Pharmacodynamic analysis of apremilast in Japanese patients with moderate to severe psoriasis: Results from a phase 2b randomized trial

We evaluated the pharmacodynamic effects of apremilast in 69 patients who were included in biomarker subanalyses of a phase 2b study that demonstrated the long‐term safety and efficacy of apremilast in Japanese adults with moderate to severe psoriasis. The association between cytokine levels and Psoriasis Area and Severity Index (PASI) improvement was evaluated using linear regression and Spearman’s rank correlation coefficient analysis. At baseline, median plasma levels of interleukin (IL)‐17A, IL‐17F and IL‐22 were elevated versus reference values for healthy individuals, whereas tumor necrosis factor‐α levels were close to normal. With apremilast 30 mg b.i.d., there were significant associations between percentage change in PASI score and percentage change in IL‐17A, IL‐17F and IL‐22 levels at week 16. Findings demonstrate that the efficacy of apremilast in psoriasis is associated with inhibition of key cytokines involved in the pathology of psoriasis.     

Involvement of an Orphan Transporter,SLC22A18, in Cell Growth and Drug Resistance of Human Breast Cancer MCF7 Cells

The SLC22A18 gene, which encodes an orphan transporter, is located at the 11p15.5 imprinted region, an important tumor suppressor gene region. However, the role of SLC22A18 in tumor suppression remains unclear. Here, we investigated the involvement of SLC22A18 in cell growth, invasion, and drug resistance of MCF7 human breast cancer cell line. Western blot analysis indicated that SLC22A18 is predominantly expressed at intracellular organelle membranes. Quantitative proteomics showed that knockdown of SLC22A18 significantly altered the expression of 578 (31.0%) of 1867 proteins identified, including proteins related to malignancy and poor prognosis of breast cancer. SLC22A18 knockdown (1) increased MCF7 cell growth concomitantly with a >7-fold increase of annexin A8 (involved in cell growth and migration; a predictor of poor prognosis), (2) induced spherical morphology of MCF7 cells concomitantly with a nearly 3-fold increase of CD44 (involved in regulation of malignant phenotypes), and (3) increased chemosensitivity to vinca alkaloids concomitantly with a >80% reduction of doublecortin-like kinase 1 (involved in regulation of microtubule polymerization). Our results suggest that SLC22A18 may act as a tumor suppressor by regulating the expression levels of cell growth–related proteins, and vinca alkaloids might show therapeutic efficacy against low-SLC22A18–expressing breast cancer.     

Blood flow structure and dynamics, and ejection mechanism in the left ventricle: analysis using echo-dynamography

Using our "echo-dynamography", blood flow structure and flow dynamics during ventricular systole were investigated in 10 normal volunteers. The velocity vector distribution demonstrated blood flow during ejection was laminar along the ventricular septum. The characteristic flow structure was observed in each cardiac phases, early, mid- and late systole and was generated depending on the wall dynamic events such as peristaltic squeezing, hinge-like movement of the mitral ring plane, bellows action of the ventricle and dimensional changes in the funnel shape of the basal part of the ventricle, which were disclosed macroscopically by using the new technology of high speed scanning echo-tomography and microscopically by the strain rate distribution measured by phase tracking method. The pump function was reflected on the changes in the flow structure represented by the flow axis line distribution and the acceleration along the flow axis line. The acceleration of the ejection had three modes, "A", "B" and "C", and generated by the wall dynamic events. "A" appeared from the apical to the outflow area along the main flow axis line, "B" along the anterior mitral leaflet and the branched flow axis line, and "C" generated by the high speed vortex behind the mitral valve. The magnitude of the acceleration was estimated quantitatively from the velocity gradient along the flow axis line. Macroscopic and microscopic asynchrony in the myocardial contraction and extension appeared systematically in the local part of the ventricular wall, which was helpful for making the flow structure and for performing the smooth pump function.     

