Involvement of Cerulospinal Glutamatergic Neurotransmission in Fentanyl-induced Muscular Rigidity in the Rat

Background: Investigators in the authors' laboratory previously established the critical participation of the cerulospinal noradrenergic pathway in muscular rigidity elicited by fentanyl. The identification of colocalization of glutamate with tyrosine hydroxylase in most locus ceruleus neurons suggests a role for cerulospinal glutamatergic neurotransmission in fentanyl-induced muscular rigidity. This suggestion and the subtype(s) of glutamate receptors involved were investigated here.

Methods: Electromyographic signals activated by bilateral microinjection of 2.5 micro gram fentanyl into the locus ceruleus were recorded differentially from the left sacrococcygeus dorsi lateralis muscle of adult male Sprague-Dawley rats. The effect of intrathecal administration at the lower lumbar spinal cord of various N-methyl-D-aspartate (NMDA) and non-NMDA receptor antagonists or agonists on this index of muscular rigidity was studied. Rats were under mechanical ventilation, and intravenous infusion of ketamine (30 mg [center dot] kg sup -1 [center dot] h sup -1) was maintained until 10 min before fentanyl was administered.

Results: Microinjection of fentanyl bilaterally into the locus ceruleus increased the root mean square and decreased the mean power frequency values of electromyographic signals. The efficacy of fentanyl to elicit muscular rigidity in this manner was significantly reduced by previous intrathecal administration of either 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801), D-(-)-2-amino-5-phosphonovaleric acid (AP5), or (+/- (CPP). Intrathecal administration of kainic acid or NMDA also resulted in significant electromyographic activation.     

Identifying amino acid residues that influence plasma clearance of murine IgG1 fragments by site-directed mutagenesis

Site-directed mutagenesis has been used to change amino acid residues of a recombinant Fc-hinge fragment derived from the murine immunoglobulin (Ig)G1 molecule, and the effects of these mutations on the pharmacokinetics of the Fc-hinge fragment have been determined. Specifically, Ile-253, His-310 and Gln-311 of the CH2 domain and His-433 and Asn-434 of the CH3 domain have been changed. In the three dimensional structure of an antibody, these amino acids are in close proximity to each other at the CH2-CH3 domain interface. The mutated Fc-hinge fragments have been purified from recombinant Escherichia coli cells and their pharmacokinetic parameters determined in mice and compared with those of the wild-type Fc-hinge fragment. The results show that the site of the IgG1 molecule that controls the catabolic rate (the ‘catabolic site’) is located at the CH2-CH3 domain interface and overlaps with the Staphylococcal protein A binding site.     

Secukinumab demonstrates superior efficacy and a faster response in clearing skin in Asian subjects with moderate to severe plaque psoriasis compared with ustekinumab: Subgroup analysis from the CLEAR study

The 52‐week results from the CLEAR (NCT02074982) study showed high and superior efficacy of secukinumab versus ustekinumab in clearing skin and improving patient‐reported outcomes, with comparable safety profile in subjects with moderate to severe psoriasis. Here, we analyzed the efficacy and safety of secukinumab in Asian subjects from the CLEAR study. In this double‐blind, phase IIIb study, eligible subjects with moderate to severe plaque psoriasis were randomized (1:1) to receive s.c. injection of secukinumab 300 mg or ustekinumab as per label. Of 62 subjects included in Asian subanalyses, 23 were randomized to secukinumab and 39 to ustekinumab. A significantly higher proportion of subjects achieved 90% or more improvement in Psoriasis Area and Severity Index (PASI 90) with secukinumab versus ustekinumab at week 16 (78.3% vs 35.9%, P = 0.0010) and at week 52 (60.9% vs 33.3%, P = 0.0196). Similarly, a higher proportion of subjects achieved PASI 100 with secukinumab versus ustekinumab at week 16 (43.5% vs 10.3%, P = 0.0029) and at week 52 (30.4% vs 12.8%, P = 0.0704). The median time to achieve 50% improvement in baseline PASI was 2.8 weeks in the secukinumab group versus 6.3 weeks in the ustekinumab group. The safety profile of secukinumab was in line with the known profile and no deaths occurred. Overall, 95.7% and 84.6% of subjects remained on secukinumab and ustekinumab, respectively. Similar to the core study, secukinumab showed sustained and superior efficacy with faster response versus ustekinumab, and no new or unexpected safety concerns were identified, in Asian subjects with moderate to severe plaque psoriasis.     

Efficacy and safety of secukinumab in Taiwanese patients with moderate to severe plaque psoriasis: Subanalysis from ERASURE phase III study

The efficacy and safety of secukinumab, a fully human anti‐interleukin‐17A monoclonal antibody, has been evaluated for moderate to severe plaque psoriasis in global trials which have included a low proportion of Asian subjects. We analyzed the efficacy and safety of secukinumab in Taiwanese patients in a phase III global clinical trial (ERASURE). Fifty‐one Taiwanese patients were randomized into s.c. placebo, 150 and 300 mg secukinumab treatment groups. The proportions of patients who achieved 75% or more improvement in Psoriasis Area and Severity Index (PASI‐75) at week 12 were 87.5% with 300 mg secukinumab, 70% with 150 mg secukinumab, 0% with placebo. Of the patients receiving 300 mg secukinumab, 68.8% achieved PASI‐90 at week 12. Analysis of overall patients receiving 300 mg secukinumab for 12 weeks showed that the proportion of PASI‐75 responders was less in patients with body mass index of 25 or more than less than 25. During the entire 52 weeks, the incidence of adverse events (AE) was consistent with the overall population in ERASURE. The most common AE (cases/per 100 patient‐year) during the entire treatment period were upper respiratory tract infection and pruritus. The duration of upper respiratory tract infection per 100 patient‐year was approximately 399 days in placebo, 1261 days in 150 mg secukinumab and 1805 days in 300 mg secukinumab. The safety and efficacy of secukinumab in Taiwanese patients was compatible with the global phase III study in the treatment of moderate to severe plaque psoriasis.