The Use of Statins in Patients With Chronic Liver Disease and Cirrhosis.

Curr Treat Options Gastroenterol. 2018 Mar 23;:

Authors: Moctezuma-Velázquez C, Abraldes JG, Montano-Loza AJ

Abstract
PURPOSE OF REVIEW: Statins are drugs developed to treat hypercholesterolemia. Its use in patients with liver disease has been limited because one of its potential and most feared side effects is hepatotoxicity. However, there is robust evidence that supports the safety of statins in this population in the absence of severe liver dysfunction. In this review, we will summarize the efficacy and safety of statins in cirrhosis.
RECENT FINDINGS: Statins are effective in the treatment of dyslipidemia in patients with liver disease, because of their pleiotropic properties. These properties are independent of their effect on cholesterol levels, such as improving endothelial dysfunction or having antioxidant, antifibrotic, anti-inflammatory, antiproliferative, antiangiogenic, proapoptotic, or immunomodulation properties. Statins have been studied in other areas such as in treatment of portal hypertension, prevention of hepatocellular carcinoma, and/or protection against ischemia/reperfusion injury. Approved indications for statins in patients with cirrhosis are those of the general population, including dyslipidemia and increased cardiovascular risk. Compensated cirrhosis is not a contraindication. In patients with decompensated cirrhosis, statins should be prescribed with extreme caution at low doses, and with frequent monitoring of creatinine phosphokinase levels in order to detect adverse events in a timely fashion.

PMID: 29572618 [PubMed - as supplied by publisher]

Pazopanib-Induced Hepatotoxicity in an Experimental Rat Model.

Chemotherapy. 2018;63(1):39-45

Authors: Cetin B, Yılmaz GE, Armagan B, Afsar B, Demirci U, Gulbahar O, Gumusay O, Bilgetekin I, Ozet A, Uner A

Abstract
Pazopanib is an effective treatment for advanced renal cell carcinoma and soft tissue sarcoma. Besides classical adverse events of this drug class, hepatotoxicity has been described as a frequent side effect. The aim of the present study was to evaluate the effect of pazopanib on the liver in an experimental rat model. Sixteen Wistar albino rats were divided into 3 groups: experimental toxicity was induced with pazopanib (10 mg/kg) administered for 28 days (group 2) or 56 days (group 3) orally by gavage. Group 1 (control group) received only distilled water. Rats in groups 2 and 3 were sacrificed after the collection of blood and tissue samples on the 28th and 56th days, respectively. We found significant differences in bilirubin, alkaline phosphatase, lactate dehydrogenase, glucose, triglyceride, very-low-density lipoprotein, and iron values (p < 0.050 for all) but none in any other parameter (p > 0.050). All rats in the control group had normal histological features; however, none of the rats in groups 2 and 3 showed normal histology. In group 2, we observed mild sinusoidal dilatation, congestion, enlarged Kupffer cells, accumulation of yellow-brown-black pigment in the Kupffer cells and the accumulation of hemosiderin with Prussian blue reaction in the hepatocytes. In group 3, the findings mentioned above were more prominent, and besides these findings focal acinar transformation and macrovesicular steatosis were also observed. In group 3, mild inflammation within the portal areas was observed consisting of lymphocytes, neutrophils, and eosinophils. This study is the first that reports the biochemical and histopathological evaluation of pazopanib-related hepatic toxicity.

PMID: 29393107 [PubMed - indexed for MEDLINE]

[Tocilizumab for refractory systemic juvenile idiopathic arthritis].

