Hospitalisation Resulting from Medicine-Related Problems in Adult Patients with Cardiovascular Diseases and Diabetes in the United Kingdom and Saudi Arabia.

Int J Environ Res Public Health. 2016 May 09;13(5):

Authors: Al Hamid A, Aslanpour Z, Aljadhey H, Ghaleb M

Abstract
Cardiovascular diseases (CVDs) and diabetes (DM) are two interrelated conditions that have a heavy morbidity and mortality burden worldwide. Patients with the two conditions usually take multiple medicines and thus are more susceptible to medicine-related problems (MRPs). MRPs can occur at any stage of the treatment process and in many cases can lead to unplanned hospitalisations. The aim of the study was to determine the prevalence of hospitalisation resulting from MRPs in adult patients with CVDs and/or DM and to identify the main causes, risk factors, and medicine classes involved. A retrospective study included 300 adult patients from two hospitals, one in the United Kingdom and one in Saudi Arabia. To identify MRPs, medical records were reviewed for demographic data, clinical data, laboratory assay, and prescription records. A total of 197 (65.7%) patients had MRPs, of which less than 10% were severe. The main problems were lack of treatment effectiveness and adverse drug reactions. Moreover, polypharmacy and patient non-adherence were the main risk factors contributing to MRPs. The main medicine classes associated with MRPs were insulin and antihypertensive medicines. Further research should address the pharmaceutical care processes employed in treating CVDs and DM, and to empower patients/healthcare providers in tackling MRPs.

PMID: 27171100 [PubMed - indexed for MEDLINE]

Natalizumab treatment of multiple sclerosis: new insights.

Immunotherapy. 2017 Jan;9(2):157-171

Authors: Delbue S, Comar M, Ferrante P

Abstract
Natalizumab is a monoclonal antibody directed against the α4 chain of the very late activating antigen 4 and α4β7 integrins, present on the leukocytes surface, used as monotherapy for the treatment of relapsing-remitting multiple sclerosis. It substantially reduces relapse rate and the accumulation of disability, but its use is associated with a very adverse event, that is the development of progressive multifocal leukoencephalopathy, a fatal demyelinating disease of the CNS, due to the lytic replication of the human polyomavirus JC. The main focus of the review is to describe the newest insights on natalizumab, its current use in the clinical practice, the natalizumab-treated patients' management and the risk stratification related to the progressive multifocal leukoencephalopathy development.

PMID: 28004598 [PubMed - indexed for MEDLINE]

Pathological characterization of nivolumab-related liver injury in a patient with glioblastoma.

Immunotherapy. 2016 12;8(12):1363-1369

Authors: Simonelli M, Di Tommaso L, Baretti M, Santoro A

Abstract
Immune checkpoint inhibitors such as anti-CTLA-4 and anti-PD-1/PD-L1 monoclonal antibodies have dramatically changed the paradigm of cancer therapy over the past few years. The use of these agents is associated with a unique pattern of autoimmune-like/inflammatory side effects termed immune-related adverse events (irAEs), that may cause collateral damage to normal tissues. Although severe irAEs remain rare, they can become life-threatening if not anticipated and managed appropriately. Improving our knowledge of the mechanisms underlying the development of these toxicities is crucial to optimize clinical efficacy and safety of these new immunotherapeutics. Herein we describe for the first time the pathological features of a severe liver-injury associated with the administration of the anti-PD-1 agent nivolumab in a patient with glioblastoma.

PMID: 28000537 [PubMed - indexed for MEDLINE]

Immune checkpoint inhibitors renal side effects and management.

