scholarly journals A new era for migraine: Pharmacokinetic and pharmacodynamic insights into monoclonal antibodies with a focus on galcanezumab, an anti-CGRP antibody

Cephalalgia ◽  
2019 ◽  
Vol 39 (10) ◽  
pp. 1284-1297 ◽  
Author(s):  
William Kielbasa ◽  
Danielle L Helton
Keyword(s):  
Oral Absorption ◽  
Free Ligand ◽  
Subcutaneous Administration ◽  
Calcitonin Gene Related Peptide ◽  
Convective Transport ◽  
Systemic Absorption ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Related Peptide ◽  
Calcitonin Gene

Purpose To review pharmacokinetic and pharmacodynamic characteristics of antibodies that bind to soluble ligands within the framework of calcitonin gene-related peptide antibodies. Overview Calcitonin gene-related peptide has been implicated in the pathophysiology of migraine. Galcanezumab is an antibody that binds to the ligand calcitonin gene-related peptide. Other antibodies that target calcitonin gene-related peptide include eptinezumab and fremanezumab. To understand how antibodies can affect the extent and duration of free ligand concentrations, it is important to consider the dose and pharmacokinetics of an antibody, and the kinetics of the ligand and antibody–ligand complex. Insights regarding the pharmacokinetic/pharmacodynamic properties of galcanezumab as a probe antibody drug and calcitonin gene-related peptide as its binding ligand regarding its clinical outcomes are provided. Discussion Antibodies are administered parenterally because oral absorption is limited by gastrointestinal degradation and inefficient diffusion through the epithelium. The systemic absorption of antibodies following intramuscular or subcutaneous administration most likely occurs via convective transport through lymphatic vessels into blood. The majority of antibody elimination occurs via intracellular catabolism into peptides and amino acids following endocytosis. Binding of ligand to an antibody reduces the free ligand that is available to interact with the receptor and efficacy is driven by the magnitude and duration of the reduction in free ligand concentration. A galcanezumab pharmacokinetic/pharmacodynamic model shows that galcanezumab decreases free calcitonin gene-related peptide concentrations in a dose- and time-dependent manner and continues to suppress free calcitonin gene-related peptide with repeated dosing. The model provides evidence for a mechanistic linkage to galcanezumab therapeutic effects for the preventive treatment of migraine.

scholarly journals Renal microvascular actions of calcitonin gene-related peptide

1998 ◽  
Vol 274 (6) ◽  
pp. F1078-F1085 ◽  
Author(s):  
Martina Reslerova ◽  
Rodger Loutzenhiser
Keyword(s):  
Angiotensin Ii ◽  
Rat Kidney ◽  
Elevated Pressure ◽  
Calcitonin Gene Related Peptide ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Renal Vasoconstriction ◽  
Related Peptide ◽  
Calcitonin Gene

Calcitonin gene-related peptide (CGRP) is a potent vasodilator that is suggested to act via ATP-sensitive K channels (KATP). In the present study, we examined the actions of CGRP on pressure- and angiotensin II-induced vasoconstriction, using the in vitro perfused hydronephrotic rat kidney. Elevated pressure (from 80 to 180 mmHg) and 0.1 nM angiotensin II elicited similar decreases in afferent diameter in this model. CGRP inhibited myogenic reactivity in a concentration-dependent manner, completely preventing pressure-induced constriction at 10 nM (95 ± 10% inhibition). These effects were partially attenuated by 10 μM glibenclamide (62 ± 16% inhibition, P = 0.025), indicating both KATP-dependent and -independent actions of CGRP. In contrast, 10 nM CGRP inhibited angiotensin II-induced vasoconstriction by only 54 ± 11%, and this action was not affected by glibenclamide (41 ± 11%, P = 0.31). CGRP also inhibited the efferent arteriolar response to angiotensin II in the absence and presence of glibenclamide. Pinacidil (1.0 μM), a KATP opener also preferentially inhibited pressure- vs. angiotensin II-induced vasoconstriction (97 ± 5 and 59 ± 13% inhibition, respectively; P = 0.034). We conclude that the renal vasodilatory mechanisms of CGRP are pleiotropic and involve both KATP-dependent and -independent pathways. The effectiveness of CGRP in opposing renal vasoconstriction and the role of KATP in this action appear to depend on the nature the underlying vasoconstriction. We suggest that this phenomenon reflects an inhibition of KATP activation by angiotensin II.

