Creatinine Phosphokinase Elevation Research Articles

Reported Adverse Events in a Multicenter Cohort of Patients Ages 6-18 Years with Cystic Fibrosis and at Least One F508del Allele Receiving Elexacaftor/Tezacaftor/Ivacaftor

The objective of this study was to describe reported adverse events (AEs) associated with elexacaftor/tezacaftor/ivacaftor (ETI) in a pediatric sample with cystic fibrosis (CF) aged 6-18years, with at least one F508del variant, followed at multiple Italian CF centers. This was a retrospective, multicenter, observational study. All children receiving ETI therapy from October 2019 to December 2023 were included. We assessed the prevalence and type of any reported potential drug-related AEs, regardless of discontinuation necessity. Persistent AEs were defined as those continuing at the end of the observation period. Among 608 patients on ETI, 109 (17.9%) reported at least 1 AE. The majority (n=85, 77.9%) were temporary, with a median duration of 11days (range 1-441days). Only 7 (1.1%) patients permanently discontinued treatment, suggesting good overall safety of ETI. The most common AEs leading to discontinuation were transaminase elevations (temporary 14.1%, persistent 25.9%) and urticaria (temporary 41.2%, persistent 7.4%). Creatinine phosphokinase elevation was uncommon. No significant differences in AEs were observed based on sex, age groups (6-11 vs 12-18years), or genotype. Pre-existing CF-related liver disease was associated with an increased risk of transaminase elevations. We identified significant variability in the percentage of reported AEs (ANOVA P value .026). This real-world study highlights significant variability in reported AEs. Our findings suggest that ETI is a safe and well-tolerated therapy in children and adolescents with CF. However, further long-term safety and effectiveness investigations are warranted.

Association of Plasma Creatinine Phosphokinase Elevation and a History of Idiopathic Cardiomyopathy in Recipients of Heart Transplant

Plasma creatinine phosphokinase (CPK) elevation is frequent after heart transplantation. In the present study, we tested the hypothesis that this CPK elevation is related to idiopathic cardiomyopathy as primary cardiac disease. We included 203 patients who survived >1 year after heart transplantation. Plasma CPK was measured every 4 months during a 15.1 ± 7.7-year follow-up. In univariate analysis, CPK elevation was significantly associated with age at transplantation, length of follow-up, treatment with everolimus, and idiopathic cardiomyopathy as primary cardiac disease. In multivariate analysis, idiopathic cardiomyopathy and length of follow-up were the only significant predictors of CPK elevation (p=0.002 and p=0.0001, respectively). A subgroup of 19 patients had frequent CPK elevation (>20% of the dosages). All these patients but 1 had an idiopathic cardiomyopathy as primary disease. In 5 of these 19 patients, we identified a syndrome known to affect both cardiac and skeletal muscles. In conclusion, underlying idiopathic cardiomyopathy is a major determinant of plasma CPK elevation after heart transplantation. Our results show that besides well-described syndromes associating skeletal and cardiac muscle disease, idiopathic cardiomyopathy may be associated with subclinical skeletal muscle myopathy.

Comparison of Sequential Dalbavancin With Standard-of-Care Treatment for Staphylococcus aureus Bloodstream Infections.

BackgroundDalbavancin (DAL) is a long-acting lipoglycopeptide with activity against Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA). This study investigates DAL as sequential therapy in S. aureus bloodstream infections (BSIs).MethodsWe conducted a retrospective cohort study from 2014 to 2021 comparing sequential DAL with standard-of-care therapy (SoC) for S. aureus BSI. The primary outcome was 90-day clinical failure (90-day all-cause mortality or 90-day recurrence). Secondary outcomes were incidence of acute kidney injury, creatinine phosphokinase elevations, catheter-related thrombosis, and hospital-acquired infections. Analyses were adjusted using inverse probability of treatment weighting (IPTW).ResultsOverall, 225 patients (45 DAL, 180 SoC) were included. DAL patients had a higher incidence of community-acquired infection and persons who use drugs; SoC patients had more comorbidities and a longer duration of bacteremia. MRSA incidence was similar between the DAL and SoC groups. The median length of stay was 16 days among DAL recipients compared with 24 days among SoC recipients. Central catheter placement was 17.8% compared with 57.2% in the SoC group. Ninety-day clinical failure occurred in 13.3% and 18.3% of participants in the DAL and SOC groups, respectively. In IPTW-adjusted analysis, sequential DAL was not associated with 90-day clinical failure (adjusted odds ratio, 0.94; 95% CI, 0.333–2.32).ConclusionsThis study provides preliminary evidence that select patients with S. aureus BSI treated with sequential DAL have similar clinical failure rates, with significant reductions in catheter placement and hospital length of stay compared with SoC. Further prospective evaluation is needed.

