Increased Creatine Phosphokinase Research Articles

1472 Hypokalemia-Induced Rhabdomyolysis From Budesonide Therapy in Crohn's Disease: A Case Report and Review of the Pathophysiology

INTRODUCTION: Here we present the case of a 71-year-old white male with active ileocolonic Crohn's disease, recently started on budesonide therapy, who presents with extreme weakness and muscle aches. He was diagnosed with hypokalemia induced rhabdomyolysis, three weeks after starting budesonide therapy. CASE DESCRIPTION/METHODS: We present the case of a 71-year-old male with hypertension and ileocolonic stricturing crohn's disease (CD) presents with severe muscle weakness and malaise. He presented for a five-month history of worsening watery diarrhea and unintentional weight loss. Colonoscopy to neoterminal ileum revealed Rutgeerts score of i3. He was started on oral 9 mg budesonide and began to experience weakness and muscle aches to a point where he was unable to walk or lift his arms above his head. He presented to the hospital and labs revealed hypomagnesemia 0.8 mg/dL, hypokalemia of potassium 1.7 mmol/L, creatinine 1.52 mg/dL, creatine phosphokinase (CPK) 15913 IU/L, hypocalcemia 7.1 mg/dL, normal albumin 3.7 g/dL. Urinalysis showed 3+ blood and 0-3 red blood cells. Labs two months prior were unremarkable (Table 1). He was diagnosed with rhabdomyolysis. DISCUSSION: Budesonide has long been accepted as induction therapy for mild-to-moderate CD. Hypokalemia induced rhabdomyolysis is due to laxative abuse, chronic diarrhea, renal tubular acidosis, diuretics use is well reported. Hypokalemia is a known side effect of budesonide. 1 Rhabdomyolysis is a syndrome which is characterized by muscle necrosis with CPK four times more than the upper limit of normal. 1 During a muscle contraction, potassium is released from the intracellular to extracellular space mediating the vasodilation and more blood flow to the muscle. When a patient has hypokalemia, there is a decrease in blood flow to the contracting muscles. This leads to constriction of arterioles causing ischemia of the muscles and myocytes destruction. The breakdown of the myofibril causes muscle necrosis and an increase in intracellular CPK and myoglobin, which is released into the blood circulation. 2 In this patient, several factors were taken into account for the cause of hypokalemia induced rhabdomyolysis. The patient rapidly responded to intervenous fluid and discontinuation of the budesonide.

Safety and immunogenicity of an anti-Middle East respiratory syndrome coronavirus DNA vaccine: a phase 1, open-label, single-arm, dose-escalation trial

BackgroundMiddle East respiratory syndrome (MERS) coronavirus causes a highly fatal lower-respiratory tract infection. There are as yet no licensed MERS vaccines or therapeutics. This study (WRAIR-2274) assessed the safety, tolerability, and immunogenicity of the GLS-5300 MERS coronavirus DNA vaccine in healthy adults.MethodsThis study was a phase 1, open-label, single-arm, dose-escalation study of GLS-5300 done at the Walter Reed Army Institute for Research Clinical Trials Center (Silver Spring, MD, USA). We enrolled healthy adults aged 18–50 years; exclusion criteria included previous infection or treatment of MERS. Eligible participants were enrolled sequentially using a dose-escalation protocol to receive 0·67 mg, 2 mg, or 6 mg GLS-5300 administered by trained clinical site staff via a single intramuscular 1 mL injection at each vaccination at baseline, week 4, and week 12 followed immediately by co-localised intramuscular electroporation. Enrolment into the higher dose groups occurred after a safety monitoring committee reviewed the data following vaccination of the first five participants at the previous lower dose in each group. The primary outcome of the study was safety, assessed in all participants who received at least one study treatment and for whom post-dose study data were available, during the vaccination period with follow-up through to 48 weeks after dose 3. Safety was measured by the incidence of adverse events; administration site reactions and pain; and changes in safety laboratory parameters. The secondary outcome was immunogenicity. This trial is registered at ClinicalTrials.gov (number NCT02670187) and is completed.FindingsBetween Feb 17 and July 22, 2016, we enrolled 75 individuals and allocated 25 each to 0·67 mg, 2 mg, or 6 mg GLS-5300. No vaccine-associated serious adverse events were reported. The most common adverse events were injection-site reactions, reported in 70 participants (93%) of 75. Overall, 73 participants (97%) of 75 reported at least one solicited adverse event; the most common systemic symptoms were headache (five [20%] with 0·67 mg, 11 [44%] with 2 mg, and seven [28%] with 6 mg), and malaise or fatigue (five [20%] with 0·67 mg, seven [28%] with 2 mg, and two [8%] with 6 mg). The most common local solicited symptoms were administration site pain (23 [92%] with all three doses) and tenderness (21 [84%] with all three doses). Most solicited symptoms were reported as mild (19 [76%] with 0·67 mg, 20 [80%] with 2 mg, and 17 [68%] with 6 mg) and were self-limiting. Unsolicited symptoms were reported for 56 participants (75%) of 75 and were deemed treatment-related for 26 (35%). The most common unsolicited adverse events were infections, occurring in 27 participants (36%); six (8%) were deemed possibly related to study treatment. There were no laboratory abnormalities of grade 3 or higher that were related to study treatment; laboratory abnormalities were uncommon, except for 15 increases in creatine phosphokinase in 14 participants (three participants in the 0·67 mg group, three in the 2 mg group, and seven in the 6 mg group). Of these 15 increases, five (33%) were deemed possibly related to study treatment (one in the 2 mg group and four in the 6 mg group). Seroconversion measured by S1-ELISA occurred in 59 (86%) of 69 participants and 61 (94%) of 65 participants after two and three vaccinations, respectively. Neutralising antibodies were detected in 34 (50%) of 68 participants. T-cell responses were detected in 47 (71%) of 66 participants after two vaccinations and in 44 (76%) of 58 participants after three vaccinations. There were no differences in immune responses between dose groups after 6 weeks. At week 60, vaccine-induced humoral and cellular responses were detected in 51 (77%) of 66 participants and 42 (64%) of 66, respectively.InterpretationThe GLS-5300 MERS coronavirus vaccine was well tolerated with no vaccine-associated serious adverse events. Immune responses were dose-independent, detected in more than 85% of participants after two vaccinations, and durable through 1 year of follow-up. The data support further development of the GLS-5300 vaccine, including additional studies to test the efficacy of GLS-5300 in a region endemic for MERS coronavirus.FundingUS Department of the Army and GeneOne Life Science.