Pharmacological evidence that calcitonin gene-related peptide is implicated in cerebral autoregulation

1994 ◽  
Vol 266 (1) ◽  
pp. H11-H16 ◽  
Author(s):  
K. W. Hong ◽  
K. M. Pyo ◽  
W. S. Lee ◽  
S. S. Yu ◽  
B. Y. Rhim
Keyword(s):  
Blood Pressure ◽  
Substance P ◽  
Calcitonin Gene Related Peptide ◽  
K Channel ◽  
Dependent Manner ◽  
Receptor Desensitization ◽  
Arterial Diameter ◽  
Cranial Window ◽  
Related Peptide ◽  
Calcitonin Gene

In anesthetized rats, we examined the possibility that calcitonin gene-related peptide (CGRP, a neuropeptide) released in response to transient hypotension may contribute to the reflex autoregulation of cerebral blood flow. Changes in pial arterial diameter (mean 33.0 +/- 1.1 microns) with changes in systemic arterial blood pressure (mean 101.9 +/- 2.7 mmHg) were observed directly through a closed cranial window. In capsaicin-treated rats (depletor of CGRP and substance P, 50 nmol capsaicin injected intracisternally 24 h before experiment), vasodilatation, which was evoked on transient hypotension, and vasoconstriction on reverse of hypotension were markedly attenuated or almost abolished. When changes in pial arterial diameter were plotted as a function of changes in blood pressure, the slopes of regression lines for vasodilatation and vasoconstriction were markedly reduced after capsaicin treatment. Similar reductions were evidenced under suffusion of CGRP antibody serum (1:1,000) and after CGRP receptor desensitization but not after substance P receptor desensitization. Pretreatment with glibenclamide, a K(+)-channel antagonist, also caused severe alterations in the autoregulatory vasomotor responses to hypotension and its reverse. Suffusion with mock cerebrospinal fluid, containing either CGRP or cromakalim, a K(+)-channel opener, dilated the pial artery in a concentration-dependent manner, and their effects were antagonized by glibenclamide. Substance P produced a vasodilatation, which was unaffected by glibenclamide.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcitonin gene-related peptide as potential neurotransmitter in guinea pig right atrium

1986 ◽  
Vol 250 (4) ◽  
pp. H693-H698 ◽  
Author(s):  
A. Saito ◽  
S. Kimura ◽  
K. Goto
Keyword(s):  
Guinea Pig ◽  
Right Atrium ◽  
Sinus Node ◽  
Calcitonin Gene Related Peptide ◽  
Dependent Manner ◽  
Chronotropic Response ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
The Right

The potential neurotransmitter role of calcitonin gene-related peptide (CGRP) in cardioacceleratory nonadrenergic noncholinergic (NANC) nerves was examined in the guinea pig right atrium in vitro. In the presence of atropine, a muscarinic antagonist, and atenolol, a beta-adrenoceptor antagonist, transmural nerve stimulation (TNS) of the isolated right atrium caused a positive chronotropic response, which is slow in both onset and decay. This TNS-induced slow response was assumed to be mediated by NANC nerves in the right atrium since tetrodotoxin inhibited the response. Dense distribution of CGRP-like immunoreactive (CGRP-I) nerves was demonstrated in the sinus node. Exogenously applied CGRP exerted a positive chronotropic effect on the isolated right atrium in a dose-dependent manner. Both CGRP-I nerves and NANC response induced by TNS were not affected by surgical sympathectomy and reserpine pretreatment but were abolished by the pretreatment of animals with capsaicin. The results suggest that CGRP is the neurotransmitter of cardioacceleratory NANC nerves in the right atrium of the guinea pig.