Immunotherapy. 2016 Dec;8(12):1417-1425

Authors: Rassy EE, Kourie HR, Rizkallah J, Karak FE, Hanna C, Chelala DN, Ghosn M

Abstract
The choice of immunotherapy in the treatment of cancer has improved the prognosis of many patients affected by various malignancies. The high expectations foreseen with immunotherapy have led to fast approvals despite the incomplete understanding of the toxicity profiles in the different organs, including the kidneys. The high prevalence of chronic kidney disease in cancer patients complicates the issue further and requires a better knowledge of the renal safety profile to ensure an optimal safe treatment. This review summarizes the present knowledge of renal adverse events secondary to immune checkpoint inhibitors and discusses their pathophysiology, clinical presentation and adequate management. We also advocate the need for a multidisciplinary approach in patients with immune-related toxic adverse events.

PMID: 28000536 [PubMed - indexed for MEDLINE]

Dermatologic adverse events of checkpoint inhibitors: what an oncologist should know.

Immunotherapy. 2016 Dec;8(12):1437-1446

Authors: Habre M, Habre SB, Kourie HR

Abstract
Immune checkpoint inhibitors (ICI) represent a new revolutionary weapon in the armamentarium of anti-cancer therapies. The side effects of these new agents represent a new challenge for oncologists; they are usually unpredictable and sometimes life threatening, if not managed rapidly and adequately. The most frequent side effects are the dermatologic, but they are usually low grade side effects and consequently easily manageable. Rash, pruritus and vitiligo are the most frequent dermatologic side effects. We aimed in this review to describe first all the dermatologic side effects of ICI according to the subtype of ICI and combination therapies in the clinical trials, then to report all the rare case reports dermatologic side effects, and finally to present the management algorithm of these side effects.

PMID: 28000535 [PubMed - indexed for MEDLINE]

Evaluation of efficacy and safety of different pembrolizumab dose/schedules in treatment of non-small-cell lung cancer and melanoma: a systematic review.

Immunotherapy. 2016 Dec;8(12):1383-1391

Authors: Abdel-Rahman O

Abstract
AIM: Pembrolizumab is a fully humanized anti-PD-1 agent currently approved for the treatment of advanced melanoma and pretreated non-small-cell lung cancer (NSCLC).
OBJECTIVE: To assess the efficacy and safety of different dose schedules of pembrolizumab in the treatment of patients with advanced NSCLC and melanoma. Search method: MEDLINE database has been searched. Reference lists of original studies and review articles were checked for other related articles.
SELECTION CRITERIA: Prospective clinical trials reporting the outcomes of more than one dose schedule of pembrolizumab in the treatment of advanced NSCLC and melanoma.
DATA COLLECTION & ANALYSIS: The review author extracted information on the outcomes of the study for this review, and presented the results.
MAIN RESULTS: Four trials with 3425 patients were included in this systematic review. Pooled analysis for the odds ratio of objective response rate comparing 2 versus 10 mg/kg every 3 weeks in advanced melanoma was 1.03 (95% CI: 0.71-1.49; p = 0.89), while for advanced NSCLC, it was 0.97 (95% CI: 0.66-1.43; p = 0.87). Moreover, odds ratio for selected side effects between the two doses was as follows: rash: 0.83 (95 CI: 0.58-1.18; p = 0.29); vitiligo: 1.27 (95% CI: 0.62-2.61; p = 0.52); diarrhea: 0.94 (95% CI: 0.63-1.42; p = 0.79); hypothyroidism: 0.97 (95% CI: 0.63-1.50; p = 0.90); hepatitis/elevated transaminases: 1.86 (95% CI: 0.91-3.79; p = 0.09); nephritis: 0.88 (95% CI: 0.32-2.44; p = 0.80); pneumonitis: 1.17 (95% CI: 0.62-2.23; p = 0.63).

PMID: 27892744 [PubMed - indexed for MEDLINE]

Pain Treatment of Underserved Older African Americans.