Alpha2-macroglobulin as a promising biomarker for cerebral small vessel disease in acute ischemic stroke patients

Alpha2-macroglobulin is a protease inhibitor that enhances procoagulant properties via the neutralization of plasmin, plasminogen activators and metalloproteinases. Additionally, alpha2-macroglobulin is thought to be involved in inflammatory reactions as a carrier protein for interleukin-6 (IL-6). The objective of this study was to evaluate the usefulness of alpha2-macroglobulin as a biomarker for cerebrovascular diseases. Patients with acute ischemic stroke (n = 159; 93 male and 66 female, 71.6 ± 10.3 years) and patients with no previous history of stroke (n = 77; 38 male and 39 female, 70.7 ± 9.5 years) were consecutively enrolled in this study. White matter lesions were assessed via the fluid-attenuated inversion recovery image of magnetic resonance images using the Fazekas classification. The serum alpha2-macroglobulin levels were measured by nephelometry. The serum alpha2-macroglobulin levels at admission in patients with acute ischemic stroke were higher than those in the control patients (230.2 ± 73.7 vs. 205.0 ± 55.8 mg/dl, p = 0.009). The serum alpha2-macroglobulin levels were positively correlated with age and the severity of the white matter lesions (R ² = 0.048, p < 0.001 and R ² = 0.058, p < 0.001, respectively), although there was no significant association between serum alpha2-macroglobulin levels and IL-6 levels. In addition, multivariate analysis showed that increased serum alpha2-macroglobulin levels were independently associated with the severity of white matter lesions [standardized partial regression coefficient (β) 0.102, p = 0.026]. Increased serum alpha2-macroglobulin levels might be involved in the pathophysiology of acute ischemic stroke. Furthermore, serum alpha2-macroglobulin levels, which were associated with high-grade white matter lesions, may reflect the chronic pathophysiological condition of cerebral small vessel disease.     

Sensitivity and related factors in iodine-123-beta-methyl-p-iodophenyl-pentadecanoic acid myocardial scintigraphy to detect stable effort angina pectoris

OBJECTIVES: This study evaluated the sensitivity and the related factors in iodine-123-beta-methyl-p-iodophenyl-pentadecanoic acid (BMIPP) scintigraphy to detect stable angina. METHODS: The subjects were 198 patients with stable angina who underwent BMIPP before percutaneous coronary intervention or coronary bypass graft surgery. Patients with unstable angina, myocardial infarction, congestive heart failure, cardiomyopathy and vasospastic angina were excluded. After investigation of the sensitivity of BMIPP, the patients with single-vessel disease without collateral flow were classified into the normal (123)I-BMIPP uptake group (normal group)or decreased (123)I-BMIPP uptake group (decreased group), and various factors were compared between the two groups. RESULTS: Sensitivity was 61% overall, 58% in single-vessel disease, 69% in double-vessel disease, 53% in triple-vessel disease, 43% in only left main vessel disease, and 89% in left main and other vessel disease (NS). In single-vessel disease, the sensitivity was 40% in 75% coronary artery stenosis, 58% in 90% stenosis, 89% in 99% stenosis, and 69% in total occlusion (p = 0.003). Comparing the deoreased and normal groups, diabetes mellitus was more frequent in the normal group (14.6% vs 39.5%), minimal lumen diameter was smaller (0.75 +/- 0.37 vs 0.98 +/- 0.49 mm) and lesion length was longer in the decreased group (15.4 +/- 4.9 vs 11.6 +/- 5.5 mm). Logistic multivariate analysis showed that the independent factors were diabetes mellitus [odds ratio 0.20, 95% confidence interval (CI) 0.04-0.87, p = 0.03], minimal lumen diameter (odds ratio 0.10, 95% CI 0.02-0.48, p = 0.003) and lesion length (odds ratio 1.12, 95% CI 1.00-1.25, p = 0.03). CONCLUSIONS: BMIPP is useful in stable angina patients because of the acceptable sensitivity. Diabetes mellitus, minimal lumen diameter and lesion length were independent factors associated with decreased BMIPP uptake.     