Should Isotretinoin be Stopped Prior to Surgery?

Should Isotretinoin be Stopped Prior to Surgery?

Proposal for the Recognition of a New Disease Concept from Japan: Parechovirus A3-Associated Myalgia

Parechovirus A3 (PeVA3) was first reported in 2004 and has been recognized as a causative agent of mild and severe infectious diseases in children. We first reported an outbreak of PeVA3-associated myalgia (PeVA3-M) in Yamagata, Japan, in 2008. We have repeatedly observed PeVA3-M cases in 2011, 2014, and 2016, and identified the first child case in 2014. Reports of PeVA3-M have increased since 2014, indicating that the recognition of PeVA3-M has spread across Japan. The findings showed that PeVA3-M commonly occurs among adults aged 30-40 years, particularly in males. Elevation of creatinine phosphokinase, C-reactive protein, and myoglobin, as well as magnetic resonance imaging findings, suggest inflammation of the muscles and/or fascia of the four limbs. Patients recover within 1-2 weeks without any sequelae. A longitudinal molecular epidemiological study in Yamagata revealed that PeVA3 strains cause a variety of diseases, ranging from mild to severe, including PeVA3-M, in subjects ranging from neonates to adults, irrespective of their genetic cluster. As PeVA3-M has not yet been reported abroad, more widespread recognition of PeVA3-M as an emerging disease is important. We hope this review will help clinicians and researchers in understanding PeVA3-M and therefore advance related research in Japan as well as around the world.

Electromuscular Incapacitation Current Induced Neuromuscular Tissue Injury.

Electrical stun devices (ESDs) serve a basic role in law enforcement and provide an alternative to lethal options for target control by causing electromuscular incapacitation (EMI). A fundamental concern is the adverse health consequences associated with their use. The capability of EMI electric field pulses to disrupt skeletal muscle cells (i.e. rhabdomyolysis) was investigated over the operational range commonly used in commercial EMI devices. Functional and structural alteration and recovery of muscle and nerve tissue were assessed. In an anesthetized swine model, the left thigh was exposed to 2 min of electrical pulses, using a commercially available ESD or a custom-made EMI signal power amplifier. Serum creatinine phosphokinase (CPK), troponin, aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) levels were monitored intermittently for 6 h post-EMI exposure. A standard external cardiac defibrillator served as a positive control. Muscle and nerve tissue histology adjacent to the EMI contacts were examined. Post-EMI shock skeletal muscle function was evaluated by analyzing the compound muscle action potentials (CMAPs) of the rectus femoris muscle. Maximal energy cardiac defibrillator pulses resulted in rhabdomyolysis and marked elevation of CPK, LDH, and AST 6 h post-shock. EMI field pulses resulted in the animals developing transient acidosis. CMAP amplitudes decreased approximately 50% after EMI and recovered to near-normal levels within 6 h. Within 6 h post-EMI exposure, blood CPK was mildly increased, LDH was normal, and no arrhythmia was observed. Minimal rhabdomyolysis was produced by the EMI pulses. These results suggest that EMI exposure is unlikely to cause extremity rhabdomyolysis in normal individuals. Bioelectromagnetics. © 2020 Bioelectromagnetics Society.

Abstract CT255: EATON: A phase I dose-escalation trial of nazartinib (EGF816) and trametinib in EGFR-mutant NSCLC

