Fatal hyperkalemia related to combined therapy with a COX-2 inhibitor,ACE inhibitor and potassium rich diet

We describe the case of a 77-year old mildly hypertensive woman with no underlying renal disease who was admitted to the Emergency Department (ED) in a comatose state with fever. The patient had been on low dose enalapril and a potassium rich diet. Five days before admission, rofecoxib, a new selective COX-2 inhibitor nonsteroidal anti-inflammatory drug (NSAID), was added for leg pain. She was found to have severe hyperkalemia and died 90 min after her arrival. We cannot absolutely determine whether the COX-2 inhibitor was the dominant contributor to the development of hyperkalemia or the combination itself, with an intercurrent infection and some degree of dehydration. Physicians should be aware of this possible complication and only prescribe NSAIDs, including the new COX-2 drugs, to the elderly under close monitoring of kidney function and electrolyte tests.     

Prospects for Creation of Cardioprotective and Antiarrhythmic Drugs Based on Opioid Receptor Agonists

It has now been demonstrated that the μ, δ₁, δ₂, and κ₁ opioid receptor (OR) agonists represent the most promising group of opioids for the creation of drugs enhancing cardiac tolerance to the detrimental effects of ischemia/reperfusion (I/R). Opioids are able to prevent necrosis and apoptosis of cardiomyocytes during I/R and improve cardiac contractility in the reperfusion period. The OR agonists exert an infarct‐reducing effect with prophylactic administration and prevent reperfusion‐induced cardiomyocyte death when ischemic injury of heart has already occurred; that is, opioids can mimic preconditioning and postconditioning phenomena. Furthermore, opioids are also effective in preventing ischemia‐induced arrhythmias.     

Changes in paraspinal muscles and their association with low back pain and spinal degeneration: CT study

The objectives of the study were to evaluate the association between lumbar paraspinal muscle density, evaluated on computed tomography (CT) and age, sex and BMI; and to evaluate the association of those changes with low back pain (LBP) and spinal degeneration features in a community-based sample. This study was an ancillary project to the Framingham Study. A sample of 3,529 participants aged 40–80 years had a CT scan performed to assess aortic calcification. 187 individuals were randomly enrolled in this study. LBP in the last 12 months was evaluated using self-report questionnaire. Density (in Hounsfield units) of multifidus and erector spinae was evaluated on CT. The prevalence of intervertebral disc narrowing, facet joint osteoarthritis (FJOA), spondylolysis, spondylolisthesis and spinal stenosis were also evaluated. We used linear regression models to examine the association of paraspinal muscles density with age, sex, BMI, LBP, and spinal degeneration features. The results show that in our study, men have higher density of paraspinal muscles than women, younger individuals have higher density than older ones and individuals with lower weight have higher muscle density than overweight. No differences between individuals with and without LBP were found. Significant association was found between L4 multifidus/erector spinae density and FJOA at L4–L5; between multifidus at L4 and spondylolisthesis at L4–5; and between erector spinae at L4 and L5 with disc narrowing at L4–5 and L5–S1, respectively. We conclude that the paraspinal muscle density decreases with age, and increases BMI. It is associated with at some levels FJOA, spondylolisthesis and disc narrowing at the same level, but not associated with occurrence of LBP.     

Comparison of Nonmem 7.2 estimation methods and parallel processing efficiency on a target-mediated drug disposition model

The paper compares performance of Nonmem estimation methods--first order conditional estimation with interaction (FOCEI), iterative two stage (ITS), Monte Carlo importance sampling (IMP), importance sampling assisted by mode a posteriori (IMPMAP), stochastic approximation expectation-maximization (SAEM), and Markov chain Monte Carlo Bayesian (BAYES), on the simulated examples of a monoclonal antibody with target-mediated drug disposition (TMDD), demonstrates how optimization of the estimation options improves performance, and compares standard errors of Nonmem parameter estimates with those predicted by PFIM 3.2 optimal design software. In the examples of the one- and two-target quasi-steady-state TMDD models with rich sampling, the parameter estimates and standard errors of the new Nonmem 7.2.0 ITS, IMP, IMPMAP, SAEM and BAYES estimation methods were similar to the FOCEI method, although larger deviation from the true parameter values (those used to simulate the data) was observed using the BAYES method for poorly identifiable parameters. Standard errors of the parameter estimates were in general agreement with the PFIM 3.2 predictions. The ITS, IMP, and IMPMAP methods with the convergence tester were the fastest methods, reducing the computation time by about ten times relative to the FOCEI method. Use of lower computational precision requirements for the FOCEI method reduced the estimation time by 3-5 times without compromising the quality of the parameter estimates, and equaled or exceeded the speed of the SAEM and BAYES methods. Use of parallel computations with 4-12 processors running on the same computer improved the speed proportionally to the number of processors with the efficiency (for 12 processor run) in the range of 85-95% for all methods except BAYES, which had parallelization efficiency of about 70%.     

Subcutaneous Absorption of Monoclonal Antibodies: Role of Dose, Site of Injection, and Injection Volume on Rituximab Pharmacokinetics in Rats

Purpose  

To determine the effect of dose, the anatomical site of injection, and the injection volume on subcutaneous absorption of rituximab in rats and to explore absorption mechanisms using pharmacokinetic modeling.