Anti-HMGCR immune-mediated necrotizing myopathy: A case report / 北京大学学报(医学版)

The patient was a 55-year-old man who was admitted to hospital with "progressive myalgia and weakness for 4 months, and exacerbated for 1 month". Four months ago, he presented with persistent shoulder girdle myalgia and elevated creatine kinase (CK) at routine physical examination, which fluctuated from 1 271 to 2 963 U/L after discontinuation of statin treatment. Progressive myalgia and weakness worsened seriously to breath-holding and profuse sweating 1 month ago. The patient was post-operative for renal cancer, had previous diabetes mellitus and coronary artery disease medical history, had a stent implanted by percutaneous coronary intervention and was on long-term medication with aspirin, atorvastatin and metoprolol. Neurological examination showed pressure pain in the scapularis and pelvic girdle muscles, and V- grade muscle strength in the proximal extremities. Strongly positive of anti-HMGCR antibody was detected. Muscle magnetic resonance imaging (MRI) T2-weighted image and short time inversion recovery sequences (STIR) showed high signals in the right vastus lateralis and semimembranosus muscles. There was a small amount of myofibrillar degeneration and necrosis, CD4 positive inflammatory cells around the vessels and among myofibrils, MHC-Ⅰ infiltration, and multifocal lamellar deposition of C5b9 in non-necrotic myofibrils of the right quadriceps muscle pathological manifestation. According to the clinical manifestation, imageological change, increased CK, blood specific anti-HMGCR antibody and biopsy pathological immune-mediated evidence, the diagnosis of anti-HMGCR immune-mediated necrotizing myopathy was unequivocal. Methylprednisolone was administrated as 48 mg daily orally, and was reduced to medication discontinuation gradually. The patient's complaint of myalgia and breathlessness completely disappeared after 2 weeks, the weakness relief with no residual clinical symptoms 2 months later. Follow-up to date, there was no myalgia or weakness with slightly increasing CK rechecked. The case was a classical anti-HMGCR-IMNM without swallowing difficulties, joint symptoms, rash, lung symptoms, gastrointestinal symptoms, heart failure and Raynaud's phenomenon. The other clinical characters of the disease included CK as mean levels >10 times of upper limit of normal, active myogenic damage in electromyography, predominant edema and steatosis of gluteus and external rotator groups in T2WI and/or STIR at advanced disease phase except axial muscles. The symptoms may occasionally improve with discontinuation of statins, but glucocorticoids are usually required, and other treatments include a variety of immunosuppressive therapies such as methotrexate, rituximab and intravenous gammaglobulin.

Evaluation of plasma stability and pharmacokinetics of parthenolide in rats with LC-MS/MS analysis / 药学学报

Parthenolide is a sesquiterpene lactone derived from the plant feverfew (Tanacetum parthenium) that possesses multiple anti-inflammatory and anti-cancer properties. A specific, sensitive, accurate and precise LC-MS/MS method was developed and validated in the quantitative analysis of parthenolide in rat plasma. A liquid-liquid extraction method was used to separate the analyte and the internal standard (IS, costunolide) from plasma. A water-methanol mobile phase system was utilized in the gradient chromatographic separation. The calibration curve with good linearity (r2>0.99) was established between 2 and 128 ng·mL-1 with accuracy and precision within acceptable limits at different QC levels. High extraction recovery was achieved for both parthenolide (89.55%-95.79%) and IS (96.87%). Based on this LC-MS/MS method, the plasma stability and pharmacokinetics of parthenolide were assessed in rats. Parthenolide was proved to be very unstable in rat plasma, and was distributed and eliminated quickly in vivo, with a half-life less than 90 min. A high dose of parthenolide (80 mg·kg-1) resulted in a very low initial concentration (138.86±21.07 ng·mL-1). The systemic exposure of parthenolide (area under the curve) increased disproportionally from 40 mg·kg-1 dose group to 80 mg·kg-1 dose group. The present study may provide helpful information for the development of parthenolide as a drug candidate.

Elimination Rate of Serum Lactate is Correlated with Amyotrophic Lateral Sclerosis Progression / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Mitochondrial dysfunction plays an important role in the pathogenesis of amyotrophic lateral sclerosis (ALS). We aimed to demonstrate mitochondrial dysfunction in ALS using a lactate stress test and to examine the relationship between mitochondrial dysfunction with motor deterioration.</p><p><b>METHODS</b>We enrolled 116 patients and observed clinical variables, including the survival state.</p><p><b>RESULTS</b>Patients with a rapid slope of revised ALS functional rating scales (ALSFRS-r) (>20 U/year) exhibited the slowest elimination rate (median -4.67 × 10-3 mmol·L-1·min-1 , coefficient of variation, 590.15%), the shortest duration (0.63 ± 0.28 years) and the worst ALSFRS-r (32.59 ± 4.93). Patients with a moderate slope of ALSFRS-r (10-20 U/year) showed a moderate elimination rate (median -11.33 × 10-3 mmol·L-1·min-1 , coefficient of variation, 309.89%), duration (1.16 ± 0.45 years), and ALSFRS-r (34.83 ± 6.11). The slower progressing (<10 U/year group) patients exhibited a rapid elimination rate (median: -12.00 × 10-3 mmol·L-1·min-1 , coefficient of variation: 143.08%), longer duration (median: 3 years, coefficient of variation: 193.33%), and adequate ALSFRS-r values (39.58 ± 9.44). Advanced-phase ALS patients also showed slower elimination rate (ER, quartiles -17.33, -5.67, 4.00) and worse ALSFRS-r (34.88 ± 9.27), while early-phase patients showed a more rapid ER (quartiles -25.17, -11.33, -3.50) and better ALSFRS-r (39.28 ± 7.59). These differences were statistically significant. Multiple linear regression analysis revealed strong direct associations among ER, ALSFRS-r slope (standard beta = 0.33, P = 0.007), and forced vital capacity (predict %) (standard beta = -0.458, P = 0.006, adjusted for ALSFRS-r, course and onset region). However, the data obtained from 3 years of follow-up showed no statistically significant difference in the survival rates between the most rapid and slowest ER groups.</p><p><b>CONCLUSION</b>There is a potential linear relationship between ER and motor deterioration in ALS. Slower ER might be associated with faster disease progression.</p>