Abstract Background: EGFR tyrosine kinase inhibitor (TKI) treatment is highly effective in EGFR-mutant NSCLC. However, resistance to treatment inevitably develops. Multiple mechanisms of resistance to EGFR TKIs have been described. Besides secondary EGFR mutations, RAS/MEK pathway activation through different mechanisms has been found in cell models and in patients, resulting in TKI failure. Inhibition of MEK, resensitized cells to EGFR-targeted treatment in pre-clinical models. We thus hypothesize that combined MEK and EGFR inhibition may break resistance and delay treatment failure in EGFR-mutant NSCLC patients. Methods: EATON (NCT03516214) is an investigator-initiated, multicenter, phase I, dose-escalation trial investigating the recommended phase 2 dose (RP2D), pharmacokinetic parameters and safety/efficacy of the combination of EGF816 (nazartinib) and trametinib. Eligibility criteria: Advanced/metastatic EGFR-mutant (del19 or p.L858R) NSCLC, EGFR p.T790M-positive/-negative, absence of other secondary EGFR-mutations, MET amplification-negative (MET/CEN7 ratio ≥2.0 and/or average MET gene copy number per cell ≥6.0), first-line or after failure of any EGFR TKI, including osimertinib. Dose level escalation will be based on a 3+3 up-and-down design (total number: 24 patients) with a dose-limiting toxicity (DLT) period of 28 days. Minimum treatment exposure for DLT assessment is 21 days. Exploratory endpoints: Identification of mechanisms of resistance by analysis of baseline tissue, PD biopsies and ctDNA. Results: At the time of data cut-off, three patients received treatment at dose-level 1 (nazartinib (EGF816) 100 mg QD and trametinib 1 mg QD). All patients met the minimum exposure criterion for DLT assessment. In one patient a grade 3 creatinine phosphokinase elevation was observed and assessed as a DLT. No other DLTs were reported. Other related adverse events (AEs) grade ≥2 were rash (n=2), anemia (n=1), soft-tissue infection (n=1), diarrhea (n=1), and elevated liver enzymes (n=1). Two patients were evaluable for efficacy assessment. One stopped treatment prior to first assessment due to a grade 4 soft tissue infection at day 37. Best objective response according to RECIST 1.1 was stable disease in one patient (afatinib-resistant, T790M-negative), lasting for more than 4 months and progressive disease in the other patient (osimertinib-resistant, T790M-negative). Conclusions: Treatment with nazartinib 100 mg QD and trametinib 1 mg QD resulted in a DLT in one of three patients. Thus, three additional patients will be enrolled at the same dose level. Efficacy data is premature. But, a significant progression-free survival period was observed in one EGFR p.T790M-negative patient. Citation Format: Sebastian Michels, Lucia Nogova, Matthias Scheffler, Barbara Deschler-Baier, Martin Sebastian, Martin Schuler, Martin Wermke, Enriqueta Felip, Rafael Rosell, Delvys Rodriguez Abreu, Diana S.Y. Abdulla, Rieke N. Fischer, Sophia Koleczko, Anna Kron, Richard Riedel, Jan-Philipp Weber, Jana Fassunke, Sabine Merkelbach-Bruse, Heinz Haverkammp, Martin Hellmich, Reinhard Büttner, Jürgen Wolf, Lung Cancer Group Cologne (LCGC) and Network Genomic Medicine (NGM). EATON: A phase I dose-escalation trial of nazartinib (EGF816) and trametinib in EGFR-mutant NSCLC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT255.

Observational retrospective single-centre study in Japan to assess the clinical significance of serum daptomycin levels in creatinine phosphokinase elevation.

Daptomycin-induced creatinine phosphokinase (CPK) elevation is reported to be associated with its trough level (Ctrough ; breakpoint of 24.3μg/mL). However, even with high-dose treatment (ie, > 8mg/kg), the safety of daptomycin treatment is widely demonstrated with low or no significant incidence of CPK elevation or other adverse effects, despite the possibility of Ctrough above 24.3μg/mL. Therefore, we questioned the clinical significance of Ctrough levels of 24.3μg/mL. In this study, we retrospectively evaluated the significance of Ctrough in the clinical setting, in addition to completing a retrospective safety assessment of daptomycin utilizing electronic health records. Patients who had received daptomycin treatment for >4days from July 2011 to June 2015 were enrolled. Serum daptomycin levels, including Ctrough and peak (Cpeak ), were measured by high-performance liquid chromatography equipped with a photodiode array. To evaluate the safety, patients' characteristics and relevant laboratory test values were reviewed retrospectively using an electronic medical record system. A total of 52 therapeutic cases for 46 patients were identified; of these, Ctrough and Cpeak levels were measured in 27 and 28 cases, respectively, and 6 patients received multiple courses of daptomycin treatment. The median age of the 52 patients was 68years (range: 19-88years), and 14 patients initially had an estimated creatinine clearance of less than 30mL/min. Seven cases indicated a Ctrough of above 24.3μg/mL; however, none of these presented CPK elevation, which meets with the study definition for abnormality. Furthermore, of the two patients with abnormal CPK elevations, only one patient had a measured Ctrough (of 10.9μg/mL). Their CPK abnormalities were temporal and did not result in treatment discontinuation. The other four patients discontinued daptomycin treatment due to suspicions of adverse effects. Of the discontinued patients, two had measured Ctrough levels; these were 8.6 and 8.1μg/mL. All patients with abnormal CPK elevation or treatment discontinuation exhibited Ctrough levels lower than 24.3μg/mL. In this study, two patients receiving high-dose daptomycin (ie, 9.4 and 10.0mg/kg) had observed Ctrough levels similar to patients who received doses of daptomycin <9mg/kg. The safety of daptomycin treatment was suggested in this study. Ctrough level of 24.3μg/mL was not suggested as a significant clinical index for the incidence of CPK elevation, adverse effects or treatment discontinuation. Thus, acceptable tolerability towards higher Ctrough levels than 24.3μg/mL was also suggested, though further studies are required. On the other hand, low levels of daptomycin in blood were unexpectedly observed in two cases, despite the high-dose treatments. Accordingly, the monitoring of serum daptomycin levels may also be useful to assess cases in which subtherapeutic levels were achieved.

