SKY59, A Novel Recycling Antibody for Complement-mediated Diseases

2020 ◽  
Vol 27 (25) ◽  
pp. 4157-4164 ◽  
Author(s):  
Taku Fukuzawa ◽  
Junichi Nezu
Keyword(s):  
Inhibitory Effect ◽  
Biologic Agent ◽  
Microbial Infection ◽  
Duration Of Action ◽  
Complement Activity ◽  
Body Of Knowledge ◽  
Therapeutic Benefits ◽  
Long Duration ◽  
Recycling Technology ◽  
Current Therapies

Background: The complement system usually helps protect against microbial infection, but it could also be involved in the onset of various diseases. Inhibition of complement component 5 (C5) with eculizumab has resulted in a significant reduction of hemolysis, reduction of thromboembolic events, and increased survival in patients with Paroxysmal Nocturnal Hemoglobinuria (PNH). However, eculizumab requires frequent intravenous infusions due to the abundance of C5 in plasma and some patients may still experience breakthrough hemolysis. This review introduces the recent body of knowledge on recycling technology and discusses the likely therapeutic benefits of SKY59, a novel recycling antibody, for PNH and complement-mediated disorders. Methods: By using recycling technology, we created a novel anti-C5 antibody, SKY59, capable of binding to C5 pH-dependently. Results: In cynomolgus monkeys, SKY59 robustly inhibited C5 and complement activity for significantly longer than a conventional antibody. SKY59 also showed an inhibitory effect on C5 variant p.Arg885His, whereas eculizumab does not suppress complement activity in patients with this type of mutation. Conclusion: SKY59 is a promising anti-C5 biologic agent that has significant advantages over current therapies such as long duration of action and efficacy against C5 variants.

scholarly journals Phenol sulphotransferase and uridine diphosphate glucuronyltransferase from rat liver in vivo and in vitro. 2,6-Dichloro-4-nitrophenol as selective inhibitor of sulphation

1977 ◽  
Vol 165 (3) ◽  
pp. 553-559 ◽  
Author(s):  
Gerard J. Mulder ◽  
Egbert Scholtens
Keyword(s):  
Rat Liver ◽  
Inhibitory Effect ◽  
Selective Inhibitor ◽  
Biological Processes ◽  
Uridine Diphosphate ◽  
Duration Of Action ◽  
Long Duration

Microsomal UDP-glucuronyltransferase and cytosolic sulphotransferase share many substrates, such as phenols and hydroxamic acids. In a search for a selective inhibitor of sulphation, several phenolic compounds were tested. 2,6-Dichloro-4-nitrophenol is introduced as a selective inhibitor of sulphation in vivo, having no effect on UDP-glucuronyltransferase activity. As substrate for both conjugating enzymes the phenolic drug harmol (7-hydroxy-1-methyl-9H-pyrido[3,4-b]indole) was used. In the rat in vivo 2,6-dichloro-4-nitrophenol caused almost complete inhibition of harmol sulphation after a single intraperitoneal injection (26μmol/kg) for 48h; the percentage of harmol sulphated decreased from 75% in controls to 5% in the treated rats. The percentage of harmol glucuronidated increased from 25 to 95%. Pentachlorophenol was equally effective but also highly toxic. Salicylamide had only a very-short-lasting inhibitory effect on sulphation. In vitro, 2,6-dichloro-4-nitrophenol inhibited sulphation of harmol by a rat liver postmitochondrial supernatant completely at 1μm, whereas even at 100μm it had no effect on glucuronidation of harmol. It is concluded that 2,6-dichloro-4-nitrophenol is a selective inhibitor of sulphation and, further, that its long duration of action makes it suitable for studies on the regulatory role of sulphation in some biological processes.

scholarly journals A Review of the Use of Methadone for the Treatment of Chronic Noncancer Pain

2005 ◽  
Vol 10 (3) ◽  
pp. 133-144 ◽  
Author(s):  
Mary E Lynch
Keyword(s):  
Chronic Pain ◽  
Low Cost ◽  
Interindividual Variation ◽  
Duration Of Action ◽  
Chronic Noncancer Pain ◽  
Opioid Dose ◽  
Long Duration ◽  
Attractive Option ◽  
Noncancer Pain ◽  
High Bioavailability

Methadone, although having been available for approximately half a century, is now receiving increasing attention in the management of chronic pain. This is due to recent research showing that methadone exhibits at least three different mechanisms of action including potent opioid agonism, N-methyl-D-aspartate antagonism and monoaminergic effects. This, along with methadone's excellent oral and rectal absorption, high bioavailability, long duration of action and low cost, make it a very attractive option for the treatment of chronic pain. The disadvantages of significant interindividual variation in pharmacokinetics, graduated dose equivalency ratios based on prerotation opioid dose when switching from another opioid, and the requirement for special exemption for prescribing methadone make it more complicated to use. The present review is intended to educate physicians interested in adding methadone to their armamentarium for assisting patients with moderate to severe pain.

