NK1

Vapreotide reduces the intracellular calcium increases and NF-κB activation triggered by Substance P (SP) in a dose-dependent manner. Additionally, vapreotide prevents HEK293-NK1R and U373MG cell lines from producing MCP-1 and IL-8 in response to SP. When SP pretreatment is applied, the inhibitory effect of vapreotide on HIV-1 infection of human MDM in vitro can be reversed]. Human pituitary adenoma cells that secrete GH are strongly inhibited by vapreotide at concentrations as low as 10^-12-10^-14 M from releasing GH, PRL, and/or alpha-subunits. An IC50 of 0.1 pM is required for vapreotide to inhibit GH release[2]. Vapreotide has low affinity for SSTR1 and -4 (IC50=200 and 620 nM, respectively) and moderate-to-high affinities for SSTR2, -3, and -5 (IC50=0.17, 0.1, and 21 nM, respectively). The proliferation of CHO cells expressing SSTR2 and SSTR5 (EC50=53 and 150 pM, respectively) is inhibited by RC-160 when exposed to serum[3].

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Vapreotide reduces the impact of SP on calcium release in a concentration-dependent manner. Vapreotide needs a concentration that is roughly 100 times greater than that of the NK1R antagonist aprepitant in order to fully block the effects of SP. SSTR2 is the main mediator of Vapreotide's effect on cell proliferation. U373MG cells are pretreated with SSTR2 selective antagonist CYN, then incubated with Vapreotide and stimulated with SP to further demonstrate the NK1R antagonist effect of Vapreotide. The findings demonstrate that the inhibitory effect of vapreotide on SP-stimulated IL-8 mRNA expression is not reversed by pretreatment with CYN. Vapreotide decreases HIV-1 replication in MDM, as seen by the reduced expression of HIV gag mRNA in comparison to control MDM. Furthermore, SP treatment (10 μM) reverses the inhibitory effect of vapreotide on HIV-1 replication in MDM. According to this observation, vapreotide's inhibition of HIV-1 replication is most likely caused by its interaction with NK1R[1].

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Vapreotide dose-dependently inhibits SP-induced intracellular calcium increases [1]
SP induced an increase in calcium in U373MG cells in a dose-dependent manner with a maximum response at concentration of 0.1 μM, while the NK1R antagonist, aprepitant, completely antagonized this effect at 0.1 μM (Figure 1A). Vapreotide attenuated the effect of SP on calcium release in a concentration-dependent manner (Figure 1B). The concentration required for vapreotide to completely inhibit the effect of SP is about 100 times higher than that required for the NK1R antagonist aprepitant (Figure 1B).

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Vapreotide attenuates SP activation of NF-κB and inhibits SP-induced Gene Expression in HEK293-NK1R cells [1]
SP increased NF-κB-driven-luciferase gene expression in HEK293-NK1R (Figure 2A) and this enhancement was antagonized by aprepitant or CP-96,345 and partially inhibited by vapreotide pretreatment. SP treatment up-regulates the mRNA expression of IL-8, EGR-1 and c-FOS genes in HEK293-NK1R cells. The NK1R antagonist, aprepitant, inhibited these effects (Figure 2B and C). Vapreotide pretreatment also reduced SP-mediated increases in IL-8, EGR-1 and c-FOS expression.

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Vapreotide inhibits SP-induced cytokine and chemokine expression in U373MG cells [1]
In order to further establish the NK1R antagonist effect of vapreotide, we examined its effect in U373MG cells that express endogenous NK1R. SP induced IL-8 expression at both mRNA and protein levels while both vapreotide and aprepitant inhibited this SP-induced IL-8 up-regulation (Figure 3A and B). Similarly, SP enhanced MCP-1 secretion while both vapreotide and aprepitant antagonized this up-regulation (Figure 3C and D). The effect of vapreotide on cell proliferation is mediated primarily by SSTR2. In order to further establish the NK1R antagonist effect of vapreotide, U373MG cells were pretreated with SSTR2 selective antagonist CYN followed by incubation with vapreotide and SP stimulation. The data (Figure 3A) show that pretreatment with CYN did not reverse the inhibitory effect of vapreotide on SP-stimulated IL-8 mRNA expression, suggesting that inhibition by vapreotide was not mediated by SSTR2.