J Am Geriatr Soc. 2016 Oct;64(10):2116-2121

Authors: Yazdanshenas H, Bazargan M, Smith J, Martins D, Motahari H, Orum G

Abstract
Older African Americans who experience pain are especially at high risk of underassessment and undertreatment. This study examined patterns and correlates of pain medication use: severity of pain, medical conditions, and access to care. African Americans aged 65 and older were recruited from 16 churches located in south Los Angeles (N = 400). Structured face-to-face interviews and visual inspection of each participant's medications were conducted. More than 39% of participants were aged 75 and older, and 65% were female. Forty-seven percent used at least one type of pain medication. The frequency of pain medication use according to pharmaceutical class was nonopioid, 33%; opioid, 12%; adjuvant, 9%; and other drug, 8%. Seventy-seven percent of nonopioids were nonsteroidal anti-inflammatory drugs (NSAIDs), which 25% of participants with hypertension, 28% with stroke, 26% with kidney disease, and 28% with gastrointestinal problems used. Ninety-eight percent of participants who used NSAIDs, 98% experienced potentially inappropriate medication (PIM) use, 69% experienced drug duplication, and 65% experienced drug-drug interactions. This study suggests severe mismanagement of pain in underserved older African Americans, particularly those with comorbidity, multiple providers, and limited access to health care. The use of pain medication was associated with drug-drug interactions, drug duplication, and PIM use. The data show that many participants with severe pain are not taking pain medication or experience PIM use. One in four participants was taking NSAIDs, which can cause serious side effects in older African Americans with multiple chronic conditions.

PMID: 27590566 [PubMed - indexed for MEDLINE]

Pharmacogenomics and adverse drug reactions: Primetime and not ready for primetime tests.

J Allergy Clin Immunol. 2016 Oct;138(4):943-955

Authors: Khan DA

Abstract
Adverse drug reactions (ADRs) are a relatively common cause of morbidity and mortality. Many factors can contribute to ADRs, including genetics. The degree to which genetics contributes to ADRs is not entirely clear and varies by drug, as well as the type of ADR. Pharmacogenetics and, more recently, pharmacogenomics have been applied to the field of ADRs for both predictable ADRs and hypersensitivity drug reactions. Evaluations for glucose-6-phosphate dehydrogenase and thiopurine S-methyltransferase are commonplace clinical tests to reduce hematologic problems associated with drugs, such as dapsone and azathioprine, respectively. Numerous pharmacogenetic associations have been discovered for immediate hypersensitivity reactions to β-lactams, aspirin, and nonsteroidal anti-inflammatory drugs; however, the clinical utility of testing for these genetic associations has not been established. In contrast, pharmacogenetic testing for HLA-B*1502 before carbamazepine in patients of certain Asian ethnicities and testing for HLA-B*5701 before abacavir treatment are recommended. This review will focus on pharmacogenetics and pharmacogenomics and their role in reducing ADRs, especially those caused by drug hypersensitivity reactions.

PMID: 27720019 [PubMed - indexed for MEDLINE]

Efficacy of adoptive cellular therapy in patients with gastric cancer: a meta-analysis.

Immunotherapy. 2016 Jul;8(8):971-81

Authors: Shen D, Liu ZH, Xu JN, Xu F, Lin QF, Lin F, Mao WD

Abstract
AIM: To systemically evaluate the efficacy and safety of adoptive cellular therapy for the treatment of gastric cancer (GC).
MATERIALS & METHODS: We performed a systemic review and meta-analysis of nine eligible trials with GC and evaluated the effect of adoptive cellular therapy on the overall survival (OS) rate, T-cell subsets and adverse events.
RESULTS: Overall, 829 patients were involved in the analysis. Adoptive cellular therapy significantly improved the OS rate compared with the control group. Meanwhile, we observed greatly increased percentages of CD3(+), CD4(+) and CD4(+)/CD8(+) in cellular therapy groups.
CONCLUSION: Adoptive cellular therapy combined with adjuvant therapy resulted in significantly better OS rates, progression-free survival and T-lymphocyte responses in patients with GC.

PMID: 27381688 [PubMed - indexed for MEDLINE]

Immune checkpoint inhibitors side effects and management.