Zhonghua Er Ke Za Zhi. 2017 Nov 02;55(11):830-834

Authors: Lai JM, Wu FQ, Zhou ZX, Kang M, Huang XL, Su GX, Li SN, Zhu J, Wang XN

Abstract
Objective: To evaluate the efficacy and side effects of tocilizumab for the treatment of systemic juvenile idiopathic arthritis. Method: In this prospective self case-control study, the children diagnosed with refractory systemic juvenile idiopathic arthritis admitted to Department of Rheumatism and Immunology of Children's Hospital Affiliated to Capital Institute of Pediatrics from December 2013 to June 2016 were enrolled and information before and after treatment of tocilizumab was analyzed. The tocilizumab was introvenously guttae in a dose of 8-12 mg/kg every 2 weeks. Complete blood count, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were tested before and after the application of tocilizumab. Detailed clinical manifestations were recorded. All results were analyzed by χ(2) test and t test. Result: Forty patients with a median age of (6.6±3.7) years were enrolled, including 15 males and 25 females. All of the patients presented with fever and 38 patients got normal temperature 24-48 hours after treatment with tocilizumab. Symptoms disappeared in 13 and improved in 4 patients after treatment among the 17 patients who presented with arthritis. Within the 10 patients who manifested with rashes, 9 patients' rashes disappeared without relapse accompanied by the normalization of temperature after the treatment of tocilizumab. One patient got normal temperature but intermittently emerged rashes after symptoms of arthritis improved. In the 40 patients, 38 well tolerated tocilizumab while 2 showed rashes and chill which disappeared shortly after antianaphylaxis treatment. No severe treatment-related infection was found in any patients. According to the study, the white blood cell counts(×10(9)/L), CRP(mg/L) and ESR(mm/1h) tested 2 weeks after the treatment with tocilizumab were significantly lower than that before treatment(12.1±1.2 vs. 16.5±1.8, 47±8 vs. 67±9, 21±5 vs. 57±6, t=2.75, 3.98, 5.22, P=0.009, 0, 0, respectively). No significant changes were found in concentration of IL-6 and TNF-α (65(207) vs. 45(137) ng/L, and 14(6) vs. 17(19)ng/L, Z=-1.247 and-1.285, P=0.212 and 0.199 respectively). Conclusion: Tocilizumab is a treatment with good efficacy and safety for refractory systemic juvenile idiopathic arthritis. Adverse effects would be found in some patients.

PMID: 29141313 [PubMed - indexed for MEDLINE]

Adverse kidney effects of epidermal growth factor receptor inhibitors.

Nephrol Dial Transplant. 2017 Jul 01;32(7):1089-1097

Authors: Izzedine H, Perazella MA

Abstract
The epidermal growth factor receptor (EGFR) is implicated in various malignancies. The past decade has seen the development and widespread use of EGFR inhibitors for the successful treatment of such cancers. Available EGFR inhibitors include small molecule tyrosine-kinase inhibitors and monoclonal antibodies. Class-related renal adverse events result in dual toxicity including tubular/electrolyte disorders and glomerulopathies. Tubular injury is common and mainly due to monoclonal antibodies while glomerulopathy is rare and related to various anti-EGFR agents. The exact pathogenesis of anti-EGFR agents associated with kidney disorders remains to be elucidated.

PMID: 28339780 [PubMed - indexed for MEDLINE]

An update on HLA alleles associated with adverse drug reactions.

Drug Metab Pers Ther. 2017 May 24;32(2):73-87

Authors: Fricke-Galindo I, LLerena A, López-López M

Abstract
Adverse drug reactions (ADRs) are considered as an important cause of morbidity and mortality. The hypersensitivity reactions are immune-mediated ADRs, which are dose-independent, unpredictable and have been associated with several HLA alleles. The present review aimed to describe HLA alleles that have been associated with different ADRs in populations worldwide, the recommendations of regulatory agencies and pharmacoeconomic information and databases for the study of HLA alleles in pharmacogenetics. A systematic search was performed in June 2016 of articles relevant to this issue in indexed journals and in scientific databases (PubMed and PharmGKB). The information of 95 association studies found was summarized. Several HLA alleles and haplotypes have been associated with ADRs induced mainly by carbamazepine, allopurinol, abacavir and nevirapine, among other drugs. Years with the highest numbers of publications were 2013 and 2014. The majority of the reports have been performed on Asians and Caucasians, and carbamazepine was the most studied ADR drug inducer. Two HLA alleles' databases are described, as well as the recommendations of the U.S. Food and Drug Administration, the European Medicine Agency and the Clinical Pharmacogenetics Implementation Consortium. Pharmacoeconomic studies on this issue are also mentioned. The strongest associations remain for HLA-B*58:01, HLA-B*57:01, HLA-B*15:02 and HLA-A*31:01 but only in certain populations; therefore, studies on different ethnic groups would be useful. Due to the improvement of drug therapy and the economic benefit that HLA screening represents, investigations on HLA alleles associated with ADR should continue.

PMID: 28315856 [PubMed - indexed for MEDLINE]

Pharmacological Reversal Agents in Dental Practice: Keys to Patient Safety.