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Vapreotide Inhibits HIV-1 Infection of MDM In Vitro [1]
Vapreotide reduced HIV-1 replication in MDM as indicated by limited HIV gag mRNA expression compared to control MDM (Figure 4). In addition, SP treatment (10 μM) reversed vapreotide inhibition of HIV-1 replication in MDM (Figure 4). This observation indicates that the inhibition of HIV-1 replication by vapreotide is most likely due to its interaction with NK1R.

Oesophagogastric varices rupturing, which causes bleeding, is a serious side effect of portal hypertension in cirrhosis. When rats are given vapreotide acutely, their collateral circulation blood flow is reduced, and when they are given it chronically, its development is attenuated[4]. When administered subcutaneously at a dose of 100 μg/day/animal, RC-160 reduces tumor volumes and weights by approximately 40%. When medication is initiated early in the tumor's development, dipreotide can slow the growth of androgen-independent prostate cancer[5].

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The aim of this study was to assess the hemodynamic effects of acute and chronic administration of vapreotide, a somatostatin analog, in rats with intrahepatic portal hypertension induced by dimethylnitrosamine (DMNA) administration. Acute effects were evaluated at baseline and 30 min after placebo (N = 13) or vapreotide (8 /microg/kg/hr, N = 13) infusions in DMNA rats. Chronic hemodynamic effects were evaluated using subcutaneous implants for five weeks in anesthetized DMNA rats (placebo: N = 13, vapreotide: N = 13) and in sham rats (placebo: N = 10, vapreotide: N = 10). Hemodynamic measurements included splenorenal shunt blood flow (SRS BF) by the transit time ultrasound (TTU) method and cardiac output by the combined dilution-TTU method. Acute administration of vapreotide significantly decreased SRS BF (-17.3 +/- 19 vs - 1.1 +/- 14%, P < 0.05) and portal pressure (-8 +/- 9 vs 0 +/- 8%, p < 0.05) compared to placebo without systemic effects. Chronic administration of vapreotide significantly reduced the increase in SRS BF (2.4 +/- 1.5 vs 1.2 +/- 1.0 ml/min, P < 0.05) and cardiac index (50 +/- 15 vs 33 +/- 10 ml/min/100 g, P < 0.0001) while portal pressure and blood flow, and mean arterial pressure were not significantly changed compared to placebo. In conclusion, the acute administration of vapreotide decreased collateral circulation blood flow while chronic administration attenuated its development. Vapreotide seems to have a vasoconstrictive effect on collateral circulation.[4]

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Nude mice bearing xenografts of the androgen-independent human prostate-cancer cell line PC-3 were treated for 4 weeks with somatostatin analog RC-160, bombesin/gastrin-releasing peptide (GRP) antagonist (RC-3095), or the combination of both peptides. In the first experiment, treatment was started when the tumors measured approximately 10 mm3. Tumor volumes and weights were reduced by about 40% by RC-160 or RC-3095 administered by s.c. injections at doses of 100 micrograms/day/animal and 20 micrograms/day/animal respectively. The combination of RC-3095 with RC-160 did not further potentiate suppression of tumor growth, but histologically the ratio of apoptotic and mitotic indices was significantly higher in the groups treated with the combination than in the other groups. Serum gastrin levels were significantly reduced in all treated groups. Therapy with RC-160 or the combination also significantly decreased serum growth-hormone levels. Specific high-affinity binding sites for bombesin, somatostatin and epidermal growth factor (EGF) were found on the tumor membranes. Receptors for EGF were significantly down-regulated by treatment with RC-3095, RC-160 and a combination of both analogs. Tumors from mice treated with RC-160 showed a significant increase in maximal binding capacity for somatostatin as compared with control tumors, demonstrating the absence of down-regulation. In the second experiment, treatment was started when the tumors were well developed and measured approximately 90 mm3. No significant reduction in volume, weight and growth rate of tumors was found in the groups treated with RC-160 or RC-3095. Our results suggest that somatostatin analog RC-160 and bombesin/GRP antagonist RC-3095 can inhibit the growth of androgen-independent prostate cancer when the therapy is started at an early stage of tumor development[5].

In aMEM supplemented with 10% FCS, CHO cells are cultivated. A MEM containing 10% FCS or insulin with or without vapreotide is used as the attachment medium after an overnight stay. With a Coulter counter model ZM, cells are counted to determine cell growth after 24 hours[3].