Immunotherapy. 2016 Jun;8(7):799-807

Authors: Kourie HR, Klastersky J

Abstract
The next decade in cancer therapy will be marked by the expansion of immunotherapies, namely immune checkpoint inhibitors. The increasing number and combination of checkpoint inhibitors and the variety of their mechanisms of action and indications will most likely multiply the side effects associated with these therapies and make their management more complicated and diversified. Given the growing rate of approval of different checkpoint inhibitors in different cancers in multiple settings, a review summarizing the major side effects of the new agents in use today and their management seems to be appropriate. Highlighting these adverse events and their management in a single review might help the daily practice of the physicians and consequently contribute the patient's safety and quality of life.

PMID: 27349979 [PubMed - indexed for MEDLINE]

Pembrolizumab in a BRAF-mutant metastatic melanoma patient following a severe immune-related adverse event with ipilimumab.

Immunotherapy. 2016 Jun;8(6):687-92

Authors: Aya F, Fernández-Martínez A, Gaba L, Victoria I, Tosca M, Carrera C, Prat A, Arance A

Abstract
Currently, limited data exist on the safety of pembrolizumab in patients with metastatic melanoma who have developed severe immune-related adverse events following treatment with ipilimumab. We report a 45-year-old male patient with BRAF-mutant metastatic melanoma who discontinued treatment with ipilimumab due to treatment-related grade 3 colitis and was subsequently treated with the anti-programmed cell death 1 protein (PD-1) antibody pembrolizumab. He has been on treatment with pembrolizumab for more than 20 months with no major toxicities and has achieved an objective partial response, which is ongoing.

PMID: 27115320 [PubMed - indexed for MEDLINE]

Safety assessment and attenuation of cisplatin induced nephrotoxicity by tuberous roots of Boerhaavia diffusa.

Regul Toxicol Pharmacol. 2016 Nov;81:341-352

Authors: Karwasra R, Kalra P, Nag TC, Gupta YK, Singh S, Panwar A

Abstract
Cisplatin (Cis-diaminedichloroplatinum II) is a chemotherapeutic agent having well documented adverse effect as nephrotoxicity. This study was designed to evaluate the nephroprotective role of Boerhaavia diffusa in cisplatin-induced acute kidney injury. Wistar rats (n = 6) were allocated into six groups constituting normal control, cisplatin-induced, Boerhaavia diffusa root extract in doses 50, 100 and 200 mg/kg and Boerhaavia diffusa per se group, administered orally for a period of ten days. Intraperitoneal injection of cisplatin was administered on day 7, to all groups except normal control and Boerhaavia diffusa per se group. On day 10, cisplatin resulted in substantial nephrotoxicity in Wistar rats with significant (p < 0.001) elevation in serum creatinine and blood urea nitrogen, decline in the concentrations of reduced glutathione and superoxide dismutase, elevation in TNF-α level in renal tissues. Boerhaavia diffusa at a dose of 200 mg/kg body weight significantly (p < 0.001) ameliorates increased in serum creatinine, blood urea nitrogen, oxidative stress and inflammatory markers. In parallel to this, it also exhibits antiapoptotic activity through the reduction of active caspase-3 expression in kidneys. Findings indicate that Boerhaavia diffusa is effective in mitigating cisplatin-induced nephrotoxicity and thus, for this the acute and sub-acute toxicity studies conducted to evaluate the safety profile of Boerhaavia diffusa. The no-observed adverse effect level (NOAEL) of tuberous roots of Boerhaavia diffusa root extract was 1000 mg/kg.

PMID: 27667768 [PubMed - indexed for MEDLINE]

Hot Topics in Primary Care: The Cardiovascular Safety of Nonsteroidal Anti-Inflammatory Drugs: Putting the Evidence in Perspective.

