VIP/vasoactive intestinal polypeptide; vasodilatory

In L2 cells, aviptadil acetate (1 nM–10 μM) inhibits CSE-induced cell death in a concentration-dependent manner. Aviptadil acetate inhibits caspase-3 activation and CSE-stimulated MMP activity in L2 cells at 10 μM[1].

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Aviptadil, a synthetic form of Human Vasoactive Intestinal Polypeptide (VIP) has been awarded FDA Orphan Drug Designation for the treatment of ARDS and admitted to the FDA CoronaVirus Technology Accelerator Program. VIP binds to VPAC1 receptors on the pulmonary Alveolar Type II (ATII) cell. ATII cells comprise only 5% of lung epithelial cells but are critical for oxygen transfer, surfactant production, and maintenance of Alveolar Type 1 cells. 70% of VIP binds to this receptor. The Type II cell is also the cell selectively attacked by the SARS-CoV-2 virus via the ACE2 surface receptor. [1]

Pulmonary hypertension (PH) leads to an increased right ventricular workload, cardiac failure and death. In idiopathic pulmonary arterial hypertension (PAH) the vasodilating vasoactive intestinal peptide (aviptadil) is deficient. The aim of the present study was to test the acute effects on haemodynamics and blood gases, and the safety, of a single dose of inhaled aviptadil in chronic PH. A total of 20 patients with PH (PAH in nine, PH in lung disease in eight and chronic thromboembolic PH in three) inhaled a single 100-microg dose of aviptadil during right-heart catheterisation. Haemodynamics and blood gases were measured. Aviptadil aerosol caused a small and temporary but significant selective pulmonary vasodilation, an improved stroke volume and mixed venous oxygen saturation. Overall, six patients experienced a pulmonary vascular resistance reduction of >20%. In patients with significant lung disease, aviptadil tended to improve oxygenation. The pulmonary vasodilating effect of aviptadil aerosol was modest and short-lived, did not cause any side-effects and led to a reduced workload of the right ventricle without affecting systemic blood pressure. Aviptadil inhalation tended to improve oxygenation in patients with significant lung disease. Further studies are needed to evaluate the full therapeutic potential of aviptadil aerosol, including higher doses and chronic treatment. [5]

Acute Lung Injury, which triggers Critical COVID-19 is a known lethal complication of Corona Virus (SARS-CoV-2) infection. Conventional medical therapy, including intensive care and respiratory support is associated with an 80% mortality. Aviptadil, a synthetic form of Human Vasoactive Intestinal Polypeptide (VIP) has been awarded FDA Orphan Drug Designation for the treatment of ARDS and admitted to the FDA CoronaVirus Technology Accelerator Program. VIP binds to VPAC1 receptors on the pulmonary Alveolar Type II (ATII) cell. ATII cells comprise only 5% of lung epithelial cells but are critical for oxygen transfer, surfactant production, and maintenance of Alveolar Type 1 cells. 70% of VIP binds to this receptor. The Type II cell is also the cell selectively attacked by the SARS-CoV-2 virus via the ACE2 surface receptor. Nonclinical studies demonstrate that VIP is highly concentrated in the lung and specifically bound to the ATII cell, where it prevents NMDA-induced caspase-3 activation in the lung, inhibits IL6 and TNFa production, protects against HCl-induced pulmonary edema, and upregulates surfactant production, These and other effects have been observed in numerous animal model systems of lung injury in mice, rats, guinea pigs, sheep, swine, and dogs. In these models, Aviptadil restores barrier function at the endothelial/alveolar interface and thereby protects the lung and other organs from failure. Aviptadil ihas a demonstrated 20 year history of safety in phase 2 trials for Sarcoid, Pulmonary Fibrosis, Bronchospasm, and a phase I trial in ARDS. In that phase I trial, 8 patients with severe ARDS on mechanical ventilation were treated with ascending doses of VIP. Seven of the 8 patients were successfully extubated and were alive at the five day timepoint. Six left the hospital and one died of an unrelated cardiac event. Five phase 2 trials of aviptadil have been conducted under European regulatory authority. Numerous healthy volunteer studies have shown that i.v. infusion of Aviptadil is well tolerated with few adverse effects including alterations in blood pressure, heart rate, or ECG. In addition to published studies of human use, Aviptadil has been used on a compounded basis in certain ICUs for many years in the belief that it preserves life and restores function in pulmonary hypertension, ARDS, and Acute Lung Injury (ALI). In this study, patients who are hospitalized for Critical COVID-19 infection with respiratory failure will be randomly allocated to Aviptadil administered by intravenous infusion in addition to maximal intensive care vs. maximal intensive care alone. Primary endpoints will be improvement in blood oxygenation and mortality. [1]