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For 10 minutes, either Vapreotide (0, 5, 10, 20 μM) or SP are added, and then the HEK293-NK1R and U373MG cells are incubated for three hours. In some experiments, cells are stimulated with SP for three hours after being incubated with CYN for ten minutes, after which they are added to vapreotide and left to incubate for an extra ten. There are controls in the form of mock-treated cells[1].

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Luciferase Assay for NF-κB Activation [1]
pNF-κB-luc plasmid (5 μg) was transfected into HEK293-NK1R (2 x106 cells per transfection) by Nucleofector II using the Cell Line Nucleofection Kit V following the manufacturer’s protocol. After transfection, the cells were cultured in 24-well plates (0.25 × 106 cells/well) in DMEM media containing 10% fetal bovine serum (FBS). 48 h post transfection, the cells were treated with SP (10−7M) in the presence or absence of NK1R antagonists (aprepitant or CP-96,345) (1 μM) or Vapreotide (10 μM) for 6 h. Mock treated cells were used as controls. Cell-free lysates were collected in 0.25 ml of 1 X Reporter Lysis Buffer and centrifuged at 10,000 × g for 1 min. The cell-free lysates were used to determine the NF-kB-driven luciferase activity by the Luciferase assay system and a luminometer. The luciferase activity is expressed as relative light units (RLU). The results are presented as fold-change in RLU compared to untreated controls, which are defined as 1.0.

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Vapreotide treatment [1]
The HEK293-NK1R cells and U373MG cells were incubated with or without Vapreotide for 10 minutes and then incubated with or without SP for 3 hours. In some experiments, cells were first incubated with CYN for 10 minutes, and then vapreotide was added and incubated for an additional 10 minutes, followed by stimulation with SP for 3 hours. Mock treated cells were used as controls.

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HIV Infection [1]
7–10 day-cultured MDM in 48-well plates (0.25 × 106 cells/well) were incubated with or without Vapreotide for 2 h before infection with HIV-1. Cells were first incubated with vapreotide for 10 min and then SP was added to the MDM and the cells were incubated for the additional 2 h. Mock treated MDM served as controls. After a 2 h incubation with or without vapreotide and/or SP, the cells were infected overnight with cell-free HIV based on p24 antigen content (16 ng/106 cells), and then extensively washed to remove unbound virus. Fresh medium supplemented with vapreotide and/or SP was added as described above. The culture medium and the reagents were replaced twice weekly. At day 7 post HIV infection, cellular RNA was extracted from the MDM for assessment of HIV gag mRNA expression using real time RT-PCR assays.

Rats: Acute effects in DMNA rats are assessed at baseline and 30 minutes after Vapreotide (8 μg/kg/hr) or placebo infusions. Subcutaneous implants are used to assess chronic hemodynamic effects in anesthetized DMNA rats and sham rats over a five-week period. The combined dilution–TTU method and the transit time ultrasound method are two methods used to measure hemodynamic parameters, including splenorenal shunt blood flow[4].
Mice: For four weeks, somatostatin analog vapreotide (20 μg/day/animal), bombesin/gastrin-releasing peptide (GRP) antagonist, or a combination of both peptides, are administered to nude mice containing xenografts of the androgen-independent human prostate-cancer cell line PC-3. Tumor weights and volumes are quantified [5].

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Study 1: Acute Hemodynamic Effects of Vapreotide. Acute changes in hemodynamics following vapreotide administration compared to placebo administration were assessed in rats with liver fibrosis induced by repeated injections of dimethylnitrosamine. DMNA diluted in a 1% saline solution was administered intraperitoneally at a dose of 1 ml/kg body weight (ie, 10 mg/kg) for three consecutive days per week, for five weeks, in 26 rats (initial body weight 281 ± 25 g, mean ± SD). After five weeks, hemodynamic measurements were performed at baseline and 30 min after a blind randomized bolus infusion of either vapreotide (8 µg/kg/hr, 0.6 ml over 30 min, in 13 rats) or placebo (saline 0.6 ml over 30 min, in 13 rats). At the time of hemodynamic measurements, animals weighed 323 ± 46 g.[4]