scholarly journals Purification and Characterization of a Novel Subtype A3 Botulinum Neurotoxin

2012 ◽  
Vol 78 (9) ◽  
pp. 3108-3113 ◽  
Author(s):  
William H. Tepp ◽  
Guangyun Lin ◽  
Eric A. Johnson
Keyword(s):  
Type A ◽  
Toxin Production ◽  
Mouse Bioassay ◽  
Purification Method ◽  
Duration Of Action ◽  
Content Type ◽  
Long Duration ◽  
Botulinum Neurotoxins ◽  
Subtype A

ABSTRACTBotulinum neurotoxins (BoNTs) produced byClostridium botulinumare of considerable importance due to their being the cause of human and animal botulism, their potential as bioterrorism agents, and their utility as important pharmaceuticals. Type A is prominent due to its high toxicity and long duration of action. Five subtypes of type A BoNT are currently recognized; BoNT/A1, -/A2, and -/A5 have been purified, and their properties have been studied. BoNT/A3 is intriguing because it is not effectively neutralized by polyclonal anti-BoNT/A1 antibodies, and thus, it may potentially replace BoNT/A1 for patients who have become refractive to treatment with BoNT/A1 due to antibody formation or other modes of resistance. Purification of BoNT/A3 has been challenging because of its low levels of production in culture and the need for innovative purification procedures. In this study, modified Mueller-Miller medium was used in place of traditional toxin production medium (TPM) to cultureC. botulinumA3 (CDC strain) and boost toxin production. BoNT/A3 titers were at least 10-fold higher than those produced in TPM. A purification method was developed to obtain greater than 95% pure BoNT/A3. The specific toxicity of BoNT/A3 as determined by mouse bioassay was 5.8 × 10750% lethal doses (LD50)/mg. Neutralization of BoNT/A3 toxicity by a polyclonal anti-BoNT/A1 antibody was approximately 10-fold less than the neutralization of BoNT/A1 toxicity. In addition, differences in symptoms were observed between mice that were injected with BoNT/A3 and those that were injected with BoNT/A1. These results indicate that BoNT/A3 has novel biochemical and pharmacological properties compared to those of other subtype A toxins.

scholarly journals Effects of ultrasound-guided suprascapular nerve pulsed radiofrequency on chronic shoulder pain

2018 ◽  
Vol 20 (4) ◽  
pp. 461 ◽  
Author(s):  
Tolga Ergonenc ◽  
Serbulent Gokhan Beyaz
Keyword(s):  
Shoulder Pain ◽  
External Rotation ◽  
Adhesive Capsulitis ◽  
Suprascapular Nerve ◽  
Pulsed Radiofrequency ◽  
Ultrasound Guided ◽  
Duration Of Action ◽  
Vas Score ◽  
Long Duration ◽  
Chronic Shoulder Pain

Aim: Pulsed radiofrequency (PRF) therapy has become increasingly popular in the treatment of chronic shoulder pain due to its long duration of action and non-destructive method. The aim of the study was to reveal the effects of PRF therapy of the suprascapular nerve (SSN) under ultrasound guidance (UG) in patients with chronic shoulder pain on both shoulder pain and function.Material and methods: This study included 74 patients diagnosed with at least one of the following: adhesive capsulitis, rotator cuff syndrome and impingement syndrome of shoulder. The PRF therapy of the SSN under UG was performed in those patients with a reduction of 50% or more Visual Analog Scale (VAS) score and those that reported healing in the active range of motion (AROM) in the diagnostic SSN block. The resting, motion and sleeping shoulder pain assessments of the patients were done with VAS score. The shoulder joint function was assessed with the Shoulder Pain and Disability Index (SPADI) questionnaire and the AROM of the joint was measured using a goniometer.Results: In 70 of the 74 patients a 50% or more reduction was found in the VAS score with diagnostic SSN block. After the PRF therapy of the SSN, the 15thday, 1st month, 3rd month, and 6th month follow-up VAS averages, SPADI averages and the flexion, internal rotation, external rotation, and abduction values were statistically significantly lower than the baseline values (p<0.05).Conclusion: This study is the largest series in the literature evaluating the efficacy of PRF therapy of the SSN under UG and has shown that pain canbe controlled quickly, for a long period of time, using ultrasound guided PRF therapy of the SSN in chronic shoulder pain.

scholarly journals Measurement of the dynamics of stimulation and inhibition of steroidogenesis in isolated rat adrenal cells by using column perfusion

1974 ◽  
Vol 142 (2) ◽  
pp. 287-294 ◽  
Author(s):  
P. J. Lowry ◽  
Colin McMartin
Keyword(s):  
Cyclic Amp ◽  
Time Course ◽  
Acth Stimulation ◽  
Duration Of Action ◽  
Adrenal Cells ◽  
Small Column ◽  
Long Duration ◽  
Full Effect ◽  
Rapid Fall