Compend Contin Educ Dent. 2016 Nov/Dec;37(10):681-687; quiz 688

Authors: Donaldson M, Goodchild JH

Abstract
Though uncommon, medical emergencies in the dental office are harrowing occurrences that can be the result of adverse drug reactions. Pharmacological antagonists have been developed for administration as reversal agents in emergency situations in which patients may have an untoward effect, typically caused by too much medication. Dental practitioners should be familiar with these agents to keep patients safe and help mitigate drug-induced medical emergencies. This article reviews the pharmacokinetic and pharmacodynamic principles of pharmacological antagonists; it emphasizes six specific reversal agents as they relate to the clinical practice of dentistry: naloxone, flumazenil, epinephrine, diphenhydramine, phentolamine, and atropine. Outside of emergency situations, the pharmacological antagonist phentolamine has been developed to reverse the effects of the vasoconstrictor in dental local anesthesia preparations when the effects of the agonist medication are no longer required. Such newer reversal agents are being considered for more routine use once the dental procedure is complete. This article is intended to assist dental practitioners who are familiar with pharmacological antagonists to be better able to help mitigate drug-induced medical emergencies should they occur.

PMID: 27875053 [PubMed - indexed for MEDLINE]

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

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

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Mefloquine for preventing malaria in pregnant women.

Cochrane Database Syst Rev. 2018 Mar 21;3:CD011444

Authors: González R, Pons-Duran C, Piqueras M, Aponte JJ, Ter Kuile FO, Menéndez C