Stimulation of Bladder Acupoints by Cloprostenol for Treating Back Soreness in Athletic Horses

Twenty-five Thoroughbred jumper geldings suffered back soreness with poor performance, and 5 control horses were assessed by archived computer data, clinical examination, and laboratory analyses of complete blood picture, serum enzymes, and cortisol level, before and after cloprostenol-pharmacopuncture. The 25 diseased horses before therapy showed significant increases in aspartate aminotransferase and creatine phosphokinase with clinical pains scored mild in 15 horses, moderate in 9 horses, and severe in one horse, without changes in the hormonal and hematological data. After therapy, they responded by an increase of heart rate (57.8 ± 4.3 bpm), body temperature (38.5 ± 0.7°C), respiration rate (28.3 ± 2.1 bpm), and capillary refilling time (CRT) (1.0 ± 0.0). On the 2nd day, a significant decrease in the mean levels of aspartate aminotransferase and creatine phosphokinase (P = 0.001) was detected, while on the 4th day, they mimed the level of the 5 controls, and on the 6th day, they showed a significant decrease (P = 0.002). The serum cortisol level showed a significant increase on the 6th day of treatment (P = 0.013). The blood picture showed significant increases in red blood cells, mean corpuscular volume, platelets, white blood cells, hemoglobin, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, mean platelet volume, platelet distribution width, lymphocytes, plateletcrit, and large platelet concentration ratio (P < 0.05) and nonsignificant changes in hematocrit, granulocytes, and midocytes. The improved blood parameters, enzymes, hormones, and performance progress after cloprostenol-pharmacopuncture proved its effectiveness in treating back soreness in athletic horses.

Phase 1 study of LY3022855, a colony-stimulating factor-1 receptor (CSF-1R) inhibitor, in patients with metastatic breast cancer (MBC) or metastatic castration-resistant prostate cancer (MCRPC).

2548 Background: Tumor-associated macrophages (TAM) correlate with increased invasiveness, growth, and immunosuppression. Activation of CSF-1R results in proliferation, differentiation, and migration of monocytes/macrophages. CSF-1R inhibition with LY3022855 (LY), a human immunoglobulin G subclass 1 (IgG1) monoclonal antibody (mAB), may have favorable anti-tumor effects. We evaluated the safety and clinical response of LY monotherapy. Methods: Patients (pts) with advanced refractory MBC and MCRPC received LY intravenously in 6-week cycles in cohorts: A) 1.25 mg/kg every 2 weeks [Q2W]; B) 1.0 mg/kg on Weeks 1, 2, 4, and 5; C) 100 mg once weekly; D)100 mg Q2W. MCRPC pts were enrolled in cohorts A and B; MBC pts were enrolled in all cohorts. Anti-tumor activity was assessed using RECIST v1.1 by radiological imaging every 6 weeks. Results: Thirty-four pts (22 MBC; 12 MCRPC) received ≥1 dose of LY. Median age was 57.0 years (range: 32.0–81.0) for MBC pts and 72.5 years (range: 58.0–84.0) for MCRPC pts. Baseline Eastern Cooperative Oncology Group performance status was 0 (n = 13, 38.2%), 1 (n = 18, 52.9%), or 2 (n = 3, 8.8%). MBC pts were hormone receptor (HR) positive (n = 20), HR negative (n = 1), or unknown (n = 1); 3 MBC pts received concurrent hormone therapy. Common treatment-related adverse events of any grade were fatigue (38.2%), decreased appetite (26.5%), nausea (26.5%), increased lipase (23.5%), and increased creatine phosphokinase (20.6%). No complete or partial response was observed. Stable disease (SD) was observed in 5/22 MBC pts (duration 82–302 days) and 3/7 evaluable MCPRC pts (duration 50–124 days). Two MBC pts (9%; Cohort A) had durable SD &gt; 9 months and 1 pt had palpable reduction in a nontarget neck mass. Circulating CSF1 and IL-34 increased at Day 8 suggestive of target engagement. Pharmacokinetics of LY were consistent with other IgG1 mAbs. Conclusions: LY3022855 was well tolerated and showed evidence of target engagement. Clinically meaningful SD &gt; 9 months was observed in 2 MBC pts. Tumor biomarker analyses are underway. Clinical trial information: NCT02265536.