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Study 2: Chronic Effects of Vapreotide. Vapreotide was chronically released from subcutaneous implants (a 15-mmlong and 1.5-mm-diameter polylactic acid cylinder, Debiopharm SA, 1000-Lausanne 9, Switzerland) that contained 4.8 mg of vapreotide. Placebo implants contained only vehicle (Lpolylactic acid). The subcutaneous implants were placed on the back of the rat two days before the start of DMNA or saline injection in rats (mean body weight 234 ± 19 g) under ether anesthesia. Hemodynamic measurements were performed in four groups of rats: (1) sham + placebo (N = 10): rats with saline intraperitoneal injections and subcutaneous placebo implants. (2) sham + vapreotide (N = 10): rats with saline intraperitoneal injections and subcutaneous vapreotide implants; (3) DMNA + placebo (N = 13): rats with DMNA intraperitoneal injections and subcutaneous placebo implants; and (4) DMNA + vapreotide (N = 13): rats with DMNA intraperitoneal injections and subcutaneous vapreotide implants. There were more rats in the PHT groups to take into account the variability of SRS blood flow and response to somatostatin analog in PHT rats (12). DMNA or saline were administered as described above in the acute study. At the time of hemodynamic measurements, animals weighed 380 ± 37 g.[4]

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Rats: Studies were performed in adult male Sprague-Dawley rats. All rats had free access to food and water until 14–16 hr before the hemodynamic measurements, when food was withdrawn. Hemodynamic measurements were performed in rats anesthetized with pentobarbital (Nesdonal administered intraperitoneally, 5 mg in 1 ml/kg body weight) 30 min after manipulations, ie, when hemodynamic parameters were stabilized. During hemodynamic measurements, body temperature was maintained at 37◦C with a homeothermic blanket system. Observer Hemodynamic measurements were performed by an observer who was not aware of treatment allocation (placebo or Vapreotide).[4]

Absorption, Distribution and Excretion
Vapreotide is excreted 76% via bile, with the remainder excreted via the kidneys. Biological Half-Life 30 minutes. Metabolism/Metabolites Excretion Pathway: Vapreotide is excreted 76% via bile, with the remainder excreted via the kidneys. Half-life: 30 minutes.

Toxicity Summary
Although one study provided in vitro and in vivo evidence that the tachykinin NK1 receptor antagonist plays a role in the analgesic effect of vapreotide (A2442), its exact mechanism of action remains unclear.

[1]. Analog of somatostatin vapreotide exhibits biological effects in vitro via interaction with neurokinin-1 receptor. Neuroimmunomodulation. 2013;20(5):247-55.

[2]. Relative potencies of the somatostatin analogs octreotide, BIM-23014, and RC-160 on theinhibition of hormone release by cultured human endocrine tumor cells and normal rat anterior pituitary cells. Endocrinology. 1994 Jan;134(1):301-6.

[3]. Inhibition of cell proliferation by the somatostatin analogue RC-160 is mediated by somatostatin receptor subtypes SSTR2 and SSTR5 through different mechanisms. Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1580-4.

[4]. Hemodynamic effects of acute and chronic administration of vapreotide in rats with cirrhosis. Dig Dis Sci. 2003 Jan;48(1):154-61.

[5]. Effect of somatostatin analog RC-160 and bombesin/gastrin releasing peptide antagonist RC-3095 on growth of PC-3 human prostate-cancer xenografts in nude mice.

Vapreotide is a synthetic octapeptide somatostatin analog that has been investigated for cancer treatment. Vapreotide is a synthetic cyclic octapeptide somatostatin analog with both direct and indirect antitumor effects. Vapreotide binds to the somatostatin receptor (SSTR), particularly SSTR-2, and has a lower affinity for SSTR-5. Its mechanism of action is similar to other octapeptide somatostatin analogs. Similar to octreotide, this drug exerts its direct and indirect antitumor effects by inhibiting the release of growth hormone and other peptides that regulate the release of insulin and gastrointestinal hormones. In addition, vapreotide can be used to treat acute upper gastrointestinal bleeding to induce hemostasis.
Drug Indications
It is used to treat esophageal variceal bleeding in patients with cirrhosis and has also been shown to be effective in treating HIV-related diarrhea.

Drug Indications
It is used to treat esophageal variceal bleeding in patients with cirrhosis and has also been shown to be effective in treating HIV-related diarrhea.