J Fam Pract. 2017 Apr;66(4 Suppl):S52-S57

Authors: Quan M

Abstract
The Vioxx Gastrointestinal Outcomes Research (VIGOR) trial, published in 2000, was the first to raise concerns that NSAIDs (specifically, the COX-2 selective inhibitor rofecoxib) might be associated with a higher risk for cardiovascular (CV) events. As discussed in this article, subsequent trials and meta-analyses have demonstrated a higher CV risk with use of not only COX-2 inhibitors (coxibs) but also certain tNSAIDs. These investigations have contributed to actions by the US Food and Drug Administration (FDA), most recently in July 2015, requiring strengthening of CV risk warnings on labels for all prescription and over-the-counter NSAIDs, despite evidence suggesting that differences in CV risk may exist among the NSAIDs.

PMID: 28375409 [PubMed - indexed for MEDLINE]

Safety and Efficacy of Radiation Therapy in Advanced Melanoma Patients Treated With Ipilimumab.

Int J Radiat Oncol Biol Phys. 2016 Sep 01;96(1):72-7

Authors: Qin R, Olson A, Singh B, Thomas S, Wolf S, Bhavsar NA, Hanks BA, Salama JK, Salama AK

Abstract
PURPOSE: Ipilimumab and radiation therapy (RT) are standard treatments for advanced melanoma; preclinical models suggest the potential for synergy. However, limited clinical information exists regarding safety and optimal timing of the combination.
METHODS AND MATERIALS: We reviewed the records of consecutive patients with unresectable stage 3 or 4 melanoma treated with ipilimumab. Patients were categorized as having received RT or not. Differences were estimated between these 2 cohorts.
RESULTS: We identified 88 patients treated with ipilimumab. At baseline, the ipilimumab-plus-RT group (n=44) had more unfavorable characteristics. Despite this, overall survival, progression-free survival, and both immune-related and non-immune-related toxicity were not statistically different (P=.67). Patients who received ipilimumab before RT had an increased duration of irradiated tumor response compared with patients receiving ipilimumab after RT (74.7% vs 44.8% at 12 months; P=.01, log-rank test). In addition, patients receiving ablative RT had non-statistically significantly improved median overall survival (19.6 vs 10.2 months), as well as 6-month (95.1% vs 72.7%) and 12-month (79.7% vs 48.5%) survival rates, compared with those treated with conventionally fractionated RT.
CONCLUSIONS: We found that both ablative and conventionally fractionated RT can be safely administered with ipilimumab without a clinically apparent increase in toxicity. Patients who received ipilimumab before RT had an increased duration of irradiated tumor response.

PMID: 27375168 [PubMed - indexed for MEDLINE]

IDEAL-CRT: A Phase 1/2 Trial of Isotoxic Dose-Escalated Radiation Therapy and Concurrent Chemotherapy in Patients With Stage II/III Non-Small Cell Lung Cancer.

Int J Radiat Oncol Biol Phys. 2016 Aug 01;95(5):1367-77

Authors: Landau DB, Hughes L, Baker A, Bates AT, Bayne MC, Counsell N, Garcia-Alonso A, Harden SV, Hicks JD, Hughes SR, Illsley MC, Khan I, Laurence V, Malik Z, Mayles H, Mayles WP, Miles E, Mohammed N, Ngai Y, Parsons E, Spicer J, Wells P, Wilkinson D, Fenwick JD