Intermediate-Term Efficacy and Tolerance of Statins in Children

To evaluate the intermediate-term efficacy and tolerance of statins in children and adolescents with familial hypercholesterolemia. A total of 131 children or adolescents treated with statins for familial hypercholesterolemia were prospectively included. The efficacy of treatment was established by the percentage of children who achieved low density lipoprotein-cholesterol (LDL-C) levels <160mg/dL during treatment. Treatment tolerance was evaluated by the occurrence of clinical or laboratory side effects, regularity of increases in height and weight, and pubertal development. The median duration of treatment with statins was 4years. A median decrease of 32% in LDL-C levels was observed (P<.0001). The therapeutic target (LDL-C <160mg/dL) was achieved in 67% of cases. Increases in height and weight and sexual maturation were not affected by the treatment. Minor side effects were reported for 24 (18.4%) patients including 3 cases of a clinically asymptomatic increase in creatine phosphokinase (CPK) levels, 2 cases of an increase in CPK levels with muscular symptoms, 14 cases of myalgia without an increase in CPK levels, 3 cases of abdominal pain, 1 case of dysuria, and 1 case of diffuse pain. None of these side effects led to the discontinuation of statin therapy, although a change of statin was required in 7 cases. This new statin was tolerated in all cases. No patients had abnormal liver function during treatment. The results of this large cohort confirm the intermediate-term safety and efficacy of statin therapy in children with familial hypercholesterolemia.

Indices of muscle and liver dysfunction after surviving hemorrhage and prolonged hypotension.

This study determined the long-term effects of prolonged hypotension (PH) on liver, muscle, and kidney dysfunction. The hypothesis was that longer duration of PH after hemorrhage will result in greater organ dysfunction. Baboons were sedated and hemorrhaged (30% blood volume). Systolic blood pressure greater than 80 mm Hg was maintained for 1 hour (1 hr-PH; n = 5), 2 hours (2 hr-PH; n = 5), or 3 hours (3 hr-PH; n = 5). After PH, hemorrhage volume was replaced. Animals were recovered and monitored for 21 days. Control animals were hemorrhaged and immediately resuscitated (0 hr-PH, n = 3). Data are Mean ± Standard Deviation, and analyzed by 2-way repeated measures ANOVA and Holm-Sidak test. Hemorrhage resulted in mild hypotension. Minimal resuscitation was required during the hypotensive phase, and survival rate was 100%. Significant increases (p < 0.001) in alanine aminotransferase, aspartate aminotransferase, creatine phosphokinase, and lactate dehydrogenase occurred on Day 1 after PH, and were significantly greater (p < 0.001) in the 2 hr- and 3 hr-PH groups than the 0 hr-PH group. Maximum alanine aminotransferase levels (U/L) were 140 ± 56 (0 hr-PH), 170 ± 130 (1 hr-PH), 322 ± 241 (2 hr-PH), and 387 ± 167 (3 hr-PH). Maximum aspartate aminotransferase levels (U/L) were 218 ± 44 (0 hr-PH), 354 ± 219 (1 hr-PH), 515 ± 424 (2 hr-PH), and 711 ± 278 (3 hr-PH). Maximum creatine phosphokinase values (U/L) were 7834 ± 3681 (0 hr-PH), 24336 ± 22268 (1 hr-PH), 50494 ± 67653 (2 hr-PH), and 59857 ± 32408 (3 hr-PH). Maximum lactic acid dehydrogenase values (U/L) were 890 ± 396 (0 hr-PH), 2055 ± 1520 (1 hr-PH), 3992 ± 4895 (2 hr-PH), and 4771 ± 1884 (3 hr-PH). Plasma creatinine and blood urea nitrogen were unaffected by PH (p > 0.10). These results indicate that PH up to 3 hours in duration results in transient liver and muscle dysfunction that was most severe after 2 hr-PH and 3 hr-PH. Prolonged hypotension produced minimal effects on the kidney. Basic science research, Level of evidence not required for basic science research.

Protective role of Roflumilast against cadmium-induced cardiotoxicity through inhibition of oxidative stress and NF-κB signaling in rats

Cadmium (Cd), a potent cardiotoxic environmental heavy metal, induces oxidative stress and membrane disturbances in cardiac myocytes. Phosphodiesterase (PDEs) retards the positive inotropic effects of β-adrenoceptor activation by decreasing levels of cAMP via degradation. Hence, PDE inhibitors sensitize the heart to catecholamine and are therefore, used as positive inotropic agents. The present study was designed to probe the potential attenuating effects of the selective PDE4 inhibitor (Roflumilast, ROF), on cardiac biomarkers, lipid profile, lipid peroxidation products, antioxidant status and histology of cardiac tissues against Cd-induced cardiotoxicity in rats. Rats were randomly distributed into four different groups: group 1, served as the normal control group. Group 2, served as the toxic control group and were administered Cd (3 mg/kg, i.p.) for next 7 days. Groups 3 and 4, served as treatment groups that received Cd with concomitant oral administration of ROF doses (0.5 and 1.5 mg/kg), respectively for 7 days. Serum samples of toxic control group rats resulted in significant (P < 0.001) increase in lactate dehydrogenase (LDH), creatine phosphokinase (CPK), total cholesterol (TC), triglycerides (TG) and low density lipoproteins (LDL) levels with concomitant decrease in high density lipoproteins (HDL) levels in serum which were found reversed with both of ROF treatment groups. Cd also causes significant increased (P < 0.001) in myocardial malondialdehyde (MDA) contents while cardiac glutathione (GSH) level, superoxide dismutase (SOD) and catalase (CAT) enzyme activities were found decreased whereas both doses of ROF, significantly reversed these oxidative stress markers and antioxidant enzymes. Cardiotoxicity induced by Cd also resulted in enhanced expression of non-phosphorylated and phosphorylated form of NF-κB p65 and decreased expression of glutathione-S-transferase (GST) and NQO1 which were found reversed with ROF treatments, comparable to normal control group. Histopathological changes were also improved by ROF administration as compared to Cd treated rats alone. In conclusion, Roflumilast exhibited attenuating effect against Cd-induced cardiac toxicity.