Abstract
BACKGROUND: The World Health Organization recommends intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine for malaria for all women who live in moderate to high malaria transmission areas in Africa. However, parasite resistance to sulfadoxine-pyrimethamine has been increasing steadily in some areas of the region. Moreover, HIV-infected women on cotrimoxazole prophylaxis cannot receive sulfadoxine-pyrimethamine because of potential drug interactions. Thus, there is an urgent need to identify alternative drugs for prevention of malaria in pregnancy. One such candidate is mefloquine.
OBJECTIVES: To assess the effects of mefloquine for preventing malaria in pregnant women, specifically, to evaluate:• the efficacy, safety, and tolerability of mefloquine for preventing malaria in pregnant women; and• the impact of HIV status, gravidity, and use of insecticide-treated nets on the effects of mefloquine.
SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE, Embase, Latin American Caribbean Health Sciences Literature (LILACS), the Malaria in Pregnancy Library, and two trial registers up to 31 January 2018. In addition, we checked references and contacted study authors to identify additional studies, unpublished data, confidential reports, and raw data from published trials.
SELECTION CRITERIA: Randomized and quasi-randomized controlled trials comparing mefloquine IPT or mefloquine prophylaxis against placebo, no treatment, or an alternative drug regimen.
DATA COLLECTION AND ANALYSIS: Two review authors independently screened all records identified by the search strategy, applied inclusion criteria, assessed risk of bias, and extracted data. We contacted trial authors to ask for additional information when required. Dichotomous outcomes were compared using risk ratios (RRs), count outcomes as incidence rate ratios (IRRs), and continuous outcomes using mean differences (MDs). We have presented all measures of effect with 95% confidence intervals (CIs). We assessed the certainty of evidence using the GRADE approach for the following main outcomes of analysis: maternal peripheral parasitaemia at delivery, clinical malaria episodes during pregnancy, placental malaria, maternal anaemia at delivery, low birth weight, spontaneous abortions and stillbirths, dizziness, and vomiting.
MAIN RESULTS: Six trials conducted between 1987 and 2013 from Thailand (1), Benin (3), Gabon (1), Tanzania (1), Mozambique (2), and Kenya (1) that included 8192 pregnant women met our inclusion criteria.Two trials (with 6350 HIV-uninfected pregnant women) compared two IPTp doses of mefloquine with two IPTp doses of sulfadoxine-pyrimethamine. Two other trials involving 1363 HIV-infected women compared three IPTp doses of mefloquine plus cotrimoxazole with cotrimoxazole. One trial in 140 HIV-infected women compared three doses of IPTp-mefloquine with cotrimoxazole. Finally, one trial enrolling 339 of unknown HIV status compared mefloquine prophylaxis with placebo.Study participants included women of all gravidities and of all ages (four trials) or > 18 years (two trials). Gestational age at recruitment was > 20 weeks (one trial), between 16 and 28 weeks (three trials), or ≤ 28 weeks (two trials). Two of the six trials blinded participants and personnel, and only one had low risk of detection bias for safety outcomes.When compared with sulfadoxine-pyrimethamine, IPTp-mefloquine results in a 35% reduction in maternal peripheral parasitaemia at delivery (RR 0.65, 95% CI 0.48 to 0.86; 5455 participants, 2 studies; high-certainty evidence) but may have little or no effect on placental malaria infections (RR 1.04, 95% CI 0.58 to 1.86; 4668 participants, 2 studies; low-certainty evidence). Mefloquine results in little or no difference in the incidence of clinical malaria episodes during pregnancy (incidence rate ratio (IRR) 0.83, 95% CI 0.65 to 1.05, 2 studies; high-certainty evidence). Mefloquine decreased maternal anaemia at delivery (RR 0.84, 95% CI 0.76 to 0.94; 5469 participants, 2 studies; moderate-certainty evidence). Data show little or no difference in the proportions of low birth weight infants (RR 0.95, 95% CI 0.78 to 1.17; 5641 participants, 2 studies; high-certainty evidence) and in stillbirth and spontaneous abortion rates (RR 1.20, 95% CI 0.91 to 1.58; 6219 participants, 2 studies; I2 statistic = 0%; high-certainty evidence). IPTp-mefloquine increased drug-related vomiting (RR 4.76, 95% CI 4.13 to 5.49; 6272 participants, 2 studies; high-certainty evidence) and dizziness (RR 4.21, 95% CI 3.36 to 5.27; participants = 6272, 2 studies; high-certainty evidence).When compared with cotrimoxazole, IPTp-mefloquine plus cotrimoxazole probably results in a 48% reduction in maternal peripheral parasitaemia at delivery (RR 0.52, 95% CI 0.30 to 0.93; 989 participants, 2 studies; moderate-certainty evidence) and a 72% reduction in placental malaria (RR 0.28, 95% CI 0.14 to 0.57; 977 participants, 2 studies; high-certainty evidence) but has little or no effect on the incidence of clinical malaria episodes during pregnancy (IRR 0.76, 95% CI 0.33 to 1.76, 1 study; high-certainty evidence) and probably no effect on maternal anaemia at delivery (RR 0.94, 95% CI 0.73 to 1.20; 1197 participants, 2 studies; moderate-certainty evidence), low birth weight rates (RR 1.20, 95% CI 0.89 to 1.60; 1220 participants, 2 studies; moderate-certainty evidence), and rates of spontaneous abortion and stillbirth (RR 1.12, 95% CI 0.42 to 2.98; 1347 participants, 2 studies; very low-certainty evidence). Mefloquine was associated with higher risks of drug-related vomiting (RR 7.95, 95% CI 4.79 to 13.18; 1055 participants, one study; high-certainty evidence) and dizziness (RR 3.94, 95% CI 2.85 to 5.46; 1055 participants, 1 study; high-certainty evidence).
AUTHORS' CONCLUSIONS: Mefloquine was more efficacious than sulfadoxine-pyrimethamine in HIV-uninfected women or daily cotrimoxazole prophylaxis in HIV-infected pregnant women for prevention of malaria infection and was associated with lower risk of maternal anaemia, no adverse effects on pregnancy outcomes (such as stillbirths and abortions), and no effects on low birth weight and prematurity. However, the high proportion of mefloquine-related adverse events constitutes an important barrier to its effectiveness for malaria preventive treatment in pregnant women.

PMID: 29561063 [PubMed - as supplied by publisher]

A Chinese medicine warm compress (Wen Jing Zhi Tong Fang), combined with WHO 3-step analgesic ladder treatment for cancer pain relief: A comparative randomized trial.

