed to polypharmacy to those without, no difference was observed pertaining to the dosage of imatinib, cytogenetic and molecular responses and hematological and extra-hematological toxicity.
CONCLUSION: Notwithstanding the several interactions reported in the literature between imatinib and some of the medications considered herewith, this fact does not seem to have a clinical impact on response rate and outcome.

PMID: 27579540 [PubMed - indexed for MEDLINE]

Asian perspectives on the recognition and management of levodopa 'wearing-off' in Parkinson's disease.

Expert Rev Neurother. 2015;15(11):1285-97

Authors: Bhidayasiri R, Hattori N, Jeon B, Chen RS, Lee MK, Bajwa JA, Mok VC, Zhang B, Syamsudin T, Tan LC, Jamora RD, Pisarnpong A, Poewe W

Abstract
Most Parkinson's disease patients will receive levodopa therapy, and of these, the majority will develop some levodopa-induced complications. For many patients, the first complication to develop is the decline in the duration of therapeutic benefit of each levodopa dose, a phenomenon commonly termed 'wearing-off'. There is already extensive literature documenting the epidemiology and management of wearing-off in Parkinson's disease patients of western descent. However, data derived from these studies might not always apply to patients of Asian descent due to genetic variations, differences in co-morbidities or non-availability of certain drugs. This review summarizes the current literature regarding the epidemiology of wearing-off in Asian (including Arab) patients and discusses the management issues in the context of drug availability in Asia.

PMID: 26390066 [PubMed - indexed for MEDLINE]

Propylthiouracil-induced ANCA-negative cutaneous small vessel vasculitis.

J Community Hosp Intern Med Perspect. 2018;8(1):35-37

Authors: Trusau A, Brit ML

Abstract
Propylthiouracil (PTU) is a commonly used medication for the treatment of hyperthyroidism. PTU is known to cause different adverse reactions including autoimmune syndromes. PTU-induced autoimmune syndromes can be classified into drug-induced lupus or drug-induced vasculitis. Differential diagnoses could be very challenging. PTU-induced vasculitis is more common than PTU-induced lupus, and has a higher risk of morbidity and mortality. Usually it is limited to the skin in a form of cutaneous leukocytoclastic vasculitis, but may also affect organs including kidneys and lungs. Discontinuation of PTU should be a first step in the treatment and could lead to complete resolution of symptoms. Typically, lesions resolve spontaneously within 2-4 weeks, but chronic or recurrent disease may occur in up to 10% of patients. In cases without improvement after drug discontinuation, cases refractory to glucocorticosteroids, with necrotizing skin lesions or extracutaneous organ involvement referral to rheumatologist for more aggressive immunosuppressive treatment is indicated. Optimal duration of immunosuppressive therapy is unknown, but it is reasonable to gradually taper mediations and monitor clinical response. Frequent monitoring for side effects is mandatory for patients on PTU therapy. Treatment should be stopped immediately, if patient develops any of autoimmune syndromes. An accurate and prompt diagnosis is essential, because it determines further management. We report a rare case of antineutrophil cytoplasm antibody-negative cutaneous small vessel vasculitis as a result of longstanding exposure to PTU.

PMID: 29441165 [PubMed]

Know your medicine: A novel student-led community service learning program.

Curr Pharm Teach Learn. 2017 May;9(3):353-359

Authors: Howell CK, Reveles KR, Knodel LC, Pattyn NR, Frei CR

Abstract
INTRODUCTION: The objective of this article is to describe the efforts of the student pharmacist organization called Know Your Medicine (KYM) as they conduct medication therapy management (MTM) for older adults and underserved communities.
METHODS: Patients brought medications, immunization records, and health concerns to KYM events during academic years 2012-2013 and 2013-2014. Student pharmacists performed health screenings, created personalized medication records (PMR), made recommendations, created personal action plans (PAP), and conducted follow-up phone calls.
RESULTS: Student pharmacists provided MTM services for a total of 107 patients. The mean duration of a KYM appointment was 62±21min, and student pharmacists provided a mean of 3.5±2.1 recommendations per patient. Patients had a mean age of 78±11 years, 4.5±3.2 disease states, 6.9±4.6 prescriptions, 1.9±1.9 OTC medications, and 2.8±2.6 vitamins or herbals. At the time of the follow-up phone call, a mean of 2.6±1.9 recommendations per patient had been followed.
DISCUSSION AND CONCLUSIONS: Student pharmacists successfully implemented a new MTM program for older adults and underserved communities. This program can serve as an example of how other pharmacy colleges and schools might implement MTM training and real-world MTM experience for their student pharmacists.