Brigatinib: Novel ALK Inhibitor for Non-Small-Cell Lung Cancer.

We review here the pharmacology, pharmacokinetics, efficacy, safety, dosage and administration, potential drug-drug interactions and place in therapy of brigatinib for abnormal anaplastic lymphoma kinase (ALK) specific non-small-cell lung cancer (NSCLC). A literature search using PubMed was conducted using the terms brigatinib and ALK positive NSCLC from January 2013 to November 2018. All English-language articles evaluating brigatinib were analyzed for this review. Brigatinib was granted approval for the treatment of patients with metastatic ALK+ NSCLC who have progressed on or are intolerant to crizotinib. It is administered at a dose of 90 mg orally once daily for the first 7 days then, if tolerated, increased to a dose of 180 mg orally once daily. Common adverse effects include nausea, fatigue, diarrhea, increased creatine phosphokinase levels, headache, dyspnea, and hypertension. Serious treatment-emergent adverse effects were pulmonary related. Relevance to Patient Care and Clinical Practice: This article discusses the clinical trials that led to the accelerated approval of brigatinib for its ability to overcome crizotinib-resistant mutations and for its increased central nervous system penetration properties. Brigatinib was granted accelerated approval for the treatment of patients with metastatic ALK+ NSCLC who have progressed on or are intolerant to crizotinib. In a subset of NSCLC patients, brigatinib increases survival for approximately 1 year; however, side effects were detected.

Evaluation of L-carnitine in the treatment of experimentally induced hypomagnesemia in sheep

The aim of this study was to evaluate the role of L-carnitine in the treatment of experimentally induced hypomagnesemia in sheep. This study was carried out on 10 ossimi rams aged 10-12 months old with an average live weight of 35±1.1 kg that were used for experimental induction of hypomagnesemia. Rams with induced hypomagnesaemia were divided into two groups according to the line of treatment. The first group (n=5) was treated by the traditional treatment alone while the second group (n=5) was treated by the traditional treatment in addition to L-carnitine (20 mg/kg I/V). The symptoms of hypomagnesemia appeared gradually until complete appearance of symptoms at day 28 post induction. There was significant decrease (P < 0.05) in serum magnesium (Mg), calcium (Ca), glucose and parathyroid hormone (PTH) in experimentally induced hypomagnesemic rams. However, there were significant increase (P < 0.05) in serum sodium (Na), potassium (K), urea, creatinine, cortisol, creatine phosphokinase (CPK) and troponin I (cTnI) in experimentally induced hypomagnesemic rams. Treatment of hypomagnesemia with traditional treatment and L-carnitine resulted in significant elevation (P < 0.05) of serum Mg, Ca, glucose and PTH in hypomagnesemic rams than traditional treatment only. However, there were significant reduction (P < 0.05) in serum K, urea, CPK and cTnI than traditional treatment only at 24 hour after treatment. Based on the results of this study we concluded that the addition of L-carnitine to the traditional treatment of hypomagnesaemia in sheep is effective and produced earlier and more pronounced recovery.

Tislelizumab (BGB-A317) for Relapsed/Refractory Classical Hodgkin Lymphoma: Preliminary Efficacy and Safety Results from a Phase 2 Study