[1]. Intravenous Aviptadil for Critical COVID-19 With Respiratory Failure (COVID-AIV).

[2]. Novel Targets of Drug Treatment for Pulmonary Hypertension. Am J Cardiovasc Drugs.

[3]. VIP and endothelin receptor antagonist: an effective combination against experimental pulmonary arterial hypertension. Respir Res. 2011;12(1):141.

[4]. Vasoactive intestinal peptide ameliorates reperfusion injury in rat lung transplantation. J Heart Lung Transplant. 1998;17(6):617-621.

Avicardil is a synthetic vasoactive intestinal peptide (VIP) with potential anti-cytokine, anti-inflammatory, and immunomodulatory activities. After administration, avicardil mimics the effects of endogenous VIP. In the lungs, avicardil may inhibit N-methyl-D-aspartate (NMDA)-induced caspase-3 activation, suppress the production of certain pro-inflammatory mediators such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), and may protect the lungs from cytokine storms and inflammation. Since cytokines cause alveoli to fill with water, making them impermeable to oxygen, avicardil may help prevent pulmonary edema and restore the barrier function of the endothelial/alveolar interface. This may improve blood oxygenation, alleviate respiratory distress, and prevent lung injury. VIP is a naturally occurring synthetic peptide hormone that is highly enriched in the lungs.
AVIPTADIL is a protein drug that has completed Phase III clinical trials (covering all indications) and has four investigational indications.

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Advances in biomedicine over the past decade have revealed the central role of proliferating pulmonary artery smooth muscle cells (PASMCs) in the development of pulmonary hypertension (PH). Furthermore, research has identified factors promoting PASMC and endothelial cell proliferation and anti-apoptosis, such as aberrant signaling pathways involving growth factors, G protein-coupled receptors, kinases, and microRNAs. Based on these findings, PH is now classified into different subtypes according to underlying pathology, allowing for more targeted treatments. PH is characterized by dysplastic PASMC proliferation, local inflammation, and endothelial cell anti-apoptosis, all of which ultimately lead to vascular wall remodeling. Several promising targets have been identified to assess the relative contributions of these factors. This review discusses new targets for PH treatment developed in recent years based on these advances, which are currently in preclinical and clinical trial phases (e.g., imatinib [Phase III]; nilotinib, AT-877ER, rituximab, tacrolimus, paroxetine, sertraline, fluoxetine, bardoxolone methyl ester [Phase II]; and sorafenib, FK506, avipadil, endothelial progenitor cells (EPCs) [Phase I]). Despite significant progress in targeting key molecular pathways in recent years, pulmonary arterial hypertension (PH) remains incurable. These novel therapies provide an important conceptual framework for classifying patients based on molecular phenotypes to achieve effective treatment of the disease. [2]