Calcitonin gene-related peptide promotes angiogenesis via AMP-activated protein kinase

2010 ◽  
Vol 299 (6) ◽  
pp. C1485-C1492 ◽  
Author(s):  
Shuai Zheng ◽  
Wenjing Li ◽  
Mingjiang Xu ◽  
Xue Bai ◽  
Zhou Zhou ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Calcitonin Gene Related Peptide ◽  
Tube Formation ◽  
Dependent Manner ◽  
Related Peptide ◽  
Compound C ◽  
Calcitonin Gene ◽  
And Migration ◽  
Amp Activated Protein Kinase

Ischemia induces angiogenesis as a compensatory response. Although ischemia is known to causes synthesis and release of calcitonin gene-related peptide (CGRP), it is not clear whether CGRP regulates angiogenesis under ischemia and how does it function. Thus we investigated the role of CGRP in angiogenesis and the involved mechanisms. We found that CGRP level was increased in the rat hindlimb ischemic tissue. The expression of exogenous CGRP by adenovirus vectors enhanced blood flow recovery and increased capillary density in ischemic hindlimbs. In vitro, CGRP promoted human umbilical vein endothelial cell (HUVEC) tube formation and migration. Further more, CGRP activated AMP-activated protein kinase (AMPK) both in vivo and in vitro, and pharmacological inhibition of CGRP and cAMP attenuated the CGRP-activated AMPK in vitro. CGRP also induced endothelial nitric oxide synthase (eNOS) phosphorylation in HUVECs at Ser1177 and Ser633 in a time-dependent manner, and such effects were abolished by AMPK inhibitor Compound C. As well, Compound C blocked CGRP-enhanced HUVEC tube formation and migration. These findings indicate that CGRP promotes angiogenesis by activating the AMPK-eNOS pathway in endothelial cells.

Nociceptin (1–13)NH2 Inhibits Stimulated Calcitonin-Gene-Related-Peptide Release From Primary Cultures of Rat Trigeminal Ganglia Neurones

Cephalalgia ◽  
2007 ◽  
Vol 27 (8) ◽  
pp. 868-876 ◽  
Author(s):  
A Capuano ◽  
D Curró ◽  
C Dello Russo ◽  
G Tringali ◽  
G Pozzoli ◽  
...  
Keyword(s):  
Primary Cultures ◽  
Calcitonin Gene Related Peptide ◽  
Neonatal Rat ◽  
Trigeminal Ganglia ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Related Peptide ◽  
Cgrp Release ◽  
Calcitonin Gene ◽  
Consistent Increase

In this work we have developed and characterized primary cultures of neonatal rat trigeminal ganglia neurones; calcitonin-gene-related-peptide (CGRP) released from cells was taken as a marker of neuronal function. A significant and consistent increase in CGRP secretion was elicited by non-specific (56 mM KCl or veratridine) or specific (capsaicin) depolarizing stimuli. This paradigm was subsequently used to investigate the effects of nociceptin, an opioid-like peptide involved in central and peripheral control of nociception. We found that the nociceptin analogue nociceptin (1–13)NH2 (NOC) did not affect baseline CGRP release, but it reduced in a concentration-dependent manner CGRP release induced by all tested stimuli. NOC-induced reduction was statistically significant from 0.01 nM onward and achieved maximal effects at 10 nM. Such effects of NOC were seemingly mediated by the activation of specific ORL1 receptors, as a well-known nociceptin antagonist, N(Phe1)nociceptin (1–13)NH2, was able to completely revert NOC inhibition of capsaicin-stimulated CGRP release.

Substance P, calcitonin gene-related peptide, and capsaicin release serotonin from cerebrovascular mast cells

1994 ◽  
Vol 267 (5) ◽  
pp. R1421-R1429 ◽  
Author(s):  
A. M. Reynier-Rebuffel ◽  
P. Mathiau ◽  
J. Callebert ◽  
V. Dimitriadou ◽  
N. Farjaudon ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Substance P ◽  
Calcitonin Gene Related Peptide ◽  
Dependent Manner ◽  
Granular Cells ◽  
Axon Reflex ◽  
Related Peptide ◽  
C Fibers ◽  
Calcitonin Gene