Medicine (Baltimore). 2018 Mar;97(11):e9965

Authors: Cai P, Li L, Hong H, Zhang L, He C, Chai X, Liu B, Chen Z

Abstract
INTRODUCTION: This study aimed to assess the effectiveness of Chinese medicine warm compress (CMWC) on back meridians in relieving cancer pain, reducing adjuvant analgesic doses and adverse reactions, and improving the quality of life (QOL).
METHODS: A total of 62 patients (age range 39-82 years) diagnosed with a malignant tumor and suffering from cancer-related pain were randomly divided into a treatment group (group A) and a control group (group B) (n = 31 for each). The patients in both groups were administered appropriate drugs for 2 cycles of 7-day treatments according to the World Health Organization (WHO) 3-step ladder for cancer pain relief in adults. In addition, a CMWC was given to patients in group A. Pain relief was assessed using the visual analogue scale (VAS) at various time points before and after interventions in each group. Alteration of analgesic doses, adverse reactions, performance status (PS), and QOL were evaluated and any differences between groups A and B evaluated.
RESULTS: VAS scores at various time points after treatment were significantly decreased compared with the baseline level in group A. Overall response rate was significantly improved in group A compared with group B (70.97% vs 29.03%, P < .001). Significant differences in clinical pain relief efficacy in various locations were found in group A after treatment vs before treatment (P < .05). Adjuvant analgesic doses were significantly changed in the control group compared to the treatment group after 1 cycle of 7-day treatment (22.58% vs 12.90%, P = .023). QOL were improved more in group A than in group B (3.00 ± 4.23 vs -2.06 ± 2.38, P < .001). Significantly reduced adverse reactions were observed after treatment of group A compared with group B in terms of the overall incidence (3.23% vs 80.65%, P < .05) or incidence of constipation (3.23% vs 77.42%, P < .05).
CONCLUSIONS: The application of CMWC on back meridians combined with WHO 3-step analgesic ladder treatment was effective in relieving cancer-related pain with reduced doses, less adverse reactions, and improved QOL.

PMID: 29538220 [PubMed - indexed for MEDLINE]

Improving multiple sclerosis management and collecting safety information in the real world: the MSDS3D software approach.

Expert Opin Drug Saf. 2018 Apr;17(4):369-378

Authors: Haase R, Wunderlich M, Dillenseger A, Kern R, Akgün K, Ziemssen T

Abstract
INTRODUCTION: For safety evaluation, randomized controlled trials (RCTs) are not fully able to identify rare adverse events. The richest source of safety data lies in the post-marketing phase. Real-world evidence (RWE) and observational studies are becoming increasingly popular because they reflect usefulness of drugs in real life and have the ability to discover uncommon or rare adverse drug reactions. Areas covered: Adding the documentation of psychological symptoms and other medical disciplines, the necessity for a complex documentation becomes apparent. The collection of high-quality data sets in clinical practice requires the use of special documentation software as the quality of data in RWE studies can be an issue in contrast to the data obtained from RCTs. The MSDS3D software combines documentation of patient data with patient management of patients with multiple sclerosis. Following a continuous development over several treatment-specific modules, we improved and expanded the realization of safety management in MSDS3D with regard to the characteristics of different treatments and populations. Expert opinion: eHealth-enhanced post-authorisation safety study may complete the fundamental quest of RWE for individually improved treatment decisions and balanced therapeutic risk assessment. MSDS3D is carefully designed to contribute to every single objective in this process.

PMID: 29436244 [PubMed - indexed for MEDLINE]

The safety and tolerability of cariprazine in long-term treatment of schizophrenia: a post hoc pooled analysis.

BMC Psychiatry. 2017 Aug 24;17(1):305

Authors: Nasrallah HA, Earley W, Cutler AJ, Wang Y, Lu K, Laszlovszky I, Németh G, Durgam S

Abstract
BACKGROUND: Schizophrenia is a chronic and debilitating neuropsychiatric disorder that often requires long-term pharmacotherapy to manage symptoms and prevent relapse. Cariprazine is a potent dopamine D3 and D2 receptor partial agonist that is FDA-approved in the US for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder in adults; the recommended dose range is 1.5-6 mg/d.
METHODS: To further characterize the long-term safety of cariprazine, data from two 48-week open-label, flexible-dose extension studies were pooled for post hoc analyses. Outcomes were evaluated in the pooled safety population (patients who received ≥1 dose of cariprazine during an open-label extension period); findings were summarized using descriptive statistics for the overall cariprazine group and in modal daily dose groups (1.5-3, 4.5-6, and 9 mg/d).
RESULTS: Of the 679 patients in the overall cariprazine safety population, 40.1% completed the study. The only adverse events (AEs) leading to discontinuation of ≥2% of patients in any dose group were akathisia, worsening of schizophrenia, and psychotic disorder. Treatment-emergent AEs (TEAEs) of akathisia, insomnia, weight increased, and headache were reported in ≥10% of the overall population. Mean prolactin levels decreased in all dose groups (overall, -15.4 ng/mL). Clinically insignificant changes in aminotransferase levels and alkaline phosphatase were observed; no dose-response relationship was observed across groups. Mean total (-5.3 mg/dL), low-density lipoprotein (-3.5 mg/dL), and high-density lipoprotein (-0.8 mg/dL) cholesterol levels decreased; no dose-response relationship was observed for metabolic parameters. Mean change in body weight was 1.58 kg; body weight increase and decrease ≥7% occurred in 27% and 11% of patients, respectively. Mean changes in cardiovascular parameters, including blood pressure and pulse, were generally not considered clinically significant. EPS-related TEAEs that occurred in ≥5% of patients were akathisia, tremor, restlessness, and extrapyramidal disorder.
CONCLUSION: In these post hoc pooled analyses of data from 2 long-term open-label studies, treatment with cariprazine was generally safe and well tolerated. Results support the safety and tolerability of cariprazine within the FDA-recommended dose range of 1.5-6 mg/d for schizophrenia.
CLINICAL TRIALS REGISTRATION: NCT01104792, NCT00839852.