Mechanism of Action The exact mechanism of action of vapreotide is unclear, but one study provides in vitro and in vivo evidence that its analgesic effect is related to the NK1 receptor antagonist effect of tachykinin (PMID: 7556407). Pharmacodynamics Vapreotide is a somatostatin analog with higher metabolic stability than maternal hormone. Vapreotide reduces visceral blood flow, inhibits growth hormone release, and inhibits the release of peptides and vasoactive compounds from neuroendocrine tumors. Objective: Vapreotide is a synthetic somatostatin analog whose analgesic activity is likely mediated by blocking the neurokinin-1 receptor (NK1R), a receptor that preferentially binds to substance P (SP). Vapreotide's ability to interfere with other biological effects of SP remains to be investigated. Methods: We investigated the ability of vapreotide to antagonize NK1R in three different cell types: immortalized U373MG human astrocytes, human monocyte-derived macrophages (MDM), and the human embryonic kidney cell line HEK293. Both U373MG and MDM cells expressed endogenous NK1R, while HEK293 cells, which normally do not express NK1R, were stably transformed to express human NK1R (HEK293-NK1R). Results: Vapreotide attenuated SP-induced increases in intracellular calcium and nuclear factor-κB activation in a dose-dependent manner. Vapreotide also inhibited SP-induced production of interleukin-8 and monocyte chemoattractant protein-1 in both the HEK293-NK1R and U373MG cell lines. Vapreotide inhibited HIV-1 infection in human MDM cells in vitro, and this effect was reversed by SP pretreatment. Conclusion: Our results indicate that vapreotide possesses NK1R antagonistic activity and may have potential application value as a treatment for HIV-1 infection. [1]

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In this study, we investigated the effects of somatostatin (SS) analogues octreotide, RC-160, and BIM-23014 on growth hormone release in cultured human pituitary growth hormone-secreting tumor cells, normal rat anterior pituitary cells, and human gastrinoma cells. RC-160 was the most effective compound in all growth hormone-secreting adenomas and rat anterior pituitary cells. RC-160 significantly inhibited the release of growth hormone (GH), prolactin (PRL), and/or α-subunit from human pituitary adenoma cells at concentrations as low as 10⁻¹²-10⁻¹⁴ M. At the same concentrations, octreotide and BIM-23014 showed no inhibitory effect on GH release or significantly lower inhibitory effects than RC-160 (P < 0.01, RC-160 compared to octreotide and BIM-23014). In rat anterior pituitary cell culture, the IC50 values for GH release inhibition by RC-160, SS-14, BIM-23014, octreotide, and SS-28, ranked by potency, were 0.1 pM, 5.3 pM, 47 pM, 48 pM, and 99 pM, respectively. The three analogues showed the same maximum inhibitory effect (-60%) in both human growth hormone adenoma cell culture and rat anterior pituitary cell culture. Based on these data, RC-160 was approximately 500 times more potent than octreotide and BIM-23014 in inhibiting growth hormone release from rat anterior pituitary cells in vitro. Pretreatment with fossolin (100 μM) and pertussis toxin significantly reduced the inhibitory effects of the three SS analogues, as well as SS-14 and SS-28, to the same extent. The latter data indicate that octreotide, RC-160, and BIM-23014 primarily function through a pertussis toxin-sensitive G protein and adenylate cyclase-dependent mechanism. In human gastrinoma cell culture, at concentrations of 10⁻¹² M and 10⁻¹⁴ M, RC-160 showed significantly stronger inhibitory effects on gastrin release than octreotide (P < 0.01). In summary, the SS analogues octreotide, RC-160, and BIM-23014 may have significantly different efficacies in inhibiting hormone release in vitro, with RC-160 being the most potent, while octreotide and BIM-23014 have similar efficacies. Based on the pharmacokinetic characteristics of these three octapeptide somatostatin analogues, these observations may have implications for the drug treatment of patients with somatostatin receptor-positive endocrine tumors. [2]