201. Safety and Effectiveness of Daily vs. Every Other Day Dosing of Daptomycin in Patients with Renal Insufficiency

BackgroundDaptomycin administered at 48-hour (q48h) intervals is recommended in patients with renal impairment. Our institution utilizes daily dosing (q24h) of daptomycin in patients with renal impairment to theoretically optimize the area under the curve (AUC) in each 24-hour interval. However, the safety and effectiveness of this approach are unknown.MethodsThis retrospective descriptive analysis evaluated outcomes of comparable daptomycin dosing schemes administered q24h vs. q48h in patients with renal impairment (estimated creatinine clearance < 30 mL/minute). Inpatient adults ≥18 years old were included if they had at least one creatinine phosphokinase (CPK) obtained during admission and received either a q24h or q48h renally-adjusted daptomycin dose from May 2014 through December 2018. High-dose daptomycin therapy was defined as >3 mg/kg q24h or >6 mg/kg q48h. The primary outcome was difference in CPK elevations in the q24h vs. q48h dosing groups. Secondary outcomes included clinical and microbiological response, mortality, and hospital length of stay.ResultsThirty-seven patients met inclusion criteria [23 (62%) q24h vs. 14 (38%) q48h]. Median treatment duration was 5 (7 vs. 4) days. Twenty-two (59%) patients had enterococcal infections [17 (73%) q24h vs. 5 (35%) q48h]. Twenty-two (59%) patients received high-dose daptomycin therapy [18 (82%) vs. 4 (18%)]. Nine patients [7 (19%) vs. 2 (5%)] received a statin during daptomycin therapy. One (3%) patient developed a CPK elevation (statin and q24h group). No daptomycin dose was discontinued due to CPK elevation, or rhabdomyolysis. Median hospital length of stay was 10 days in both dosing groups. Clinical response [9 (64%) vs. 16 (69%)] and microbiological response [9 (64%) vs. 15 (65%)] were similar between the two dosing groups. However, 30-day mortality [5 (35%) vs. 4 (17%)] and 90-day mortality [6 (42%) vs. 5 (21%)] were higher in the q48h dosing group. The difference in effectiveness outcomes was greatest in the subset of patients with enterococcal infections (Table 1).ConclusionA daily daptomycin dosing strategy in patients with renal insufficiency was well tolerated and may be associated with improved effectiveness outcomes, particularly for enterococcal infections. Additional investigations of this approach are warranted. Disclosures All authors: No reported disclosures.

1029. Clinical and economic outcomes of a newly implemented daptomycin dosing policy in a four-hospital health system

BackgroundIn light of recently published clinical and pharmacokinetic data regarding the use of daptomycin in obese patients, the Charleston Area Medical Center (CAMC) Antimicrobial Stewardship Program implemented an adjusted body weight dosing strategy for obese patients. Along with this new dosing strategy, an effort to reduce drug waste was also implemented by restricting the timing of routinely scheduled daptomycin doses for inpatients. This study aims to determine the clinical outcomes for patients receiving daptomycin both before and after this policy change. Secondary objectives include assessing creatinine phosphokinase (CK) levels in the study participants, defining the risk of CK elevation with the coadministration of HMG Co-A reductase inhibitors and daptomycin, and assessing any reduction in drug waste for the pharmacy department.MethodsThis study is a single-center, one-group pretest-posttest, quasi-experimental study evaluating the implementation of a two-part daptomycin dosing policy. The pretest group included all patients meeting inclusion and exclusion criteria that received daptomycin at CAMC from September 1 - November 30, 2017. The new daptomycin dosing policy was implemented on September 1, 2018. The posttest group included all patients meeting the stated criteria that received daptomycin from September 1 - November 30, 2018.ResultsA total of 118 patients were included in this study. There were 5 (7.7%) treatment failures in the pretest group and 3 (5.7%) in the posttest group (P = 0.7). Of the patients with CK levels monitored, 6 (33%) were found to have significant elevations in the pretest group and 4 (40%) were found in the posttest group (P = 0.6). There was no difference observed in the risk of CK elevation with daptomycin administration in the presence of an HMG-CoA reductase inhibitor. For the two time periods reviewed, the pharmacy department purchased fewer vials of daptomycin in the posttest group.ConclusionPatients at CAMC receiving daptomycin after implementation of a new dosing policy did not experience an increased risk of treatment failure. The Antimicrobial Stewardship Program will continue to monitor patients receiving daptomycin therapy at CAMC.Disclosures All authors: No reported disclosures.