PMID: 28836957 [PubMed - indexed for MEDLINE]

Rapid Progressive Disease After Nivolumab Therapy in Three Patients with Metastatic Renal Cell Carcinoma.

In Vivo. 2017 Jul-Aug;31(4):769-771

Authors: Kobari Y, Kondo T, Takagi T, Omae K, Nakazawa H, Tanabe K

Abstract
BACKGROUND/AIM: Rapid progressive disease (RPD), accelerated tumour growth immediate after the initiation of immune checkpoint inhibitor therapy, has been reported in melanoma and lung cancer. Herein, we describe 3 cases of RPD during the initial phase of nivolumab treatment for metastatic renal cell carcinoma.
PATIENTS AND METHODS: The first and second patients received nivolumab in the fourth-line setting. The third patient received nivolumab therapy as third-line treatment.
RESULTS: The first patient developed severe respiratory failure due to carcinomatous lymphangiosis 14 days after initiation of nivolumab therapy. The second patient developed leg paraplegia due to rapid growth of the metastatic tumour at the sixth thoracic vertebrae 5 days later. The third patient developed grade 4 hypercalcemia due to RPD on day 3.
CONCLUSION: Clinicians should be aware of RPD during the initial phase of nivolumab therapy, especially in patients with critical lesions in the late-line setting.

PMID: 28652455 [PubMed - indexed for MEDLINE]

Study of adverse drug reactions in patients with diabetes attending a tertiary care hospital in New Delhi, India.

Indian J Med Res. 2017 Feb;145(2):247-249

Authors: Singh A, Dwivedi S

Abstract
The present prospective observational study was carried out in a tertiary care hospital in New Delhi, India from May 2014 to June 2015 to report adverse drug reactions (ADRs) in patients with type 2 diabetes mellitus (T2DM) using antidiabetic drugs. A total of 220 patients (121 males, 99 females) were enrolled. ADRs were recorded on the prescribed form. Causality and severity assessment was done using Naranjo's probability scale and modified Hartwig and Siegel's severity scale, respectively. Commonly prescribed drugs were biguanides, peptide hormone and sulphonylurea. A total of 26 ADRs were recorded (16 in males and 10 in females). Most commonly observed ADRs were related to endocrine and gastrointestinal system. Severity assessment of ADRs showed seven (26.9%) ADRs as moderate, and 19 (73.1%) as mild. No severe reactions were observed. ADRs were mostly related to endocrine and gastrointestinal system. More information on prescribed drugs and their side effects is required for ensuring patient safety.

PMID: 28639602 [PubMed - indexed for MEDLINE]

Entinostat: a promising treatment option for patients with advanced breast cancer.

Future Oncol. 2017 Jun;13(13):1137-1148

Authors: Connolly RM, Rudek MA, Piekarz R

Abstract
Entinostat is a synthetic benzamide derivative histone deacetylase (HDAC) inhibitor, which potently and selectively inhibits class I and IV HDAC enzymes. This action promotes histone hyperacetylation and transcriptional activation of specific genes, with subsequent inhibition of cell proliferation, terminal differentiation and apoptosis. This oral HDAC inhibitor has been evaluated in Phase I and II trials in patients with advanced malignancies, and is in general well tolerated. Entinostat does not currently have regulatory approval for clinical use; however promising preclinical and clinical data exist in hormone-resistant breast cancer. An ECOG-ACRIN Phase III registration study is ongoing in advanced breast cancer (E2112, NCT02115282) and aims to confirm the overall survival advantage observed with the combination of exemestane and entinostat/placebo in the Phase II setting (ENCORE301 trial). This article provides an overview of the chemistry, pharmacokinetics/pharmacodynamics and available clinical data for entinostat with a focus on advanced breast cancer.