Background: Tislelizumab is a humanized IgG4 monoclonal antibody with high affinity/specificity for programmed cell death protein 1 (PD-1). Tislelizumab was specifically engineered to minimize binding to FcɤR on macrophages, thereby abrogating antibody-dependent phagocytosis, a potential mechanism of T-cell clearance and resistance to anti-PD-1 therapy (Dahan 2015). Results of tumor growth inhibition studies suggest that tislelizumab had superior antitumor activity compared with nivolumab in mice transplanted with human cancer cells and peripheral blood mononuclear cells. Favorable results with other PD-1 inhibitors in patients with relapsed or refractory (R/R) classical HL (cHL) provide a strong rationale to investigate tislelizumabin this disease.Methods: BGB-A317-203 (clinicaltrials.gov NCT03209973) is a single-arm, open-label, multicenter, phase 2 study of tislelizumab in Chinese patients with R/R cHL; all patients received tislelizumab 200 mg intravenously every 3 weeks until progression or unacceptable toxicity. Patients were eligible if they (a) failed to achieve a response or progressed after autologous stem cell transplant (ASCT) or (b) received ≥2 prior systemic chemotherapy regimens for cHL and were ineligible for ASCT. Diagnosis of cHL was confirmed in all patients by central pathologic review.The primary endpoint was overall response rate (ORR) determined using the Lugano criteria (Cheson, 2014) as assessed by an independent review committee (IRC). Key secondary endpoints included progression-free survival (PFS), duration of response, rate of complete response (CR), time to response, safety, and tolerability. Treatment emergent adverse events (TEAEs) were summarized according to NCI-CTCAE v4.03.Results: In total, 70 patients were enrolled from 11 Chinese centers; patient characteristics are shown in the Table. With a data cutoff date of 25 May 2018, the median follow-up was 7.9 months (range, 3.4 to 12.7). The IRC-assessed ORR was 85.7%, based on PET-CT scans. A total of 43 patients (61.4%) achieved CR, 38 of whom were in CR at the first on-study response assessment. At data cutoff, 53 patients remained on treatment and 17 had discontinued (11 for progressive disease [PD]; 4 for TEAEs; 1 withdrew consent; 1 due to pregnancy). The estimated 6-month PFS rate was 80%. The most frequently reported (≥15%) TEAEs due to any cause were pyrexia (52.9%), hypothyroidism (30.0%), increased weight (28.6%), upper respiratory tract infection (27.1%) and cough (17.1%). Grade ≥3 TEAEs reported in ≥2 patients were upper respiratory tract infection (2.9%) and pneumonitis (2.9%). Immune-related TEAEs were reported in 23 patients (32.9%); Grade ≥3 in 5 patients (7.1%): pneumonitis (n=2), organizing pneumonia, nephritis (focal segmental glomerulosclerosis) and increased creatine phosphokinase (each n=1). There were no Grade 5 TEAEs. TEAEs that led to treatment discontinuation in 4 patients (5.7%) included pneumonitis (n=2), organizing pneumonia (n=1), and focal segmental glomerulosclerosis (n=1). One patient died on study due to PD.Conclusions: In this study, tislelizumab therapy was shown to be highly active resulting in a high CR rate in patients with R/R cHL who had failed or were ineligible for ASCT. Tislelizumab was generally well-tolerated in Chinese patients with R/R cHL. The safety profile was generally consistent with that of other PD-1 inhibitors for the treatment of cHL. DisclosuresSong:Peking University Cancer Hospital (Beijing Cancer Hospital): Employment. Liu:West China Hospital of Sichuan University: Employment. Guo:BeiGene (Shanghai) Co., LTD: Employment. Yang:BeiGene (Beijing) Co., Ltd.: Employment. Elstrom:BeiGene (Beijing) Co., Ltd.: Employment, Equity Ownership. Huang:BeiGene (Beijing) Co., Ltd.: Employment, Equity Ownership. Novotny:BeiGene (Beijing) Co., Ltd.: Employment, Equity Ownership. Wei:BeiGene (Beijing) Co., Ltd.: Employment, Equity Ownership. Zhu:Beijing Cancer Hospital: Employment.

Creatine Phosphokinase and Urea as Biochemical Markers of Muscle Injuries in Professional Football Players

Background: Although biochemical markers have been used to monitor training loads (TL), it is unknown if they can be used to predict muscle injuries (MI) in professional football (soccer) players (PFP). Objectives: To evaluate the relationship between the incidence of MI, serum concentration of creatine phosphokinase (CPK) and urea, as well as TL in PFP. Methods: Twenty-three PFP from a Colombian first-division team were enrolled in a retrospective cohort study. CPK, urea, TL and new MI were measured during 19 weeks. CPK and urea serum levels within 4 weeks before a diagnosed MI were compared to those measured preseason. CPK and urea relationship with TL were analyzed using a mixed-effects model. Results: The subjects had an age of 25.3 ± 4.2 years. Nine subjects presented with MI during follow-up, 66.6% of which were localized to hamstrings. Serum CPK and urea profiles were constructed for each player along the season. Injured players had a significant elevation of these markers within 4 weeks before the injury was clinically evident when compared to their own preseason values. Expected individual increases in CPK and urea according to TL during the season were estimated. Conclusions: Since CPK and urea values rose several weeks before the MI became overt, constructing CPK and urea profiles for each player during the whole preseason and season may help identify peaks in their concentration as early markers of MI. A tight biochemical control of training may become a preventive strategy for MI, but the use of published reference values is discouraged.

Potential role of α-lipoic acid and Ginkgo biloba against silver nanoparticles-induced neuronal apoptosis and blood-brain barrier impairments in rats

AimsThis study explored whether silver nanoparticles (AgNPs) can disrupt tight-junctions integrity resulted in blood-brain barrier dysfunction along with oxidative stress, pro-inflammation, and apoptosis induction. Additionally, neuroprotective activities of α-lipoic acid (LA) and Ginkgo biloba (GB) were investigated. Main methodsForty adults rats were enrolled into; Control, AgNPs (50 mg/kg), LA (100 mg/kg) + AgNPs, and GB (120 mg/kg) + AgNPs. After 30 days, neuronal changes were assessed biochemically and histopathologically. Brain tissues oxidative indices, mRNA expression of proinflammatory cytokines and tight-junction proteins and pro-apoptotic biomarker, caspase-3 were investigated. Key findingsAgNPs exposure enhanced lipid peroxidation (+195%) along with declines in glutathione (−43%), glutathione peroxidase (−34%), glutathione S-transferase (−31%), catalase (−43%), and superoxide dismutase (−38%) activities in brain tissues. The apparent brain oxidative damage was associated with obvious neuronal dysfunction that was ascertained by neuropathological lesions. AgNPs lowered serum acetylcholine esterase, iron and copper levels, and increased creatine phosphokinase and creatine phosphokinase–brain type activities. Following AgNPs exposure, brain silver and iron contents were increased, but the copper level was decreased. AgNPs up-regulated TNF-α (6.5-fold) and IL-1β (8.9-fold) transcript levels, and simultaneously over-expressed the caspase-3 protein in cerebrum and cerebellum inducing cell apoptosis. Moreover, AgNPs down-regulated the transcript levels of tight-junction proteins; JP-1 (0.65-fold) and JAM-3(0.81-fold). SignificanceLA and relatively GB improved the serious effects of AgNPs on the blood-brain barrier function and tight-junction proteins through their antioxidants, anti-inflammatory, and anti-apoptotic efficacies. Co-treatment with LA or GB may be favorable in ameliorating the neurotoxic side effects of AgNPs.