Creatinine Phosphokinase (CPK) Elevation in the Coexistence of Wilson's Disease and Autoimmune Hepatitis with Atypical Presentation: A Diagnostic Dilemma

Background: Wilson's disease (WD) is a genetic disorder with various clinical presentations due to excessive accumulation of copper in the liver and other organs. It can present as acute/chronic hepatitis, liver failure, extrahepatic and neuromuscular manifestations. Autoimmune hepatitis (AIH) is a necroinflammatory disease of the liver, which affects a lot of people particularly the children population. AIH has a broad clinical presentation that is similar to WD. Coexistence of WD with elevated creatinine phosphokinase (CPK) and AIH, may be a diagnostic dilemma. Case Report: We presented a 6 years old boy with dysarthria, aggressive behavior, weak attention, concentration and weight loss with abnormal physical examination. Laboratory, histochemical, genomic studies, muscle/liver biopsy and atomic absorption test confirmed the diagnosis of both WD and AIH in the boy. Conclusion Although CPK and liver enzyme elevation is a rare presentation of chronic hepatitis with dominant feature of WD and AIH; however, simultaneous therapy with immunosuppressive drugs and Penicillamine may have superior benefit with a significant response.

Comparison of Outcomes in Outpatient Parenteral Antimicrobial Therapy (OPAT) Patients Receiving Vancomycin vs. Non-Vancomycin Anti-MRSA Therapy

BackgroundThis evaluation set out to determine whether vancomycin therapy was associated with higher rates of clinical failure compared with non-vancomycin anti-methicillin-resistant Staphylococcus aureus therapy (NVAMT) in outpatient parenteral antimicrobial therapy (OPAT).MethodsThis was a retrospective, single center cohort study including patients who received ≥7 days of OPAT with vancomycin, ceftaroline, or daptomycin from January 1, 2009 through March 31, 2016 at the VA Saint Louis Healthcare System. The primary outcome was clinical failure, defined as a composite of acute kidney injury (AKI), creatinine phosphokinase elevations ≥ 500 units/L, adverse drug events necessitating a change in therapy, readmission due to recurrence of infection, or reinitiation of antibiotics after discontinuation. Secondary outcomes were the individual components of the composite primary outcome. Multivariate logistic regression was used to evaluate independent risk factors for clinical failure. Factors evaluated for inclusion in the multivariate model were age >65 at initiation, creatinine clearance >50 mL/minute, length of therapy >28 days, concomitant antibiotic therapy, comorbid disease states, and vancomycin therapy.ResultsA total of 125 patients were included in the analysis – 72 receiving vancomycin and 53 receiving NVAMT. Baseline characteristics between groups were similar, except patients in the NVAMT group had a greater mean serum creatinine and a higher rate of CKD at baseline; 1.53 vs 1.23 (P = 0.032) and 35.9% vs. 19.4% (P = 0.04) respectively. Forty-three percent (31/72) of patients receiving vancomycin achieved clinical failure compared with 54.7% (29/53) of NVAMT patients (P = 0.197). Of the secondary outcomes analyzed, only readmission due to recurrence was significant between groups (vancomycin vs. NVAMT) – 13.8% vs. 30.2% (P = 0.026). In the univariate model only the choice of vancomycin met pre-defined criteria (P < 0.2) for inclusion in the multivariate model. In the multivariate analysis the choice of vancomycin was not found to be significant (0.71 (95% CI 0.33–1.52), P = 0.37).ConclusionVancomycin was not associated with an increased risk of clinical failure when compared with NVAMT in patients receiving OPAT.Disclosures All authors: No reported disclosures.

Treatment of Vancomycin-Resistant Enterococci: Focus on Daptomycin.