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Background: Treatment of pulmonary arterial hypertension (PAH) remains challenging, and more effective drugs and drug combinations are still being explored. We recently reported that deletion of the vasoactive intestinal peptide (VIP) gene leads to spontaneous expression of the PH phenotype, which VIP can completely correct. This study aims to answer the following questions: 1) Can VIP prevent PH in other experimental models? 2) Does the combined use of vasoactive intestinal peptide (VIP) and the endothelin (ET) receptor antagonist bosentan enhance its efficacy? Methods: Pulmonary hypertension (PAH) was induced in Sprague Dawley rats within 3 weeks following a single subcutaneous injection of monoclonal antibody (MCT), characterized by pulmonary vascular remodeling, pulmonary inflammation, and right ventricular hypertrophy, leading to death within the next 2 weeks. Animals in the MCT injection group received one of the following treatments: no treatment, oral bosentan alone, intraperitoneal VIP alone, or a combination therapy. This combination therapy was chosen because VIP downregulates endothelin receptor expression, while bosentan further inhibits endothelin receptor expression. Hemodynamics, pulmonary vascular pathology, and survival rates were compared among the treatment groups. Results: VIP treatment, initiated on the same day as the MCT injection and administered every other day for 3 weeks, almost completely halted the pathological progression of PAH and eliminated deaths within 45 days. However, VIP treatment initiated 3 weeks after MCT treatment, while more effective than bosentan, only partially reversed the pathological changes of PAH. The combined treatment of the two drugs completely reversed the pathological changes and prevented death for at least 45 days. Conclusions: 1) VIP can completely prevent and significantly reverse MCT-induced PAH; 2) VIP is more effective than bosentan, possibly because it targets a wider range of pro-remodeling pathways; 3) VIP combined with bosentan is more effective than either drug alone, possibly because the two drugs synergistically inhibit the ET-ET receptor pathway. [3]

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Background: Vasoactive intestinal peptide (VIP) has been reported to have some protective properties against lung damage. In addition, its protective effect in cold preservation of donor lungs has been confirmed. We used an in vivo rat lung transplantation model to study the effects of VIP and the timing of its administration. Methods: All lungs were flushed with low-potassium dextran-1% glucose solution and orthotopically transplanted with the left lung. Rats were divided into four groups (n=6). The first group did not undergo any preservation treatment. The transplanted lungs in the second, third and fourth groups were preserved at 4°C for 18 hours. The second group did not receive VIP treatment. The third group received VIP (0.1 g/ml) via flushing solution. Recipients in group IV received an intravenous injection of VIP (3 μg/kg) immediately after reperfusion. Twenty-four hours post-transplantation, the right pulmonary artery and right bronchus were ligated, and the recipients were ventilated with 100% oxygen for 5 minutes. Mean pulmonary artery pressure, peak airway pressure, blood gas analysis, serum lipid peroxidation levels, tissue myeloperoxidase activity, and wet/dry weight ratio were measured. Results: The partial pressure of oxygen in groups III and IV was better than that in group II (Groups II, III, and IV: 147.4±71.4, 402.1±64.8, 373.4±81.0 mmHg; p<0.05). The peak airway pressure in groups III and IV was lower than that in group II (Groups II, III, and IV: 19.7±0.8, 16.7±0.9, and 16.3±1.0 mmHg; p<0.05). The mean pulmonary artery pressure in the third group was lower than that in the second group (Group 2 and Group 3: 36.3±3.0 and 22.1±2.2 mmHg; p<0.01). The wet weight/dry weight ratio in the third group was lower than that in the second and fourth groups (Group 2, Group 3 and Group 4: 5.2±0.2, 4.4±0.2 and 5.2±0.3; Group 2 vs. Group 3: p<0.05, Group 3 vs. Group 4: p<0.01). The serum lipid peroxide levels in the third and fourth groups were significantly lower than those in the other groups (Group 2, Group 3 and Group 4: 2.643 ± 0.913, 0.455 ± 0.147 and 0.325 ± 0.124 nmol/ml, respectively; p < 0.01). Conclusion: VIP can improve reperfusion injury in an in vivo rat lung transplantation model. Whether administered via flushing fluid or immediately after reperfusion, VIP can improve lung function. [4]