PMID: 28326839 [PubMed - indexed for MEDLINE]

FDA Approval Summary: TAS-102.

Clin Cancer Res. 2017 Jun 15;23(12):2924-2927

Authors: Marcus L, Lemery SJ, Khasar S, Wearne E, Helms WS, Yuan W, He K, Cao X, Yu J, Zhao H, Wang Y, Stephens O, Englund E, Agarwal R, Keegan P, Pazdur R

Abstract
The FDA approved TAS-102 (Lonsurf; Taiho Oncology, Inc.) for the treatment of patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; an anti-VEGF biological therapy; and if RAS wild type, an anti-EGFR therapy. In an international, multicenter, double-blinded, placebo-controlled trial (TPU-TAS-102-301, herein referred to as RECOURSE), 800 patients with previously treated mCRC were randomly allocated (2:1) to receive either TAS-102 35 mg/m2 orally twice daily after meals on days 1 through 5 and 8 through 12 of each 28-day cycle (n = 534) or matching placebo (n = 266). The trial demonstrated a statistically significant improvement in overall survival for those randomized to receive TAS-102, with a median survival of 7.1 months in the TAS-102 arm [confidence interval (CI), 6.5-7.8] and 5.3 months in the placebo arm [CI, 4.6-6.0; hazard ratio (HR), 0.68; 95% CI, 0.58-0.81; P < 0.001, stratified log-rank test]. The trial also demonstrated a statistically significant prolongation of progression-free survival (HR, 0.47; 95% CI, 0.40-0.55; P < 0.001). The most common adverse reactions, in order of decreasing frequency, observed in the patients who received TAS-102 were anemia, neutropenia, asthenia/fatigue, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, abdominal pain, and pyrexia. Adverse events led to discontinuation of TAS-102 in 3.6% of patients, and 13.7% required a dose reduction. The most common adverse reactions leading to dose reduction were neutropenia, anemia, febrile neutropenia, fatigue, and diarrhea. Clin Cancer Res; 23(12); 2924-7. ©2017 AACR.

PMID: 28213365 [PubMed - indexed for MEDLINE]

Intra-laboratory validated human cell-based in vitro vasculogenesis/angiogenesis test with serum-free medium.

Reprod Toxicol. 2017 Jun;70:116-125

Authors: Toimela T, Huttala O, Sabell E, Mannerström M, Sarkanen JR, Ylikomi T, Heinonen T

Abstract
Vasculogenesis and angiogenesis are the processes by which new blood vessels are formed. We have developed a serum-free human adipose stromal cell and umbilical cord vein endothelial cell based vasculogenesis/angiogenesis test. In this study, the test was validated in our GLP laboratory following the OECD Guidance Document 34 [1] using erlotinib, acetylic salicylic acid, levamisole, 2-methoxyestradiol, anti-VEGF, methimazole, and D-mannitol to show its reproducibility, repeatability, and predictivity for humans. The results were obtained from immunostained tubule structures and cytotoxicity assessment. The performance of the test was evaluated using 26 suspected teratogens and non-teratogens. The positive predictive value was 71.4% and the negative predictive value was 50.0%, indicating that inhibition of vasculogenesis is a significant mechanism behind teratogenesis. In conclusion, this test has great potential to be a screening test for prioritization purposes of chemicals and to be a test in a battery to predict developmental hazards in a regulatory context.

PMID: 27915012 [PubMed - indexed for MEDLINE]

Association Between Commonly Prescribed Opioids and Androgen Deficiency in Men: A Retrospective Cohort Analysis.