PMID: 29233271 [PubMed - indexed for MEDLINE]

Phase I Dose-Escalation Study of Pilaralisib (SAR245408, XL147) in Combination with Paclitaxel and Carboplatin in Patients with Solid Tumors.

Oncologist. 2017 Apr;22(4):377-e37

Authors: Wheler J, Mutch D, Lager J, Castell C, Liu L, Jiang J, Traynor AM

Abstract
LESSONS LEARNED: Despite involvement of PI3K pathway activation in tumorigenesis of solid tumors, single-agent PI3K inhibitors have shown modest clinical activity.Preclinical evidence suggests that combining PI3K pathway inhibitors and chemotherapy can enhance antitumor effects.In patients with solid tumors, the PI3K inhibitor pilaralisib had a favorable safety profile but did not enhance the antitumor activity of paclitaxel plus carboplatin.Further clinical evaluation is warranted to identify effective combination strategies with PI3K pathway inhibitors.
BACKGROUND: Pilaralisib (SAR245408) is an oral, pan-class I phosphoinositide 3-kinase (PI3K) inhibitor. This phase I dose-escalation study evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics of pilaralisib in capsule and tablet formulations, administered in combination with paclitaxel and carboplatin in patients with advanced solid tumors.
METHODS: A 3 + 3 design was used. Pilaralisib was administered once daily (QD); paclitaxel (up to 175 mg/m2) and carboplatin (up to area under the curve [AUC] of 6) were administered on day 1 of 21-day cycles. An MTD expansion cohort of patients with endometrial carcinoma was included.
RESULTS: Fifty-eight patients were enrolled. Six patients (10.3%) had dose-limiting toxicities, of which only rash (two patients, 3.4%) occurred in more than one patient. The MTD of pilaralisib tablets in combination with paclitaxel and carboplatin was determined to be 200 mg QD. The most frequently reported adverse events (AEs) of any grade were neutropenia (67.2%) and thrombocytopenia (67.2%). PK data showed no interaction between pilaralisib and paclitaxel/carboplatin. Tumor tissue showed moderate inhibition of PI3K and mitogen-activated protein kinase (MAPK) pathways. Seven of 52 evaluable patients had a partial response (PR; 13.5%).
CONCLUSION: Pilaralisib had a favorable safety profile but did not enhance the antitumor activity of paclitaxel plus carboplatin in solid tumors. The Oncologist 2017;22:377-378.

PMID: 28275119 [PubMed - indexed for MEDLINE]

Safety and Tolerability of PD-1/PD-L1 Inhibitors Compared with Chemotherapy in Patients with Advanced Cancer: A Meta-Analysis.

Oncologist. 2017 Apr;22(4):470-479

Authors: Nishijima TF, Shachar SS, Nyrop KA, Muss HB

Abstract
BACKGROUND: Compared with chemotherapy, significant improvement in survival outcomes with the programmed death receptor-1 (PD-1) inhibitors nivolumab and pembrolizumab and the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab has been shown in several types of advanced solid tumors. We conducted a systematic review and meta-analysis to compare safety and tolerability between PD-1/PD-L1 inhibitors and chemotherapy.
METHODS: PubMed and American Society of Clinical Oncology (ASCO) databases were searched 1966 to September 2016. Eligible studies included randomized controlled trials (RCTs) comparing single-agent U.S. Food and Drug Administration-approved PD-1/PD-L1 inhibitors (nivolumab, pembrolizumab, or atezolizumab) with chemotherapy in cancer patients reporting any all-grade (1-4) or high-grade (3-4) adverse events (AEs), all- or high-grade treatment-related symptoms, hematologic toxicities and immune-related AEs, treatment discontinuation due to toxicities, or treatment-related deaths. The summary incidence, relative risk, and 95% confidence intervals were calculated.
RESULTS: A total of 3,450 patients from 7 RCTs were included in the meta-analysis: 4 nivolumab, 2 pembrolizumab, and 1 atezolizumab trials. The underlying malignancies included were non-small cell lung cancer (4 trials) and melanoma (3 trials). Compared with chemotherapy, the PD-1/PD-L1 inhibitors had a significantly lower risk of all- and high-grade fatigue, sensory neuropathy, diarrhea and hematologic toxicities, all-grade anorexia, nausea, and constipation, any all- and high-grade AEs, and treatment discontinuation. There was an increased risk of all-grade rash, pruritus, colitis, aminotransferase elevations, hypothyroidism, and hyperthyroidism, and all- and high-grade pneumonitis with PD1/PD-L1 inhibitors.
CONCLUSION: PD-1/PD-L1 inhibitors are overall better tolerated than chemotherapy. Our results provide further evidence supporting the favorable risk/benefit ratio for PD-1/PD-L1 inhibitors. The Oncologist 2017;22:470-479 IMPLICATIONS FOR PRACTICE: We conducted a systematic review and meta-analysis to compare summary toxicity endpoints and clinically relevant adverse events between programmed death receptor-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors and chemotherapy. PD1/PD-L1 inhibitors were associated with a lower risk of treatment-related symptoms (fatigue, anorexia, nausea, diarrhea, constipation, and sensory neuropathy) but a higher risk of immune-related adverse events (AEs). Summary toxicity endpoints favor PD1/PD-L1 inhibitors (any all- and high-grade AEs and treatment discontinuation). PD1/PD-L1 inhibitors are overall better tolerated than chemotherapy. In addition to efficacy data from trials, our findings provide useful information for clinicians for well-balanced discussions with their patients on the risks and benefits of treatment options for advanced cancer.