Clinical, morphological, and molecular characterization of an undetermined Babesia species in a maned wolf (Chrysocyon brachyurus)

A possible novel Babesia species infection of a maned wolf (Chrysocyon brachyurus) was first reported in 2012. The current case details a confirmed report of a maned wolf with infection by an undetermined species of Babesia. As the mortality and morbidity of babesiosis is high, this may become a significant concern to captive maned wolves, which are considered a near-threatened species by the World Association of Zoos and Aquariums. The aim of this study is to report the clinical, morphological and molecular characterization of this Babesia species. A 2.5-year-old, intact female maned wolf was found laterally recumbent with pale mucous membranes and jaundice the morning of presentation. Hematological and serum biochemical data were consistent with babesiosis and showed a regenerative severe anemia, leukocytosis, thrombocytopenia, hyperbilirubinemia, azotemia, increased creatine phosphokinase and increase alanine aminotransferase. On blood film review, inclusion bodies were seen in the red blood cells with cytomorphological features that were most consistent with a small form Babesia species. A blood sample was sent for polymerase chain reaction (PCR) testing and multi-locus sequence analyses. These findings suggested a unique Babesia species that is most closely related to a Babesia species (Babesia sp. AJB-2006) that has been found to infect raccoons (Procyon lotor) in North America. Although the cytomorphological features of the piroplasms and the clinical presentation were similar in both the current and 2012 case, when comparing the 18S melt curve temperature of the two Babesia isolates, the peak temperature was different. Unfortunately, genetic material from the 2012 case was not available so comparison of multi-locus gene sequences could not be performed, excluding the possibility to definitively state if the Babesia spp. from both cases were distinct from each other. The maned wolf was treated with a whole blood transfusion, dexamethazone (0.28 mg/kg IM), azithromycin (10 mg/kg in NaCl SC), atavaquone (1.5 cc PO), and 2 imidocarb (6.6 mg/kg IM) injections, and clinically improved. These findings demonstrate the need to further characterize the molecular and epidemiological differences of the Babesia species in this case report and the Babesia species known to infect raccoons.

Propofol Infusion Syndrome: Efficacy of a Prospective Screening Protocol

Propofol infusion syndrome (PIS) is a potentially lethal complication of propofol marked by rhabdomyolysis, metabolic acidosis, and cardiac arrhythmias or collapse. The objective of this study was to determine the effectiveness of a prospective screening protocol to prevent PIS. All trauma patients admitted who received propofol as a continuous infusion were prospectively screened from November 1, 2013 to December 31, 2015. Variables studied included demographics, injury severity, laboratory values, infusion rates, and mortality. Serum creatine phosphokinase (CPK) and lactate were drawn daily. Propofol was stopped for a positive screen defined as an increase in CPK to greater than 5000 IU/L or lactate greater than 4 mmol/L. Positive and negative cohorts were compared. Two hundred and twenty-five patients met the inclusion criteria and 12 patients (5.3%) had propofol stopped because of elevated CPK. No differences were identified in demographics, transfusions, injury severity, hospital length of stay, or propofol dose. The positive screened group had longer intensive care unit length of stay (20 vs 13 days; P = 0.002) and increased vent days (14.5 vs 10 days; P = 0.008). Max serum osmolality (334 vs 305 mosm/kg; P = 0.049) and max serum CPK (6782 vs 1058 IU/L; P < 0.0001) were higher in the positive cohort. No cases of PIS occurred, and mortality (16.7 vs 15.5%; P = 0.999) was not different between the cohorts. The screening protocol was effective in eliminating PIS. Serial CPK evaluations provided an effective screening tool and serum lactate can be dropped from screening.

Avelumab: A Review of Its Application in Metastatic Merkel Cell Carcinoma.

To summarize the clinical development of avelumab and its clinical relevance in metastatic Merkel cell carcinoma (MCC). An English-language literature search using PubMed was performed using the terms avelumab, anti-PD-1, anti-PD-L1, and MCC from January of 1950 to March 2018. Data were also obtained from package inserts, meeting abstracts, and clinical registries. All relevant published articles of avelumab were reviewed. Clinical trial registries and meeting abstracts were used for information about ongoing trials. Avelumab is a fully human monoclonal antibody that inhibits programmed death ligand-1, which reverses T-cell exhaustion and induces antitumor responses. Avelumab is safe and effective in previously treated metastatic MCC based on a phase II trial of previously treated patients with objective response rates in 28 of 88 patients, including 10 complete responses and 19 partial responses. Median overall survival (OS) was 12.9 months, and 1-year progression-free survival and OS were 30% and 52%, respectively. Grade 3 treatment-related side effects included lymphopenia (2 patients), serum creatine phosphokinase increase (1 patient), aminotransferase elevation (1 patient), and serum cholesterol increase (1 patient). Relevance to Patient Care and Clinical Practice: This review outlines the pharmacology and clinical trial data for avelumab in metastatic MCC and guides clinicians on avelumab's place in therapy. Avelumab is the first Food and Drug Administration-approved medication for metastatic MCC and provides an advantage of durable responses and possibly improved tolerability compared with traditional platinum-based chemotherapy. Clinical trials are under way to expand its utility into the adjuvant and frontline settings.

Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial

Combined BRAF-MEK inhibitor therapy is the standard of care for BRAFV600-mutant advanced melanoma. We investigated encorafenib, a BRAF inhibitor with unique target-binding properties, alone or in combination with the MEK inhibitor binimetinib, versus vemurafenib in patients with advanced BRAFV600-mutant melanoma. COLUMBUS was conducted as a two-part, randomised, open-label phase 3 study at 162 hospitals in 28 countries. Eligible patients were aged 18 years or older and had histologically confirmed locally advanced (American Joint Committee on Cancer [AJCC] stage IIIB, IIIC, or IV), unresectable or metastatic cutaneous melanoma, or unknown primary melanoma; a BRAFV600E or BRAFV600K mutation; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and were treatment naive or had progressed on or after previous first-line immunotherapy. In part 1 of the study, patients were randomly assigned (1:1:1) via interactive response technology to receive either oral encorafenib 450 mg once daily plus oral binimetinib 45 mg twice daily (encorafenib plus binimetinib group), oral encorafenib 300 mg once daily (encorafenib group), or oral vemurafenib 960 mg twice daily (vemurafenib group). The primary endpoint was progression-free survival by blinded independent central review for encorafenib plus binimetinib versus vemurafenib. Efficacy analyses were by intention-to-treat. Safety was analysed in patients who received at least one dose of study drug and one postbaseline safety assessment. The results of part 2 will be published separately. This study is registered with ClinicalTrials.gov, number NCT01909453, and EudraCT, number 2013-001176-38. Between Dec 30, 2013, and April 10, 2015, 577 of 1345 screened patients were randomly assigned to either the encorafenib plus binimetinib group (n=192), the encorafenib group (n=194), or the vemurafenib group (n=191). With a median follow-up of 16·6 months (95% CI 14·8-16·9), median progression-free survival was 14·9 months (95% CI 11·0-18·5) in the encorafenib plus binimetinib group and 7·3 months (5·6-8·2) in the vemurafenib group (hazard ratio [HR] 0·54, 95% CI 0·41-0·71; two-sided p<0·0001). The most common grade 3-4 adverse events seen in more than 5% of patients in the encorafenib plus binimetinib group were increased γ-glutamyltransferase (18 [9%] of 192 patients), increased creatine phosphokinase (13 [7%]), and hypertension (11 [6%]); in the encorafenib group they were palmoplantar erythrodysaesthesia syndrome (26 [14%] of 192 patients), myalgia (19 [10%]), and arthralgia (18 [9%]); and in the vemurafenib group it was arthralgia (11 [6%] of 186 patients). There were no treatment-related deaths except for one death in the combination group, which was considered possibly related to treatment by the investigator. Encorafenib plus binimetinib and encorafenib monotherapy showed favourable efficacy compared with vemurafenib. Overall, encorafenib plus binimetinib appears to have an improved tolerability profile compared with encorafenib or vemurafenib. Encorafenib plus binimetinib could represent a new treatment option for patients with BRAF-mutant melanoma. Array BioPharma, Novartis.

Alectinib for advanced ALK-positive non-small-cell lung cancer.

The pharmacology, pharmacokinetics, clinical efficacy, safety and tolerability, dosage and administration, and place in therapy of alectinib for treatment of patients with non-small-cell lung cancer (NSCLC) are reviewed. In patients with NSCLC driven by mutations of ALK, the gene coding for anaplastic lymphoma kinase (ALK), treatment with the ALK inhibitor crizotinib has been found to provide median progression-free survival (PFS) of 10.9 months; however, therapeutic failures and tumor progression to brain metastases are common with crizotinib use, prompting research to find more potent and tolerable ALK inhibitors that target major oncogenic drivers of NSCLC. Alectinib is a next-generation ALK inhibitor initially approved by the Food and Drug Administration for use in patients with metastatic ALK-positive NSCLC who are intolerant of or have disease progression during crizotinib therapy. In clinical trials, alectinib was found effective for delaying disease progression and, more importantly, reducing brain metastases in patients with NSCLC who developed resistance or intolerance to previous crizotinib therapy. Published data from clinical trials indicate that the most common grade 1 and 2 adverse effects associated with alectinib use are fatigue, constipation, peripheral edema, and myalgia; the most common grade 3 or 4 reactions include increases in creatine phosphokinase, alanine aminotransferase, and aspartate aminotransferase levels. Alectinib appears to be effective and safe for use in patients with metastatic ALK-positive NSCLC, with demonstrated superiority over crizotinib in terms of PFS rates. Research to better define ALK inhibitor resistance mechanisms and alectinib's place in therapy is ongoing.

62 A Novel Serial Dilution Protocol for the Assessment of the Value of the Advia 1800’s Hemolytic Index as a Measure of the Degree of Plasma Red Cell Contamination