Vancomycin-resistant Enterococci (VRE) infections are problematic due to limited availability of anti-VRE agents and their potential for adverse effects and drug interactions. This review focuses on the role of daptomycin in treating VRE infections by summarizing key points of relevant clinical studies. Higher doses of daptomycin (≥6mg/kg), as compared to standard doses, were found to be safe in terms of creatinine phosphokinase elevation and associated with successful infection outcomes and microbiological clearance. High doses are especially important in treatment of infections involving elevated daptomycin minimum inhibitory concentration (MIC) values (3-4μg/mL). Daptomycin, especially in higher doses, has been shown to be an effective and safe VRE agent for a variety of serious infection types, such as catheter-associated bloodstream and intra-abdominal infections, and for different populations including oncology. Infections involving higher daptomycin MIC values were associated with previous daptomycin use and prosthetic devices.

Creatinine phosphokinase elevation among exertional heat stroke patients

Background: Rhabdomyolysis, which can be defined as a CPK level greater than five times the upper limit of normal, is related to muscle breakdown and hypovolemia in heat stroke patients.1 CPK levels will likely be higher because of increased muscle breakdown in exertional heat stroke when compared with classic heat stroke. Methods: We reviewed 50 patients who came into the Emergency Department of Hamad General Hospital during the months of July to September 2015, and who were diagnosed with exertional heat stroke. Results: In 44 out of 50 heat stroke patients, the level of serum CPK was markedly elevated (mean 20,300 ± 25,500 U/l) compared with the elevated levels of other lab values (serum myoglobin 2500 ± 3000 ng/ml, creatinine 1.8 ± 2.4 mg/dL, BUN 90 ± 104 mg/dL, potassium 2.6 ± 3.6 mEq/L, sodium 135 ± 155 mEq/L) on admission. The repeated lab values after the 12th hour showed that the CPK rose further (28,500 ± 32,500 U/L) while the others (serum myoglobin 800 ± 1,200 ng/ml, creatinine 1.1 ± 1.4 mg/dl, BUN 35 ± 60 mg/dL, potassium 2.2 ± 3.4 mEq/L, sodium 110 ± 130 mEq/L) recorded a decrease. Conclusion: In our cohort of patients, CPK levels were significantly high in the setting of exertional heat stroke. A possible relation to renal failure need to be explored in a prospective research design. Keywords: exertional heat stroke, rhabdomyolysis, creatinine phosphokinase REFERENCE: [1] Santelli J, Sullivan J. An evidence based approach on emergency medicine. Emerg Med Prac. 2014;16:6–15.

Can Rhabdomyolysis Lead to Transaminitis?

Introduction: Rhabdomyolysis occurs secondary to muscle injury in the setting of physical exertion, immobilization, infection or medications. This injury results in the accumulation of cellular proteins, such as creatinine phosphokinase (CPK), in the serum. Our case describes an association of elevated transaminases and CPK with rhabdomyolysis. Case: An 81 year old male with history of hypertension and lacunar stroke was brought in by his home health aid to a tertiary care center after a presumed mechanical fall with unknown downtime. Review of systems was largely negative including lack of gastrointestinal symptoms. In the emergency room, he was found to be hypothermic to 93.9°F with otherwise stable vital signs. Physical exam was significant for marked confusion and disorientation. He was placed in a forced-air warming blanket and temperature improved to 97°F. At this time, the decision was made to admit the patient to the General Medicine service for further evaluation. The ensuing workup resulted negative, including complete blood count, electrocardiogram, chest x-ray, blood cultures, transthoracic echocardiogram, CT of the head, MRI brain and MRA of the brain and neck. Labs were significant for CPK of greater than 7000 and marked transaminitis. He was administered aggressive intravenous crystalloid hydration for a working diagnosis of rhabdomyolysis, and subsequently improved. Serum markers down-trended over the next few days, and the patient was discharged to a sub-acute rehabilitation center. Discussion: Rhabdomyolysis is commonly associated with an elevation of CPK in the setting of muscle injury. Limited data suggests an association of elevated aminotranferases with CPK. When identifying this relationship, it is important to first exclude alternate etiologies for transaminitis. A concomitant improvement in liver enzymes with CPK is highly suggestive. AST, located in the liver, heart, skeletal muscle, kidney, brain, pancreas, lungs, leukocytes, and erythrocytes, tends to be the predominant aminotransferase to rise. Studies suggest that the elevation of serum AST in rhabdomyolsysis is likely secondary to its release from damaged skeletal muscle fibers. Another possible explanation is that the transaminases released during muscle injury may propagate acute hepatic inflammation. Summary: Our case highlights the association of transaminitis with elevated serum CPK levels in rhabdomyolysis despite the lack of pathologic liver injury.Figure 1Figure 2