PMID: 28275115 [PubMed - indexed for MEDLINE]

Long-term safety and efficacy of telbivudine in infants born to mothers treated during the second or third trimesters of pregnancy.

J Viral Hepat. 2017 Jun;24(6):514-521

Authors: Han GR, Jiang HX, Wang CM, Ding Y, Wang GJ, Yue X, Zhou L, Zhao W

Abstract
Telbivudine, an FDA pregnancy category B drug, has been found to reduce hepatitis B virus (HBV) perinatal transmission with no safety concerns in infants aged up to 1 year. This study evaluated the long-term efficacy and safety of telbivudine in 214 infants born to 210 pregnant women with chronic hepatitis B infection who were treated with telbivudine during pregnancy (weeks 20-32 of gestation). The infants were followed for up to 5 years after birth. The efficacy endpoint was the rate of perinatal transmission, which was established by HBsAg and HBV DNA levels at 7 and 12 months. Safety endpoints included head circumference, weight, height, congenital abnormality and hospitalization rates. In addition, the Denver Developmental Screening Test was performed in 92 randomly selected infants. None of the 214 infants born to these women were infected with HBV, and all had effective serum hepatitis B surface antibody (HBsAb) levels. Compared with Chinese standard values, there were few differences in the infants' mean head circumference, weight, and height values. No birth defects were diagnosed, and the congenital abnormality rate was 0.934%. Serious adverse events requiring hospitalization occurred in 20 infants (9.35%). The qualified Denver Developmental Screening Test rate in 92 infants was 97.82%, which was comparable to a rate of 92% in normal Chinese children. Thus, treatment with telbivudine during the second or third trimesters of pregnancy safely blocked perinatal transmission of HBV. Infants born to telbivudine-treated mothers showed normal growth and development during long-term follow-up of up to 5 years.

PMID: 28039902 [PubMed - indexed for MEDLINE]

Therapy with ombitasvir/paritaprevir/ritonavir plus dasabuvir is effective and safe for the treatment of genotypes 1 and 4 hepatitis C virus (HCV) infection in patients with severe renal impairment: A multicentre experience.

J Viral Hepat. 2017 Jun;24(6):464-471

Authors: Muñoz-Gómez R, Rincón D, Ahumada A, Hernández E, Devesa MJ, Izquierdo S, Ortiz M, Hernández-Albujar A, Fernández-Rodríguez C, Calvo M, González R, Lozano M, Castellano G, Fernández-Vázquez I

Abstract
Limited data are available on direct-acting antivirals for treating hepatitis C virus (HCV) infection in patients with severe renal impairment. The aim of this study was to evaluate the effectiveness and safety of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) ± dasabuvir (DSV) ± ribavirin (RBV) in patients with stage 4 or 5 chronic kidney disease (CKD) and HCV genotype 1 or 4 infection in real clinical practice, and to investigate pharmacological interactions. This retrospective study included patients treated with OBV/PTV/r+DSV±RBV or OBV/PTV/r+RBV with CKD stage 4 (eGFR: 15-29 mL/min/1.73m2 ) or 5 (eGFR<15 mL/min/1.73m2 or requiring dialysis) and HCV infection by genotypes 1 and 4 between April 2015 and October 2015 in nine Spanish centres. Sustained virological response at 12 weeks (SVR12) was assessed, and clinical and laboratory data, fibrosis stage, adverse events and pharmacological interactions were reported. Forty-six patients were included: 10 (21.7%) had CKD stage 4 and 36 (78.2%) CKD stage 5. Seventeen (36.9%) had cirrhosis. SVR12 rate in the intention-to-treat population was 95.7%. Twenty-one (45.6%) received RBV, which was discontinued in two (9.5%) patients. Anaemia (haemoglobin <10 g/dl) occurred in 12 patients (57.1%) with RBV vs 10 (40.0%) without RBV (P=.246). Renal function remained stable during antiviral therapy. Nine patients (19.5%) experienced serious adverse events unrelated to antiviral therapy. Concomitant medication was discontinued or modified in 41.3% of patients. In conclusion, the effectiveness of OBV/PTV/r±DSV±RBV in patients with CKD 4-5 was similar to that observed in those with normal renal function and was not associated with severe adverse events.