Rabbit leptomeningeal arteries contain granular cells resembling mast cells that frequently contact autonomic and sensory nerve profiles. In the present in vitro study, we determined whether these cells could be stimulated by substance P (SP) and calcitonin gene-related peptide (CGRP), which are stored and released by sensory C fibers. Immunohistochemistry of the middle cerebral artery showed that 5-HT was stored only in mast cell-like granules. This pool of 5-HT decreased in a dose-dependent manner when exogenous SP and CGRP were added to the incubation solution or when endogenous neuropeptides were released from nerve terminals by capsaicin. The simultaneous administration of CGRP and SP induced a dramatic exocytosis and a 5-HT release significantly greater than the sum of the individual effects of the two neuropeptides. We conclude that, as in classical connective tissue mast cells, the amine content of these granular cells can be released by a degranulation process induced by neuropeptides. The effects of capsaicin suggest that this phenomenon can be triggered by axon reflex of C fibers. The data also provide the first evidence of a synergistic action of SP and CGRP on mast cell degranulation.

scholarly journals Up-regulation of calcitonin gene-related peptide receptors underlying elevation of skin temperature in ovariectomized rats

2002 ◽  
Vol 175 (1) ◽  
pp. 177-183 ◽  
Author(s):  
M Noguchi ◽  
Y Ikarashi ◽  
M Yuzurihara ◽  
K Mizoguchi ◽  
K Kurauchi ◽  
...  
Keyword(s):  
Skin Temperature ◽  
Calcitonin Gene Related Peptide ◽  
Mesenteric Arteries ◽  
Hormone Deficiency ◽  
Ovariectomized Rats ◽  
Dependent Manner ◽  
Ovarian Hormone ◽  
Related Peptide ◽  
Ovx Rats ◽  
Calcitonin Gene

We investigated the mechanism for the augmentation of the calcitonin gene-related peptide (CGRP)-induced elevation of skin temperature in ovariectomized (OVX) rats. I.v. injection of alphaCGRP (10 micro g/kg) elevated skin temperature of the hind paws. The elevation was significantly greater in OVX rats than in sham-operated rats and was inhibited by pretreatment with human CGRP(8-37) (100-1000 micro g/kg i.v.), a CGRP receptor antagonist, in a dose-dependent manner. In addition, ovariectomy not only potentiated vasorelaxation due to alphaCGRP but increased the number of CGRP receptors in mesenteric arteries. Further, the plasma concentration of endogenous CGRP was significantly lower in OVX rats. These results suggest that the low concentration of plasma CGRP due to ovarian hormone deficiency may induce the increase in the number of CGRP receptors due to up-regulation. Therefore, the increased number of CGRP receptors may be responsible for potentiation of exogenous alphaCGRP-induced elevation of skin temperature in OVX rats. The mechanism underlying the hot flashes observed in menopausal women may also involve, in part, the up-regulation of CGRP receptors following ovarian hormone deficiency.

Basal tail skin temperature elevation and augmented response to calcitonin gene-related peptide in ovariectomized rats

1995 ◽  
Vol 146 (3) ◽  
pp. 431-437 ◽  
Author(s):  
T Kobayashi ◽  
O Ushijima ◽  
J-T Chen ◽  
M Shiraki ◽  
T Ohta ◽  
...  
Keyword(s):  
Skin Temperature ◽  
Temperature Response ◽  
Calcitonin Gene Related Peptide ◽  
Female Rats ◽  
Ovariectomized Rats ◽  
Dependent Manner ◽  
Related Peptide ◽  
Ovx Rats ◽  
Calcitonin Gene ◽  
Drastic Increase