CHEMOPROTECTIVE EFFECT OF NONI (MORINDA CITRIFOLIA L.) FRUIT JUICE AGAINST CISPLATIN-INDUCED NEPHROTOXICITY

&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;Cisplatin&lt;strong&gt; (&lt;/strong&gt;CIS) consumption has become a common problem that affects the health of patients around the globe. Kidney has been suspected to be particularly susceptible to the destructive effects of CIS and nephrotoxic effects are still contentious which in turn affects the Quality of Life (QoL) of patients and increase the mortality rate. This study was conducted to investigate the nephroprotective effect of Noni Juice (NJ) and Divine Noni Gold (DNG) as herbal medicine with established antioxidant properties against the controversial nephrotoxic effect of CIS in mice.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Mice were divided into four groups, each group contained six mice. Group I was kept as normal, Group II received CIS (5.0 mg/kg b. wt. i. p.) on day one for 14 d. &lt;strong&gt;G&lt;/strong&gt;roup III and IV received NJ (0.35 ml/mouse p. o.) and DNG (0.35 ml/mouse p. o.) respectively once daily for 14 d, Group V received CIS (5.0 mg/kg b. wt. i. p.) on day one and NJ (0.35 ml/mouse p. o.) once daily for 14 d. Similarly, Group VI received CIS (5.0 mg/kg b. wt. i. p.) on day one and DNG (0.35 ml/mouse p. o.) once daily for 14 d. On day 15 blood from all the mice was collected from the carotid vein and cardiac puncture routes, and the biochemical markers viz. lactate dehydrogenase (LDH), creatinine phosphokinase (CPK), urea were assessed. Kidney from all the animals was isolated, and catalase (CAT), glutathione (GSH), superoxide dismutase (SOD), thiols and lipid peroxidase (LPO) were estimated.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;CIS-induced marked kidney injury; congestion of tubules, glomerular distortion foci, thickened and blocked blood vessels. Also showed significant elevation of LDH, CPK, and urea with significant inhibition of CAT, GSH, SOD, thiols activities and simultaneously elevation of LPO level. Co-administration of NJ and DNG respectively with CIS protected kidney tissues via oxidative stress inhibition.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;NJ and DNG possess protective effect against CIS-induced cellular damage in the kidney by decreasing the level of serum biochemical markers, enhancing the level of enzymatic and non-enzymatic antioxidants and maintaining the LPO level. Results suggest that NJ and DNG have strong nephroprotective effect against CIS-induced nephrotoxicity.&lt;/p&gt;

Risk factors for the delayed onset of neuropsychologic sequelae following carbon monoxide poisoning.

AimCarbon monoxide (CO) poisoning often manifests delayed neuropsychological sequelae. The risks and preventive factors for the development of delayed neuropsychological sequelae are controversial at present. The purpose of this retrospective study was to assess the risk factors for this condition.MethodWe studied 81 patients with CO poisoning admitted to the Critical Care and Emergency Medicine Center at the Kansai Medical University from 2006 to 2012. All patients (64 males and 17 females; average age, 45.9 years) were divided into non‐ delayed neuropsychological sequelae and delayed neuropsychological sequelae groups and retrospectively studied. Patient data were analyzed by univariate and multivariate analyses.ResultsThe results of our study indicated that prolonged CO exposure, elevated serum creatinine phosphokinase levels, head image abnormality in the basal ganglion or white matter region, low Glasgow Coma Scale score, bedsore occurrence, and CO poisoning attributable to burning charcoal were each predictive risk factors for the development of delayed neuropsychological sequelae. Bedsore occurrence and serum creatinine phosphokinase elevation were significant risk factors by multivariate analysis, whereas no significant differences were found for age, gender, mean blood pressure, heart rate, arterial carboxyhemoglobin and lactate concentrations, or base excess.ConclusionWe identified several predictive risk factors of delayed neuropsychological sequelae. We believe that these factors will contribute to identifying optimum therapeutic methods and follow‐up terms for patients with acute CO poisoning at risk of developing delayed neuropsychological sequelae.