While today’s automated chemistry analyzers routinely provide hemolytic, lipemic, and icteric indices in order to assess potential interferences in patient results, the hemolytic index (HI) is by far the best indicator of the degree of contamination of serum/plasma samples with red cell constituents. In vitro hemolysis, often due to poor sample collection and handling, is a well-known source of interference error in the core laboratory. Several analytes, especially potassium and lactate dehydrogenase (LDH), are significantly affected by contamination from red cell constituents. Since the standard of care in our laboratory involves routine testing and reporting of patient samples with an HI of 1+ or greater, a significant technologist effort is required in the decision to validate and release results. This study presents a novel serial dilution protocol to assess the degree of hemolysis/contamination interference on selected analytes including potassium, LDH, and creatine phosphokinase (CPK) with triglyceride levels included as a negative control. Ten lithium heparin whole blood specimens were analyzed for baseline laboratory values on the Rapidpoint 500 analyzer. Two aliquots were made with one frozen at –70°C for 10 minutes to cause complete hemolysis, then thawed and centrifuged for three minutes at 3,100g. Serial dilutions of the supernatant hemolysate up to 1:64 were performed using the unfrozen sample as a diluent, with results of various analytes calculated on the Advia 1800 chemistry analyzer (Siemens Healthcare Diagnostics, Tarrytown, NY). Plasma-free hemoglobin was determined on each sample on the HemoCue analyzer (HemoCue America, Brea, CA). Evaluation of various analytes on all 10 samples obtained by the Advia 1800 showed a significant increase in potassium, LDH, and CPK with an increased HI, with no significant change in the triglyceride level. An example of serial dilution revealed a decreasing potassium level of 9.2 mmol/L, LDH of 1,698 U/L, and CPK of 513 U/L at 4+ hemolysis (no dilution), to 5.3 mmol/L, 187 U/L, and 340 U/L at 1+ hemolysis, respectively (1:32 dilution), compared to a baseline potassium level of 5.2 mmol/L, LDH of 126 U/L, and CPK of 332 U/L with no hemolysis. The HI of 1+ correlates with plasma hemoglobin levels of 50–100 mg/dL, with 18 mg/dL giving an HI of 2+, 350 mg/dL giving an HI of 3+, and 1,390 mg/dL giving an HI of 4+. We conclude that HI values of 1+ on the Advia 1800 are associated with a clinically insignificant 0.1–0.2 mmol/L increase in potassium on all 10 samples. Enzymes, however, showed an increase in all HI levels.

STUDY OF LEVELS OF SERUM CREATINE PHOSPHOKINASE AND LIVER ENZYMES AS A PROGNOSTIC INDICATORS IN ACUTE ORGANOPHOSPHORUS POISONING

Background: Organophosphorus (OP) poisoning is one of the most common poisoning in rural and in developing country. Due to their easy availability and cost effective it is used frequently for homicidal and suicidal attempts. Routinely used biochemical markers like Erythrocyte cholinesterase (EChE) and Plasma cholinesterase (PChE) are used for the diagnosis of acute organophosphorus (OP) poisoning but estimation of these are very costly and not easily available. The mortality increases with increase in initial creatine phosphokinase level and can be used as alternative biomarker. Hence study was done to estimate levels of serum Creatine Phosphokinase (CPK) and liver enzymes in acute OP poisoning patients and its prognostic significance. Methodology: Patients (80) admitted in our hospital were included in this study. A brief history and detailed clinical examination was performed and patients were categorized on the basis Modified Dreisbach’s clinical criteria classification. Serum levels of Creatine kinase (CK) and Liver enzymes were analysed at the time of admission. The outcome of the patients were observed. Results: Out of 80 patients recruited for the study, 41 cases (51.3%) were females, and 39 cases (48.8%) were males. Majority of them were in the age group of 21-30 years. More cases of OP poisoning were among agriculturalists 28 (35%) and housewife 21 (28.8%) and among students 15 (18.8%). Malathion was the most common compound used followed by Monocrotphos. 60% had mild, 31.3% had moderate and 8.8% had severe poisoning. There is increase in Creatine Phosphokinase (CPK) levels in 6 patients who survived with ventilator support and also in 2 patients who died with ventilator support which was statistically highly significant (p<0.05). Serum liver enzymes were within normal limits. Conclusion: Elevated Creatine kinase is commonly seen in OPC poisoning. High initial serum Creatine Phosphokinase (CPK) levels are associated with severe degree of poisoning and are associated with complications and mortality. Serum liver enzymes (SGOT AND SGPT) are not elevated in OP poisoning.

Toxicological evaluation of chronic oral administration of Melissa officinalis hydro-ethanol extract in Sprague-Dawley rats

Melissa officinalis is a plant that has been widely used as an herbal medicine in many countries. Unfortunately, despite the prevalent medicinal uses of the plant, there are no reports on the possible toxic effects of M. officinalis. This study was designed to evaluate the effect of long-term administration of hydro-alcoholic extract of M. officinalis on some biochemical and hematological parameters and histopathology of organs. Thirty Sprague-Dawley rats were allocated to three equal groups. The animals in groups A and B received 600 and 1200 mg/kg M. officinalis extract, respectively, for 30 days. The rats in group C were given gavaged saline as control. The animals were euthanized at the end of experiment and the blood samples were collected for biochemical and hematology analysis. Additionally, appropriate tissue samples were collected from kidney, liver, spleen, heart and lung for light microscopic examination. M. officinalis caused a significant increase in the alanine aminotransferase level in the treated rats. Although the increase in creatine phosphokinase and lactate dehydrogenase levels were observed in group A and B, respectively, but there were no significant differences. A significant decrease was observed in the total protein and albumin concentrations in serum of treated rats as compared to the control group. The creatinine concentrations were significantly higher in the group B when compared to the other groups. There were no significant differences in cholesterol, triglyceride and urea concentrations between all groups of rats. The main histopathologic findings in the liver were included hepatocyte degeneration, congestion and dilation of sinusoids, proliferation of bile ducts and infiltration of mononuclear cells around the portal area. Histopathologic examination of the kidneys showed a tubular degeneration and necrosis, tubular and glomerular atrophy and congestion. These lesions were more prominent in the high dose treated rats. The findings suggest that long-term administration of M. officinalis extract even at low doses induces hepatic and renal lesions in rats.