Isolated adrenal cells were perfused in a small column by using Bio-Gel polyacrylamide beads as an inert supporting matrix, and the time-course of the response to various stimuli was observed by measuring fluorogenic 11-hydroxycorticosteroids in the effluent. A small but significant response was observed 1 min after stimulation with physiological concentrations of ACTH (adrenocorticotrophin), but the response did not start to build up rapidly for 3–4min and eventually reached a plateau after 9–10min. A similar pattern of events was observed for the decay of the steroid output on removal of ACTH. ACTH analogues, including one with a long duration of action in vivo, were found to produce responses with similar kinetics. However, cyclic AMP caused a more rapid increase in steroidogenesis and its effects were more short-lived after withdrawal. If, as present evidence suggests, cyclic AMP is produced rapidly after ACTH stimulation the delayed build-up of the steroidogenic response to ACTH would indicate that cyclic AMP may not be the intracellular mediator. When inhibitors were applied during ACTH stimulation, aminoglutethimide, which blocks mitochondrial conversion of cholesterol into pregnenolone (3β-hydroxypregn-5-en-20-one), caused a rapid fall in steroid output (1 min), whereas cycloheximide took longer to achieve its full effect. Nevertheless, the response had fallen by 50% in 2 min, indicating a much shorter half-life than that previously reported for the labile protein implicated in steroidogenesis. In addition the rapid response to cyclic AMP makes it unlikely that steroid production is induced as a result of initiation of protein synthesis. This suggests that the labile protein plays an obligatory but permissive role in the development of the response. Column perfusion has proved to be a simple technique which can readily yield accurate data on responses of cells to stimulants and inhibitors.

scholarly journals Therapeutic Effects of Curcumin—From Traditional Past to Present and Future Clinical Applications

2019 ◽  
Vol 20 (15) ◽  
pp. 3757 ◽  
Author(s):  
Beatrice Bachmeier ◽  
Dieter Melchart
Keyword(s):  
Molecular Mechanisms ◽  
Malignant Tumors ◽  
Scientific Evidence ◽  
Treatment Strategies ◽  
Therapeutic Effects ◽  
Microbial Infection ◽  
Therapeutic Benefits ◽  
Novel Treatment Strategies

The efficacy of the plant-derived polyphenol curcumin, in various aspects of health and wellbeing, is matter of public interest. An internet search of the term “Curcumin” displays about 12 million hits. Among the multitudinous information presented on partly doubtful websites, there are reports attracting the reader with promises ranging from eternal youth to cures for incurable diseases. Unfortunately, many of these reports are not based on scientific evidence, but they feed the desideratum of the reader for a “miracle cure”. This circumstance makes it very difficult for researchers, who work in a scientifically sound and evidence-based manner on the therapeutic benefits (or side effects) of curcumin, to demarcate their results from sensational reports that circulate in the web and in other media. This is only one of many obstacles making it difficult to pave curcumin’s way into clinical application; others are its nonpatentability and low economic usability. A further impediment comes from scientists who never worked with curcumin or any other natural plant-derived compound in their own labs. They have never tested these compounds in any scientific assay, neither in vitro nor in vivo; however, they claim, in a sometimes polemic manner, that everything that has so far been published on curcumin’s molecular effects is based on artefacts. The here presented Special Issue comprises a collection of five scientifically sound articles and nine reviews reporting on the therapeutic benefits and the molecular mechanisms of curcumin or of chemically modified curcumin in various diseases ranging from malignant tumors to chronic diseases, microbial infection, and even neurodegenerative diseases. The excellent results of the scientific projects that underlie the five original papers give reason to hope that curcumin will be part of novel treatment strategies in the near future—either as monotherapy or in combination with other drugs or therapeutic applications.

scholarly journals Constrained Corticotropin Releasing Factor Antagonists (Astressin Analogues) with Long Duration of Action in the Rat†

1999 ◽  
Vol 42 (16) ◽  
pp. 3175-3182 ◽  
Author(s):  
Jean E. Rivier ◽  
Dean A. Kirby ◽  
Sabine L. Lahrichi ◽  
Anne Corrigan ◽  
Wylie W. Vale ◽  
...  
Keyword(s):  
Corticotropin Releasing Factor ◽  
Duration Of Action ◽  
Long Duration

Orally active zwitterionic factor Xa inhibitors with long duration of action

2011 ◽  
Vol 21 (24) ◽  
pp. 7337-7343 ◽  
Author(s):  
Akiyoshi Mochizuki ◽  
Tsutomu Nagata ◽  
Hideyuki Kanno ◽  
Daisuke Takano ◽  
Masamichi Kishida ◽  
...  
Keyword(s):  
Factor Xa ◽  
Factor Xa Inhibitors ◽  
Duration Of Action ◽  
Long Duration ◽  
Orally Active
Sign in / Sign up

Export Citation Format

Share Document