Pain Med. 2017 04 01;18(4):637-644

Authors: Rubinstein AL, Carpenter DM

Abstract
Objective: Androgen deficiency is common among men who use opioids daily for chronic pain. In previous studies, we found that long-acting opioids are associated with greater odds of androgen suppression than equipotent doses of short-acting opioids. Here we examined whether specific commonly prescribed opioids were associated with greater odds of androgen deficiency compared to hydrocodone.
Design: Retrospective cohort study.
Setting and Patients: Within a large, integrated health care delivery system, this study was comprised of men ages 18-80 on a stable regimen of a single opioid for chronic non-cancer pain.
Methods: Morning serum total testosterone levels were measured in subjects prescribed one opioid for at least 90 days. The association between individual opioids and androgen deficiency was assessed with logistic regression, controlling for dose, obesity, age, hypertension, hyperlipidemia, and diabetes, using hydrocodone as a referent.
Results: This study included 1,159 men. Men on fentanyl (odds ratio [OR] 25.7, 95% CI 2.82-234.97), methadone (OR 7.33, 95% CI 3.29-16.33), or oxycodone (OR 3.15, 95% CI 1.87-5.33) were more likely to be androgen deficient than men on hydrocodone. Increases in dose affected the odds of androgen deficiency differently for different opioids. Increased doses of hydrocodone (OR 1.18 per 10-mg increase in drug, 95% CI 1.09-1.28) and oxycodone (OR 1.01, 95% CI 1.00-1.02) were associated with increased odds of androgen deficiency.
Conclusions: Our results suggest that certain opioids are associated with increased odds of androgen deficiency compared with hydrocodone. Transdermal fentanyl, methadone and oxycodone were associated with higher odds of androgen deficiency than hydrocodone.

PMID: 27516365 [PubMed - indexed for MEDLINE]

Occurrence of composite cardiac endpoints with change in resting heart rate among Chinese patients with coronary artery disease: Chinese cohort from the real-world BISO-CAD study.

Curr Med Res Opin. 2018 Mar 20;:1-11

Authors: Chen Y, Yang X, Huang S, Fu G, Chen X, Yang Y, Liu S, Xu H, Ma T, Zhou X, Lv Z, Yang M, Gan X, Xu D, Cao F, Liu H, Li J, Zheng Q, Wang N, Yuan Y, Liu W, Yang T

Abstract
OBJECTIVE: We evaluated change in resting heart rate (RHR) and its impact on the prognosis in Chinese coronary artery disease (CAD) patients treated with bisoprolol and also assessed the drug safety and tolerability.
METHODS: This phase IV, single arm observational study was a sub-study of the BISO-CAD study conducted across 20 hospitals in China, between October 2011 to July 2015 with follow-up at 6, 12 and 18 months after baseline. The primary endpoint was occurrence of composite cardiac events.
RESULTS: A total of 663 CAD patients (baseline RHR 75.47 ± 6.62 bpm) were enrolled in intent-to-treat (ITT) set, whereas efficacy analysis (EA) set enrolled 513 patients. In the ITT set, the risk and the number of composite cardiac events in patients with mean RHR 69-74bpm was significantly higher compared with <65 bpm group (ITT: estimate: 1.03 ± 0.47, P = 0.029). Incidence of composite cardiac endpoint was not affected by continuous mean RHR (P = 0.5070). RHR significantly decreased from baseline to 18-months, most obvious in first six months (p <0.0001). Ejection fraction and fractional shortening significantly improved in both ITT and EA sets. Average RHR of 69-74 bpm had significant effect on admission to hospital for acute coronary syndrome in ITT (estimate 1.10, HR 3.004, P = 0.0196) and EA (estimate 1.26, HR3.526, P = 0.0132) groups. 7 (1.1%) patients reported drug related adverse events.
CONCLUSION: Reduction in RHR with bisoprolol lowered the incidence of composite cardiac events along with an acceptable safety and tolerability profile.

PMID: 29557206 [PubMed - as supplied by publisher]

Atrial Septal Defect as Unexpected Cause of Pulmonary Artery Hypertension.

Tex Heart Inst J. 2018 Feb;45(1):42-44

Authors: Parikh RV, Boyd J, Lee DP, Witteles R

Abstract
Methamphetamine abuse is an increasingly prevalent cause of pulmonary artery hypertension in the United States. Conversely, an atrial septal defect rarely presents late as pulmonary artery hypertension. We present the case of a 44-year-old methamphetamine abuser who had a 3-month history of worsening fatigue and near-syncope. She had elevated cardiac enzyme levels and right-sided heart strain. Angiographic findings suggested methamphetamine-induced pulmonary artery hypertension; however, we later heard S2 irregularities that raised suspicion of an atrial septal defect. Ultimately, the diagnosis was pulmonary artery hypertension and a large secundum atrial septal defect with left-to-right flow. One year after defect closure, the patient was asymptomatic. In addition to discussing this unexpected case of a secundum atrial septal defect masquerading as methamphetamine-induced pulmonary artery hypertension, we briefly review the natural history of atrial septal defects and emphasize the importance of thorough examination in avoiding diagnostic anchoring bias.

PMID: 29556152 [PubMed - in process]