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The effects of the stable somatostatin analogue RC-160 on cell proliferation, tyrosine phosphatase activity, and intracellular calcium concentration were investigated in CHO cells expressing five somatostatin receptor subtypes SSTR1 to -5. Binding assays were performed on crude membranes using [125I-labeled Tyr11]somatostatin-14; RC-160 exhibited moderate to high affinity for SSTR2, -3, and -5 (IC50 values of 0.17, 0.1, and 21 nM, respectively), but low affinity for SSTR1 and -4 (IC50 values of 200 and 620 nM, respectively). In CHO cells, 10% (v/v) fetal bovine serum, 1 μM insulin, or 0.1 μM cholecystokinin (CCK)-8 induced cell proliferation; RC-160 inhibited serum-induced proliferation of SSTR2 and SSTR5-expressing CHO cells (EC50 values of 53 pM and 150 pM, respectively), but had no effect on the growth of cells expressing SSTR1, SSTR3, or SSTR4. In SSTR2-expressing cells, orthovanadate inhibited the growth-inhibiting effect of RC-160. This analogue inhibited insulin-induced cell proliferation and rapidly stimulated tyrosine phosphatase activity only in this cell clone. The latter effect was observed at a dose of RC-160 (EC50, 4.6 pM) similar to that required to inhibit cell growth (EC50, 53 pM) and receptor binding (IC50, 170 pM), indicating that tyrosine phosphatases are transducing molecules of growth inhibition signals in SSTR2-expressing cells. In SSTR5-expressing cells, the phosphatase pathway was not involved in the inhibitory effect of RC-160 on cell growth, as neither tyrosine nor serine/threonine phosphatase inhibitors affected this effect. Furthermore, in SSTR5-expressing cells, the dose of RC-160 required to inhibit CCK-stimulated intracellular calcium mobilization (EC50, 0.35 nM) was similar to that required to inhibit somatostatin-14 binding (IC50, 21 nM) and CCK-induced cell proliferation (EC50, 1.1 nM). This suggests that the inositol phospholipid/calcium pathway may be involved in the antiproliferative effect of RC-160 mediated by SSTR5. RC-160 had no effect on basal calcium concentration or carbacholine-stimulated calcium concentration in cells expressing SSTR1 to SSTR4. Therefore, we conclude that SSTR2 and SSTR5 bind with high affinity to RC-160 and mediate RC-160-induced cell growth inhibition through different mechanisms. [3]

C59H74N12O11S2

1191.42267084122

1190.5041

C, 59.48; H, 6.26; N, 14.11; O, 14.77; S, 5.38

849479-74-9

Vapreotide; 103222-11-3; 936560-75-7 (diacetate); 849479-74-9 (acetate)

6918025

H-D-Phe-Cys(1)-Tyr-D-Trp-Lys-Val-Cys(1)-Trp-NH2.CH3CO2H; D-phenylalanyl-L-cysteinyl-L-tyrosyl-D-tryptophyl-L-lysyl-L-valyl-L-cysteinyl-L-tryptophanamide (2->7)-disulfide acetic acid; {d-Phe}-Cys-Tyr-{d-Trp}-Lys-Val-Cys-Trp-NH2 (Disulfide bridge: Cys2-Cys7)

FCYWKVCW; {d-Phe}-CY-{d-Trp}-KVCW-NH2 (Disulfide bridge: Cys2-Cys7)

White to off-white solid powder

14

15

18

84

2110

8

C(=O)(O)C.C([C@@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(=O)N[C@H](C(=O)N)CC2=CNC3C=CC=CC2=3)CSSC[C@H](NC(=O)[C@H](N)CC2C=CC=CC=2)C(=O)N[C@@H](CC2C=CC(O)=CC=2)C(=O)N1)C1=CNC2C=CC=CC1=2

KBIZSMHYSQUHDH-UHFFFAOYSA-N

InChI=1S/C57H70N12O9S2.C2H4O2/c1-32(2)49-57(78)68-48(55(76)64-44(50(60)71)26-35-28-61-41-16-8-6-14-38(35)41)31-80-79-30-47(67-51(72)40(59)24-33-12-4-3-5-13-33)56(77)65-45(25-34-19-21-37(70)22-20-34)53(74)66-46(27-36-29-62-42-17-9-7-15-39(36)42)54(75)63-43(52(73)69-49)18-10-11-23-58;1-2(3)4/h3-9,12-17,19-22,28-29,32,40,43-49,61-62,70H,10-11,18,23-27,30-31,58-59H2,1-2H3,(H2,60,71)(H,63,75)(H,64,76)(H,65,77)(H,66,74)(H,67,72)(H,68,78)(H,69,73);1H3,(H,3,4)

acetic acid;10-(4-aminobutyl)-N-[1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]-19-[(2-amino-3-phenylpropanoyl)amino]-16-[(4-hydroxyphenyl)methyl]-13-(1H-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxamide

BMY-41606; BMY 41606; Vapreotide acetate; 116430-60-5; Docrised; OCTASTATIN ACETATE; RC-160 acetate; Vapreotide monoacetate; Octastatin; ...; 849479-74-9; BMY41606; RC160; RC 160; RC-160; DP-05-094; Octastatin; Vapreotide acetate

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, avoid exposure to moisture.

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

H2O: ~14.3 mg/mL (~12 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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