Case of pemphigus with immunoglobulin G and A antibodies,binding to both the intercellular spaces and basement membrane zone

We report a case involving a 62‐year‐old woman with in vivo‐bound immunoglobulin (Ig)G and IgA antibodies in both the intercellular space (ICS) and basement membrane zone (BMZ). Her clinical and histopathological features were identical with those of pemphigus vulgaris, while the immunopathological findings suggested IgG/IgA pemphigus. Direct immunofluorescence (IF) showed in vivo‐bound IgG and IgA antibodies in the ICS and BMZ, whereas indirect IF showed circulating IgG but not IgA antibodies in the ICS and BMZ. The anti‐ICS IgG bound to desmoglein‐3, while the anti‐BMZ antibodies bound to the epidermal side of 1 mol/L NaCl‐split skin. To the best of our knowledge, only two similar cases have been reported so far. Furthermore, we also examined IgG subclass distribution of the in vivo‐bound and circulating anti‐ICS and BMZ antibodies, and found that IgG1, IgG2 and IgG4 bound to ICS of the lesional skins, while IgG1 and IgG3 bound to the BMZ. The circulating anti‐ICS antibodies belonged to IgG1 and IgG4, while the circulating anti‐BMZ antibodies to IgG1, IgG2 and IgG4. We report a case involving a 62‐year‐old woman with in vivo‐bound immunoglobulin (Ig)G and IgA antibodies in both the intercellular space (ICS) and basement membrane zone (BMZ). Her clinical and histopathological features were identical with those of pemphigus vulgaris, while the immunopathological findings suggested IgG/IgA pemphigus. Direct immunofluorescence (IF) showed in vivo‐bound IgG and IgA antibodies in the ICS and BMZ, whereas indirect IF showed circulating IgG but not IgA antibodies in the ICS and BMZ. The anti‐ICS IgG bound to desmoglein‐3, while the anti‐BMZ antibodies bound to the epidermal side of 1 mol/L NaCl‐split skin. To the best of our knowledge, only two similar cases have been reported so far. Furthermore, we also examined IgG subclass distribution of the in vivo‐bound and circulating anti‐ICS and BMZ antibodies, and found that IgG1, IgG2 and IgG4 bound to ICS of the lesional skins, while IgG1 and IgG3 bound to the BMZ. The circulating anti‐ICS antibodies belonged to IgG1 and IgG4, while the circulating anti‐BMZ antibodies to IgG1, IgG2 and IgG4.     

Apremilast,an oral phosphodiesterase 4 inhibitor,in the treatment of Japanese patients with moderate to severe plaque psoriasis: Efficacy,safety and tolerability results from a phase 2b randomized controlled trial

Apremilast, an oral, small‐molecule phosphodiesterase 4 inhibitor, works intracellularly within immune cells to regulate inflammatory mediators. This phase 2b randomized, placebo‐controlled study evaluated efficacy and safety of apremilast among Japanese patients with moderate to severe plaque psoriasis. In total, 254 patients were randomized to placebo, apremilast 20 mg b.i.d. (apremilast 20) or apremilast 30 mg b.i.d. (apremilast 30) through week 16; thereafter, all placebo patients were re‐randomized to apremilast 20 or 30 through week 68. Efficacy assessments included achievement of 75% or more reduction from baseline in Psoriasis Area and Severity Index score (PASI‐75; primary) and achievement of static Physician Global Assessment (sPGA; secondary) score of 0 (clear) or 1 (minimal) at week 16. Safety was assessed through week 68. At week 16, PASI‐75 response rates were 7.1% (placebo), 23.5% (apremilast 20; P = 0.0032 vs placebo) and 28.2% (apremilast 30; P = 0.0003 vs placebo); sPGA response rates (score of 0 or 1) were 8.8% (placebo), 23.9% (apremilast 20; P = 0.0165 vs placebo) and 29.6% (apremilast 30; P = 0.0020 vs placebo). Responses were maintained with apremilast through week 68. Most common adverse events (AEs) with placebo, apremilast 20 and apremilast 30 (0–16 weeks) were nasopharyngitis (8.3%, 11.8%, 11.8%), diarrhea (1.2%, 8.2%, 9.4%), and abdominal discomfort (1.2%, 1.2%, 7.1%), respectively. Exposure‐adjusted incidence of these AEs did not increase with continued apremilast treatment (up to 68 weeks). Apremilast demonstrated efficacy and safety in Japanese patients with moderate to severe plaque psoriasis through 68 weeks that was generally consistent with prior studies.