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

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.

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Use of insulin degludec, a new basal insulin with an ultra-long duration of action, in basal–bolus therapy in type 1 and type 2 diabetes

Annales d Endocrinologie ◽

10.1016/j.ando.2013.04.004 ◽

2013 ◽

Vol 74 (5-6) ◽

pp. 487-490 ◽

Cited By ~ 2

Author(s):

Véronique Kerlan ◽

Didier Gouet ◽

Michel Marre ◽

Éric Renard

Keyword(s):

Type 2 Diabetes ◽

Basal Insulin ◽

Insulin Degludec ◽

Duration Of Action ◽

Long Duration ◽

Basal Bolus

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

Pain Research and Management ◽

10.1155/2005/286713 ◽

2005 ◽

Vol 10 (3) ◽

pp. 133-144 ◽

Cited By ~ 33

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.

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Purification and Characterization of a Novel Subtype A3 Botulinum Neurotoxin

Applied and Environmental Microbiology ◽

10.1128/aem.07967-11 ◽

2012 ◽

Vol 78 (9) ◽

pp. 3108-3113 ◽

Cited By ~ 22

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.

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

Medical Ultrasonography ◽

10.11152/mu-1543 ◽

2018 ◽

Vol 20 (4) ◽

pp. 461 ◽

Cited By ~ 6

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.

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

Biochemical Journal ◽

10.1042/bj1420287 ◽

1974 ◽

Vol 142 (2) ◽

pp. 287-294 ◽

Cited By ~ 59

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.

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Topical application of ASN008, a permanently charged sodium channel blocker, shows robust efficacy, a rapid onset and long duration of action in a mouse model of pruritus

Journal of the American Academy of Dermatology ◽

10.1016/j.jaad.2019.06.518 ◽

2019 ◽

Vol 81 (4) ◽

pp. AB138

Keyword(s):

Mouse Model ◽

Sodium Channel ◽

Topical Application ◽

Channel Blocker ◽

Rapid Onset ◽

Sodium Channel Blocker ◽

Duration Of Action ◽

Long Duration

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Effect of Synthetic Ovine Corticotropin-Releasing Factor: Prolonged Duration of Action and Biphasic Response of Plasma Adrenocorticotropin and Cortisol*

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem-57-2-294 ◽

1983 ◽

Vol 57 (2) ◽

pp. 294-298 ◽

Cited By ~ 43

Author(s):

C. ROWAN DEBOLD ◽

G. STEPHEN DECHERNEY ◽

RICHARD V. JACKSON ◽

WILLIAM R. SHELDON ◽

A. NANCYE ALEXANDER ◽

...

Keyword(s):

Corticotropin Releasing Factor ◽

Biphasic Response ◽

Duration Of Action ◽

Prolonged Duration

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Orally active zwitterionic factor Xa inhibitors with long duration of action

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2011.10.021 ◽

2011 ◽

Vol 21 (24) ◽

pp. 7337-7343 ◽

Cited By ~ 2

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

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Metabolism of a New Local Anesthetic, Ropivacaine, by Human Hepatic Cytochrome P450

Anesthesiology ◽

10.1097/00000542-199501000-00026 ◽

1995 ◽

Vol 82 (1) ◽

pp. 214-220 ◽

Cited By ~ 46

Author(s):

Yutaka Oda ◽

Katsuji Furuichi ◽

Kazuo Tanaka ◽

Toyoko Hiroi ◽

Susumu Imaoka ◽

...

Keyword(s):

Cytochrome P450 ◽

Plasma Concentration ◽

Local Anesthetic ◽

Major Metabolite ◽

Duration Of Action ◽

Hepatic Microsomes ◽

Long Duration ◽

P450 Isozymes ◽

Lymphoblast Cells ◽

Hepatic Cytochrome

Background Ropivacaine is a local anesthetic with a long duration of action. Although it is less toxic than bupivacaine, local anesthetic toxicity is possible when the plasma concentration is increased. Because ropivacaine is an amide-type local anesthetic, it is metabolized by cytochrome P450 (P450) in the liver, and its elimination and plasma concentration can be dependent on the level of P450. The purpose of this investigation was to elucidate the metabolism of ropivacaine by human hepatic P450. Methods The metabolism of ropivacaine was compared using recombinant human and purified rat hepatic P450 isozymes. An inhibition study using antibodies against rat P450 was performed using hepatic microsomes from human and rat to identify which P450s are involved in ropivacaine metabolism. Results Ropivacaine was metabolized to 2',6'-pipecoloxylidide (PPX), 3'-hydroxyropivacaine (3'-OH Rop), and 4'-hydroxyropivacaine (4'-OH Rop) by hepatic microsomes from human and rat. PPX was a major metabolite of both human and rat hepatic microsomes. In a reconstituted system with rat P450. PPX was produced by CYP2C11 and 3A2, 4'-OH Rop by CYP1A2, and 3'-OH Rop by CYP1A2 and 2D1. Formation of PPX in rat hepatic microsomes was inhibited by anti CYP3A2, but not by CYP2C11 antibody, and formation of 3'-OH Rop was inhibited by CYP1A2 and 2D1 antibodies. Anti CYP3A2 and 1A2 antibodies inhibited the formation of PPX and 3'-OH Rop in human hepatic microsomes, respectively. Recombinant human P450s expressed in lymphoblast cells were used for further study. CYP3A4 and 1A2 formed the most PPX and 3'-OH Rop, respectively. Ropivacaine N-dealkylation and 3'-hydroxylation activities correlated well with the level of CYP3A4 and 1A2 in human hepatic microsomes, respectively. Conclusions Ropivacaine was metabolized to PPX, 3'-OH Rop, and 4'-OH Rop by hepatic P450. PPX was a major metabolite in human hepatic microsomes. CYP3A4 was involved in producing PPX. CYP1A2 was involved in the formation of 3'-OH Rop in human hepatic microsomes.

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