Abstract Hyper-release of calcitonin gene-related peptide (CGRP) plays a direct and pivotal role in the induction of menopausal hot flushes (HFs), in which a drastic increase in skin temperature occurs. However, it is not possible to investigate whether CGRP induces skin temperature increase and whether skin temperature response to CGRP changes and contributes to the occurrence of HFs in postmenopausal women who are in oestrogen deficiency. By using rats' tail skin temperature (TST), a good marker to evaluate skin temperature regulation, we examined the effects of CGRP and calcitonin (3, 10 and 30 μg/kg, i.v.) on TST in female rats and further investigated the TST change induced by CGRP (10 μg/kg, i.v.) in ovariectomized (OVX) rats compared with that in sham-operated (Sham) rats. We found that CGRP, but not calcitonin, induced a TST increase in a dose-dependent manner and that the TST change induced by CGRP (0·6 ±0·2 °C for OVX rats vs 0·3 ±0·1 °C for Sham rats, P<0·05) and also the basal TST (26·0 ± 0·2 °C for OVX rats vs 25·5 ±0·1 °C for Sham rats) were significantly greater in OVX rats (P<0·05). Furthermore, treatment with oestradiol (30 μg/kg, s.c.) for 8 days partially inhibited the augmented TST response to CGRP in OVX rats and almost completely inhibited (P<0·05) the basal TST elevation, with the concomitant recovery of the serum oestradiol level to that in Sham rats. These results suggest that the augmented skin temperature response to CGRP and the elevation of basal skin temperature that are found in OVX rats, animals which are oestradiol deficient, may also occur in menopausal women and contribute to their HFs. Journal of Endocrinology (1995) 146, 431–437

Abstract P102: Generation Of A Novel Peptoid-peptide Analog Of Alpha-calcitonin Gene Related Peptide (α-CGRP) For The Treatment And Prevention Of Cardiovascular Diseases

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Ambrish Kumar ◽  
Shannon Servoss ◽  
Donald J DiPette ◽  
Jay D Potts
Keyword(s):  
Amino Acid ◽  
Cardiovascular Diseases ◽  
Calcitonin Gene Related Peptide ◽  
Therapeutic Drug ◽  
Dependent Manner ◽  
Related Peptide ◽  
Native Peptide ◽  
Calcitonin Gene ◽  
Long Term Treatment

Alpha-calcitonin gene related peptide (α-CGRP) is a 37-amino acid cardioprotective neuropeptide. Studies carried out in our laboratory and others establish α-CGRP as a potential therapeutic agent against a variety of cardiovascular diseases. However, the short half-life of α-CGRP limits its use in any long-term treatment regime. The goal of the present study is to develop an α-CGRP agonist analog with extended bioavailability using peptoid chemistry. A peptoid is a N -substituted glycine peptidomimetic molecule and is identical to α-amino acid except that the side chain in a peptoid is attached on the nitrogen rather than the α-carbon atom. Inclusion of a peptoid makes the native peptide protease-resistant and thus biostable in vivo . Using a solid-phase submonomer method, we synthesized a novel human α-CGRP analog containing two monomers of N -methoxyethylglycine (NMEG) peptoid at the N-terminus. Electrospray mass spectrometry (MALDI-TOF) analysis showed that the molecular mass of synthesized peptoid-peptide hybrid, NMEG-α-CGRP, was 4044 that is ~6.7% more than native peptide. An in vitro trypan blue cell exclusion assay demonstrated that incubation of NMEG-α-CGRP (5 μM) for 7 days did not affect the viability of rat H9C2 and mouse HL-1 cardiac cells. To evaluate the biological activity of NMEG-α-CGRP, a subcutaneous injection of human α-CGRP (10 μg/mice) and NMEG-α-CGRP (1, 3, 10, and 30 μg/mice) were given in 9-week-old C57BL6 mice (n=2 mice/dose), and blood pressure (BP) was measured using a tail-cuff method. A dose response curve showed that NMEG-α-CGRP decreased BP in mice in a time-dependent manner. Beginning with and injection of 3 μg of NMEG-α-CGRP, a dip in BP (85 ± 1 mmHg; in ±SD) was observed at 10 min after injection, and BP returned to baseline (125 mmHg) by 6 h, 18 h, and 24 h when injected with 3, 10, and 30 μg doses, respectively. Moreover, 10 μg of human-α-CGRP and NMEG-α-CGRP lowered BP from baseline for 2 h and 18 h, respectively, suggesting that NMEG addition increased stability, and thus bioavailability, of α-CGRP in vivo . In summary, our results show that a NMEG based α-CGRP modification is an effective approach to increase stability and, thus, bioavailability of α-CGRP in vivo making α-CGRP a viable therapeutic drug to treat cardiovascular diseases.

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