A phase 1 study investigating DX-2930 in healthy subjects

BackgroundDX-2930 is a human monoclonal antibody inhibitor of plasma kallikrein under investigation for long-term prophylaxis of hereditary angioedema. ObjectiveTo assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of DX-2930 in healthy subjects. MethodsA single-center, double-blinded study was performed in 32 healthy subjects randomized 3:1 to receive a single subcutaneous administration of DX-2930 or placebo within 1 of 4 sequential, ascending dose cohorts (n = 8 each): 0.1, 0.3, 1.0, or 3.0 mg/kg. ResultsNo dose-limiting toxicity was observed. Headache was the most commonly reported treatment emergent adverse event (AE), occurring at a rate of 25% in the DX-2930- and placebo-treated groups; none were severe and all resolved. There were no serious AEs, discontinuations owing to an AE, or deaths. Two subjects had a severe AE reported as related to treatment by the blinded investigator; the 2 AEs were asymptomatic creatinine phosphokinase elevations of 902 U/L in 1 subject receiving 0.1 mg/kg DX-2930 and 1,967 U/L in 1 subject receiving placebo. For the 0.1-, 0.3-, 1.0-, and 3.0-mg/kg dose groups, respectively, mean maximum plasma concentrations were 0.6, 1.4, 5.6, and 14.5 μg/mL and mean elimination half-lives were 20.6, 16.8, 17.6, and 21.2 days. Exploratory biomarker assays, involving ex vivo activation of the kallikrein pathway, showed dose- and time-dependent inhibition of plasma kallikrein, with evidence of sustained bioactivity consistent with the pharmacokinetics profile. ConclusionA single administration of DX-2930 in healthy subjects up to doses of 3.0 mg/kg was well tolerated without dose-limiting toxicity. Pharmacokinetic and pharmacodynamic data provide evidence for a long-acting biological effect relevant to long-term prophylaxis for hereditary angioedema with C1-inhibitor deficiency. Trial RegistrationClinicalTrials.gov identifier: NCT01923207.

Targeting the Hedgehog and Notch Signaling Pathways

Targeting the Hedgehog and Notch Signaling Pathways

Efficacy and tolerability of a generic and a branded formulation of atorvastatin 20 mg/d in hypercholesterolemic Korean adults at high risk for cardiovascular disease: A multicenter, prospective, randomized, double-blind, double-dummy clinical trial

Background: The reduction in plasma LDL-C concentrations with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapy has been reported to reduce cardiovascular risk and mortality in individuals with or without preexisting coronary artery disease and elevated LDL-C concentrations. Atorvastatin is a statin used for lowering LDL-C concentrations. A generic formulation of atorvastatin is being developed in Korea. This study was undertaken for the purposes of marketing the generic formulation. Objective: This study was designed to compare the efficacy and tolerability of a generic formulation of atorvastatin 20 mg/d versus a branded formulation at the same dosage in hypercholesterolemic Korean adults at high risk for cardiovascular events. Methods: This 8-week, multicenter, randomized, double-blind, double-dummy study was conducted at 10 clinical centers in Korea between September 2008 and May 2009. Male and female patients aged 20 to 85 years at high risk for cardiovascular events (defined as an elevated LDL-C concentration [≥100 mg/dL]) were enrolled. Eligible patients were randomly assigned to receive generic or branded atorvastatin 20 mg once daily for 8 weeks. The primary end point was the percentage change from baseline to 8 weeks in LDL-C concentration. Secondary end points were the percentage changes from baseline in total cholesterol (TC), triglycerides (TG), HDL-C, apolipoprotein (apo) A1 and B, and high-sensitivity C-reactive protein concentrations; small, dense LDL (sdLDL) fraction; and tolerability. Tolerability was assessed using physical examination, laboratory testing, and by recording adverse events (AEs) at each visit. An additional secondary end point was the proportion of patients who achieved an LDL-C goal of <100 mg/dL. Results: A total of 244 patients were randomized to treatment, and 33 patients were withdrawn from the study (9 patients did not receive the study medication, 11 patients due to AEs, and 13 patients due to withdrawal of consent). A total of 211 patients completed the study (50.7% male; 100% Asian; mean [SD] age, 61.7 [9.2] years) (106 patients in the group that received Accepted for publication October 5, 2010. the generic formulation and 105 patients in the group that received the branded formulation). LDL-C concentrations were reduced from the baseline by 44% and 46% after 8 weeks of treatment with the generic and branded formulations, respectively ( P = NS). The percentage changes from baseline to study end in HDL-C, TC, TG, apo A1, apo B, and hsCRP concentrations and sdLDL fraction the proportions of patients who achieved the LDL-C goal between the 2 groups did not reach statistical significance. The most commonly reported events were hepatobiliary laboratory abnormality (1.7%), general somatic discomfort (1.7%), and epigastric pain (0.8%) in the group that received the generic formulation, and myalgia (1.7%), epigastric pain (0.9%), and elevation of creatinine phosphokinase (0.9%) in the group that received the branded formulation. No serious AEs were reported in either group. Conclusions: After 8 weeks of treatment, the differences in the LDL-C-lowering effects between the generic and branded formulations of atorvastatin 20 mg/d did not reach statistical significance in these Korean patients at high risk for cardiovascular events. Both formulations were generally well tolerated.