C149H242N44O44S

3385.84921216965

3384.78

1444827-29-5

Aviptadil;40077-57-4

91820620

HSDAVFTDNYTRLRKQMAVKKYLNSILN
HSDAVFTDNYTRLRKQMAVKKYLNSILN-NH2
L-histidyl-L-seryl-L-alpha-aspartyl-L-alanyl-L-valyl-L-phenylalanyl-L-threonyl-L-alpha-aspartyl-L-asparagyl-L-tyrosyl-L-threonyl-L-arginyl-L-leucyl-L-arginyl-L-lysyl-L-glutaminyl-L-methionyl-L-alanyl-L-valyl-L-lysyl-L-lysyl-L-tyrosyl-L-leucyl-L-asparagyl-L-seryl-L-isoleucyl-L-leucyl-L-asparagine

H-HSDAVFTDNYTRLRKQMAVKKYLNSILN-OH

White to off-white solid powder

52

52

115

238

7610

31

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ZPFJSONBPCXUTA-JEBDDVQLSA-N

InChI=1S/C147H238N44O42S.C2H4O2/c1-18-75(12)115(143(231)182-97(56-72(6)7)131(219)174-94(118(156)206)61-108(153)199)189-140(228)106(68-193)186-135(223)102(63-110(155)201)179-132(220)96(55-71(4)5)176-133(221)98(58-81-37-41-84(196)42-38-81)177-126(214)88(33-23-26-49-149)168-124(212)89(34-24-27-50-150)172-141(229)113(73(8)9)187-119(207)76(13)165-122(210)93(47-53-234-17)171-128(216)92(45-46-107(152)198)170-123(211)87(32-22-25-48-148)167-125(213)90(35-28-51-162-146(157)158)169-130(218)95(54-70(2)3)175-127(215)91(36-29-52-163-147(159)160)173-144(232)116(78(15)194)190-137(225)99(59-82-39-43-85(197)44-40-82)178-134(222)101(62-109(154)200)180-136(224)104(65-112(204)205)184-145(233)117(79(16)195)191-138(226)100(57-80-30-20-19-21-31-80)183-142(230)114(74(10)11)188-120(208)77(14)166-129(217)103(64-111(202)203)181-139(227)105(67-192)185-121(209)86(151)60-83-66-161-69-164-83;1-2(3)4/h19-21,30-31,37-44,66,69-79,86-106,113-117,192-197H,18,22-29,32-36,45-65,67-68,148-151H2,1-17H3,(H2,152,198)(H2,153,199)(H2,154,200)(H2,155,201)(H2,156,206)(H,161,164)(H,165,210)(H,166,217)(H,167,213)(H,168,212)(H,169,218)(H,170,211)(H,171,216)(H,172,229)(H,173,232)(H,174,219)(H,175,215)(H,176,221)(H,177,214)(H,178,222)(H,179,220)(H,180,224)(H,181,227)(H,182,231)(H,183,230)(H,184,233)(H,185,209)(H,186,223)(H,187,207)(H,188,208)(H,189,228)(H,190,225)(H,191,226)(H,202,203)(H,204,205)(H4,157,158,162)(H4,159,160,163);1H3,(H,3,4)/t75-,76-,77-,78+,79+,86-,87-,88-,89-,90-,91-,92-,93-,94-,95-,96-,97-,98-,99-,100-,101-,102-,103-,104-,105-,106-,113-,114-,115-,116-,117-;/m0./s1

acetic acid;(3S)-4-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-1-[[(2S)-4-amino-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-4-amino-1-[[(2S)-1-[[(2S,3S)-1-[[(2S)-1-[[(2S)-1,4-diamino-1,4-dioxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-methylsulfanyl-1-oxobutan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-[[(2S)-2-[[(2S)-2-amino-3-(1H-imidazol-5-yl)propanoyl]amino]-3-hydroxypropanoyl]amino]-4-oxobutanoic acid

Aviptadil; Vasoactive intestinal octacosapeptide; invicorp; Vip human vip; RLF-100; UNII-A67JUW790C; Aviptadil [USAN:INN:BAN]; A67JUW790C;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O: 100 mg/mL (29.53 mM)
DMSO: 100 mg/mL (29.53 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (0.74 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.5 mg/mL (0.74 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (0.74 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 50 mg/mL (14.77 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)