PMID: 27976490 [PubMed - indexed for MEDLINE]

Herb-Drug Interactions: An Insight into Cardiovascular Diseases Based on Case Reports.

Cardiovasc Hematol Agents Med Chem. 2017;14(3):142-149

Authors: Batista C, Jesus NR, Silva CM, Silva TP, Campos MG

Abstract
Cardiovascular patients frequently use herbal medicinal products, in order to contribute to the improvement of their chronic condition without medical intervention. However, they are likely to suffer from adverse effects from natural products and herb-drug interactions. In this work we present the results collected from a public campaign "Learning Health, among Plants and Medicines", carried out by the Observatory of Herb-Drug Interactions (www.oipm.uc.pt), to alert cardiovascular patients and healthcare providers for the potential occurrence of herb-drug interactions with cardiovascular therapy. From the data received, it was highlighted the prevalence of certain natural products used by many cardiovascular patients in Portugal, particularly goji berries, green tea, mangosteen and rooibos that have significant cardiovascular effects. For this reason their intake should be carefully monitored in these patients. This prevalence of consumption suggests a pattern in their use in Portugal and a prevention of herb-drug interactions should be carried out by the health professionals. The ending results also indicate that there is still a lack of knowledge about the possible risks of herbal products intake, which may adversely affect the health of any patient. Thus becomes clear the value of the role of health professionals in the screening of such interactions.

PMID: 27748172 [PubMed - indexed for MEDLINE]

A multidisciplinary approach to toxicity management of modern immune checkpoint inhibitors in cancer therapy.

Melanoma Res. 2016 Oct;26(5):469-80

Authors: Kottschade L, Brys A, Peikert T, Ryder M, Raffals L, Brewer J, Mosca P, Markovic S, Midwest Melanoma Partnership

Abstract
Immune-related Adverse Events (irAEs) are the most significant toxicities associated with the use of checkpoint inhibitors, and result from disinhibition of the host's immune homeostasis. The adverse effects experienced from immunotherapy are significantly different from those of chemotherapy and, to a lesser extent, targeted therapy. Early recognition and diagnosis of these toxicities is often challenging, but is critically important because of the potentially life-threatening nature and associated morbidity. Gastrointestinal, dermatologic, endocrine, and liver toxicities are the most commonly observed. Less commonly, the eyes, pancreas, kidneys, lungs, bone marrow, or nervous system may be affected. Although most irAEs may resolve with supportive care or discontinuation of drug, in severe cases, they may require hospitalization and immune suppressants, such as steroids, and/or may even cause death. The management of immune-related side effects requires a multidisciplinary approach.

PMID: 27306502 [PubMed - indexed for MEDLINE]

α1-Antitrypsin Infusion for treatment of Steroid Resistant Acute Graft-versus-Host Disease.

Blood. 2018 Feb 02;:

Authors: Magenau JM, Goldstein SC, Peltier D, Soiffer RJ, Braun T, Pawarode A, Riwes MM, Kennel M, Antin JH, Cutler CS, Ho VT, Alyea EP, Parkin BL, Yanik GA, Choi SW, Lewis EC, Dinarello CA, Koreth J, Reddy P

Abstract
Corticosteroid resistance following acute GVHD (SR-aGVHD) results in high morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Current immunosuppressive therapies for SR-aGVHD provide marginal effectiveness due to poor response or excessive toxicity, primarily from infection. Alpha-1 antitrypsin (AAT), a naturally abundant serine protease inhibitor, is capable of suppressing experimental GVHD by down-modulation of inflammation and increasing ratios of regulatory to effector T cells. In this prospective multicenter clinical study we sought to determine the safety and response rate of AAT administration in SR-aGVHD (NCT01700036). Forty patients at a median age of 59 years received intravenous AAT twice weekly for four weeks as first line treatment for SR-aGVHD. The primary endpoint was overall response rate (ORR), the proportion of SR-aGVHD in CR+PR by day 28 without addition of further immunosuppression. Treatment was well tolerated without drug related adverse events. A significant increase in serum levels of AAT was observed after treatment. The ORR and CR rate by day 28 was 65% and 35%, respectively, and included responses in all aGVHD target organs. At day 60, responses were sustained in 73% of patients without intervening immunosuppression. Infectious-mortality was 10% at 6 months and 2.5% within 30 days of last AAT infusion. Consistent with pre-clinical data, correlative samples showed an increase in ratio of activated Tregs to effector T cells after AAT treatment. These data suggest that AAT is safe, and may be potentially efficacious in treating SR-aGVHD.