Abstract
PURPOSE: To report toxicity and early survival data for IDEAL-CRT, a trial of dose-escalated concurrent chemoradiotherapy (CRT) for non-small cell lung cancer.
PATIENTS AND METHODS: Patients received tumor doses of 63 to 73 Gy in 30 once-daily fractions over 6 weeks with 2 concurrent cycles of cisplatin and vinorelbine. They were assigned to 1 of 2 groups according to esophageal dose. In group 1, tumor doses were determined by an experimental constraint on maximum esophageal dose, which was escalated following a 6 + 6 design from 65 Gy through 68 Gy to 71 Gy, allowing an esophageal maximum tolerated dose to be determined from early and late toxicities. Tumor doses for group 2 patients were determined by other tissue constraints, often lung. Overall survival, progression-free survival, tumor response, and toxicity were evaluated for both groups combined.
RESULTS: Eight centers recruited 84 patients: 13, 12, and 10, respectively, in the 65-Gy, 68-Gy, and 71-Gy cohorts of group 1; and 49 in group 2. The mean prescribed tumor dose was 67.7 Gy. Five grade 3 esophagitis and 3 grade 3 pneumonitis events were observed across both groups. After 1 fatal esophageal perforation in the 71-Gy cohort, 68 Gy was declared the esophageal maximum tolerated dose. With a median follow-up of 35 months, median overall survival was 36.9 months, and overall survival and progression-free survival were 87.8% and 72.0%, respectively, at 1 year and 68.0% and 48.5% at 2 years.
CONCLUSIONS: IDEAL-CRT achieved significant treatment intensification with acceptable toxicity and promising survival. The isotoxic design allowed the esophageal maximum tolerated dose to be identified from relatively few patients.

PMID: 27296040 [PubMed - indexed for MEDLINE]

Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy.

Eur J Cancer. 2016 Jun;60:190-209

Authors: Hofmann L, Forschner A, Loquai C, Goldinger SM, Zimmer L, Ugurel S, Schmidgen MI, Gutzmer R, Utikal JS, Göppner D, Hassel JC, Meier F, Tietze JK, Thomas I, Weishaupt C, Leverkus M, Wahl R, Dietrich U, Garbe C, Kirchberger MC, Eigentler T, Berking C, Gesierich A, Krackhardt AM, Schadendorf D, Schuler G, Dummer R, Heinzerling LM

Abstract
BACKGROUND: Anti-programmed cell death receptor-1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma as well as for other cancer entities. They act via blockade of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects affect skin, gastrointestinal tract, liver, endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential.
METHODS AND FINDINGS: In total, 496 patients with metastatic melanoma from 15 skin cancer centers were treated with pembrolizumab or nivolumab; 242 side-effects were described in 138 patients. In 116 of the 138 patients, side-effects affected the skin, gastrointestinal tract, liver, endocrine, and renal system. Rare side-effects included diabetes mellitus, lichen planus, and pancreas insufficiency due to pancreatitis.
CONCLUSION: Anti-PD1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.

PMID: 27085692 [PubMed - indexed for MEDLINE]

Phase I Study of Neoadjuvant Chemotherapy with Capecitabine and Oxaliplatin for Locally Advanced Gastric Cancer.

Anticancer Res. 2017 Jul;37(7):3703-3710

Authors: Satake H, Kondo M, Mizumoto M, Kotake T, Okita Y, Ogata T, Hatachi Y, Yasui H, Miki A, Imai Y, Ichikawa C, Murotani K, Kotaka M, Kato T, Kaihara S, Tsuji A

Abstract
AIM: To determine the recommended dose of neoadjuvant chemotherapy of combined capecitabine and oxalipatin (G-XELOX) for locally advanced gastric cancer.
PATIENTS AND METHODS: Patients received two cycles of neoadjuvant chemotherapy with oxaliplatin on day 1 and capecitabine (2,000 mg/m(2)/day, b.i.d.) on days 1-14, repeated every 3 weeks. They then underwent gastrectomy with curative D2/3 lymph-node dissection followed by adjuvant therapy with S-1 for 1 year. De-escalation of oxaliplatin dose was planned (starting at level 1, oxalipatin 130 mg/m(2)).
RESULTS: Six patients were enrolled. The maximum tolerated dose was not reached at level 1. Oxaliplatin at 130 mg/m(2) combined with capecitabine at 2,000 mg/m(2)/day, b.i.d. had acceptable toxicity. No treatment-related death occurred. Most frequent drug-related adverse events during neoadjuvant G-XELOX were nausea and peripheral sensory neuropathy. One patient declined surgical resection, leaving five undergoing resection with curative intent, of whom four achieved pathological down-staging after neoadjuvant G-XELOX.
CONCLUSION: Neoadjuvant G-XELOX was feasible in patients with locally advanced gastric cancer.