PMID: 29437593 [PubMed - as supplied by publisher]

[Safety data of the new, reduced-dose influenza vaccine FluArt after its first season on the market].

Orv Hetil. 2017 Dec;158(49):1953-1959

Authors: Vajó P, Gyurján O, Szabó ÁM, Kalabay L, Vajó Z, Torzsa P

Abstract
INTRODUCTION: The currently licensed seasonal influenza vaccines contain split, subunit or whole virions, typically in amounts of 15 µg hemagglutinin per virus strain for adult and up to 60 µg in elderly patients.
AIM: The present study reports safety data of the newly licensed, reduced dose vaccine with 6 µg of hemagglutinin per strain produced by Fluart (Hungary) after its first season on the market. The main objective of enhanced safety surveillance was to detect a potential increase in reactogenicity and allergic events that is intrinsic to the product in near real-time in the earliest vaccinated cohorts.
METHOD: The study methods were based on the Interim guidance on enhanced safety surveillance for seasonal influenza vaccines in the EU by the European Medicines Agency.
STATISTICS: We used the Fisher exact test with 95% confidence intervals.
RESULTS: We studied 587 patients and detected a total 24 adverse events, all of which have already been known during the licensing studies of the present vaccine. The frequencies of the adverse events were not different from what had been seen with the previously licensed 15 µg vaccine.
CONCLUSIONS: Based on the results, the authors conclude that the new, reduced dose vaccine FluArt is safe and tolerable. Orv Hetil. 2017; 158(49): 1953-1959.

PMID: 29199437 [PubMed - indexed for MEDLINE]

Large-scale detection of drug off-targets: hypotheses for drug repurposing and understanding side-effects.

BMC Pharmacol Toxicol. 2017 Apr 28;18(1):18

Authors: Chartier M, Morency LP, Zylber MI, Najmanovich RJ

Abstract
BACKGROUND: Promiscuity in molecular interactions between small-molecules, including drugs, and proteins is widespread. Such unintended interactions can be exploited to suggest drug repurposing possibilities as well as to identify potential molecular mechanisms responsible for observed side-effects.
METHODS: We perform a large-scale analysis to detect binding-site molecular interaction field similarities between the binding-sites of the primary target of 400 drugs against a dataset of 14082 cavities within 7895 different proteins representing a non-redundant dataset of all proteins with known structure. Statistically-significant cases with high levels of similarities represent potential cases where the drugs that bind the original target may in principle bind the suggested off-target. Such cases are further analysed with docking simulations to verify if indeed the drug could, in principle, bind the off-target. Diverse sources of data are integrated to associated potential cross-reactivity targets with side-effects.
RESULTS: We observe that promiscuous binding-sites tend to display higher levels of hydrophobic and aromatic similarities. Focusing on the most statistically significant similarities (Z-score ≥ 3.0) and corroborating docking results (RMSD < 2.0 Å), we find 2923 cases involving 140 unique drugs and 1216 unique potential cross-reactivity protein targets. We highlight a few cases with a potential for drug repurposing (acetazolamide as a chorismate pyruvate lyase inhibitor, raloxifene as a bacterial quorum sensing inhibitor) as well as to explain the side-effects of zanamivir and captopril. A web-interface permits to explore the detected similarities for each of the 400 binding-sites of the primary drug targets and visualise them for the most statistically significant cases.
CONCLUSIONS: The detection of molecular interaction field similarities provide the opportunity to suggest drug repurposing opportunities as well as to identify potential molecular mechanisms responsible for side-effects. All methods utilized are freely available and can be readily applied to new query binding-sites. All data is freely available and represents an invaluable source to identify further candidates for repurposing and suggest potential mechanisms responsible for side-effects.

PMID: 28449705 [PubMed - indexed for MEDLINE]

Consumption of antihistamines in Serbia in the period 2011-2015 and the correlation with adverse drug reaction reports.

Vojnosanit Pregl. 2016 Nov;73(11):1076-7

Authors: Radonjić V, Jović I, Kalaba M, Godman B, Košutić J

PMID: 29341563 [PubMed - indexed for MEDLINE]