PMID: 28668863 [PubMed - in process]

Effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on cardiovascular events and residual renal function in dialysis patients: a meta-analysis of randomised controlled trials.

BMC Nephrol. 2017 Jun 30;18(1):206

Authors: Liu Y, Ma X, Zheng J, Jia J, Yan T

Abstract
BACKGROUND: The role of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) reducing risk of cardiovascular events (CVEs) and preserving kidney function in patients with chronic kidney disease is well-documented. However, the efficacy and safety of these agents in dialysis patients is still a controversial issue.
METHODS: We systematically searched MEDLINE, Embase, Cochrane Library and Wanfang for randomized trials. The relative risk (RR) reductions were calculated with a random-effects model. Major cardiovascular events, changes in GFR and drug-related adverse events were analyzed.
RESULTS: Eleven trials included 1856 participants who were receiving dialysis therapy. Compared with placebo or other active agents groups, ARB therapy reduced the risk of heart failure events by 33% (RR 0.67, 95% CI 0.47 to 0.93) with similar decrement in blood pressure in dialysis patients. Indirect comparison suggested that fewer cardiovascular events happened during treatment with ARB (0.77, 0.63 to 0.94). The results indicated no significant differences between the two treatment regimens with regard to frequency of myocardial infarction (1.0, 0.45 to 2.22), stroke (1.16, 0.69 to 1.96), cardiovascular death (0.89, 0.64 to 1.26) and all-cause mortality (0.94, 0.75 to 1.17). Five studies reported the renoprotective effect and revealed that ACEI/ARB therapy significantly slowed the rate of decline in both residual renal function (MD 0.93 mL/min/1.73 m(2), 0.38 to 1.47 mL/min/1.73 m(2)) and urine volume (MD 167 ml, 95% CI 21 ml to 357 ml). No difference in drug-related adverse events was observed in both treatment groups.
CONCLUSIONS: This study demonstrates that ACE-Is/ARBs therapy decreases the loss of residual renal function, mainly for patients with peritoneal dialysis. Overall, ACE-Is and ARBs do not reduce cardiovascular events in dialysis patients, however, treatment with ARB seems to reduce cardiovascular events including heart failure. ACE-Is and ARBs do not induce an extra risk of side effects.

PMID: 28666408 [PubMed - in process]

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Evaluation of the Potential Risk of Drugs to Induce Hepatotoxicity in Human-Relationships between Hepatic Steatosis Observed in Non-Clinical Toxicity Study and Hepatotoxicity in Humans.

Int J Mol Sci. 2017 Apr 12;18(4):

Authors: Goda K, Kobayashi A, Takahashi A, Takahashi T, Saito K, Maekawa K, Saito Y, Sugai S

Abstract
In the development of drugs, we sometimes encounter fatty change of the hepatocytes (steatosis) which is not accompanied by degenerative change in the liver in non-clinical toxicity studies. In this study, we investigated the relationships between fatty change of the hepatocytes noted in non-clinical toxicity studies of compound X, a candidate compound in drug development, and mitochondrial dysfunction in order to estimate the potential risk of the compound to induce drug-induced liver injury (DILI) in humans. We conducted in vivo and in vitro exploratory studies for this purpose. In vivo lipidomics analysis was conducted to investigate the relationships between alteration of the hepatic lipids and mitochondrial dysfunction. In the liver of rats treated with compound X, triglycerides containing long-chain fatty acids, which are the main energy source of the mitochondria, accumulated. Accumulation of these triglycerides was considered to be related to the inhibition of mitochondrial respiration based on the results of in vitro mitochondria toxicity studies. In conclusion, fatty change of the hepatocytes (steatosis) in non-clinical toxicity studies of drug candidates can be regarded as a critical finding for the estimation of their potential risk to induce DILI in humans when the fatty change is induced by mitochondrial dysfunction.

PMID: 28417920 [PubMed - indexed for MEDLINE]