In HepG2 cells, perhexiline (5–25 μM, 2–6 h) decreases cell viability[2]. In HepG2 cells, perhexiline (5–25 μM, 2–6 h) lowers the amount of cellular ATP and the release of lactate dehydrogenase (LDH)[2]. In HepG2 cells, perhexiline (20 μM, 2 h) activates caspase 3/7[2]. In HepG2 cells, perhexiline (5–25 μM, 4 h) results in mitochondrial dysfunction[2]. Perhexiline (5 μM, 48 h) specifically causes CLL cells (high expression of CPT) to undergo extensive apoptosis[3].

In female DA rats, perhexiline (200 mg/kg, po, daily for 8 weeks) decreases peripheral neuronal function[4]. In a glioblastoma mouse model, perhexiline (80 mg/kg, oral gavage, for 3 days) exhibits anti-tumor action[5].

Cell Viability Assay[2]
Cell Types: HepG2 cells
Tested Concentrations: 5, 10, 15, 25 μM
Incubation Duration: 2, 4, 6 h
Experimental Results: Induced time- and concentration-dependent cytotoxicity in hepatic cells.

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Western Blot Analysis[2]
Cell Types: HepG2 cells
Tested Concentrations: 5, 10, 15, 25 μM
Incubation Duration: 2 h
Experimental Results: decreased Bcl-2 and Mcl-1 level, and increased Bad level.

Animal/Disease Models: Orthotopic glioblastoma mouse model[5]
Doses: 80 mg/kg
Route of Administration: po (oral gavage), for 3 days.
Experimental Results: Reduces tumor size (MR imaging) and improves in overall survival.

Absorption, Distribution and Excretion
Following oral administration, this product is well absorbed in the gastrointestinal tract (>80%). Metabolisms/Metabolites The major metabolites of piperacillin in the human body are monohydroxypiperacillin (partially excreted as a glucuronide conjugate) and dihydroxypiperacillin, the latter accounting for a relatively small proportion of total metabolites. Two unidentified metabolites have also been found in feces. The pharmacological activities of these metabolites are unknown. Hydration of piperacillin is regulated by cytochrome P450 2D6 (CY P450 2D6). The major metabolites of piperacillin in the human body are monohydroxypiperacillin (partially excreted as a glucuronide conjugate) and dihydroxypiperacillin, the latter accounting for a relatively small proportion of total metabolites. Two unidentified metabolites have also been found in feces. The pharmacological activities of these metabolites are unknown. Hydroxylation of piperacillin is regulated by cytochrome P450 2D6 (CY P450 2D6). Half-life: Varies considerably and is non-linear. Some reports indicate a half-life of 2-6 days, while others suggest it may be as long as 30 days.

Toxicity Summary
Piperacillin binds to mitochondrial enzymes carnitine palmitoyltransferase (CPT)-1 and CPT-2. It alters myocardial substrate utilization by inhibiting CPT-1 (and to a lesser extent, CPT-2), shifting it from long-chain fatty acids to carbohydrates, thereby increasing glucose and lactate utilization. This results in increased ATP production at the same oxygen consumption, thus improving myocardial efficiency. Protein Binding Piperacillin and its metabolites have a high protein binding rate (>90%). Toxicity Data
LD50: 2150 mg/kg (oral, rat) (A308) LD50: 2641 mg/kg (oral, mouse) (A308)

[1]. 27 - Refractory Angina. Chronic Coronary Artery Disease, 2018, 412-431.

[2]. Mitochondrial dysfunction and apoptosis underlie the hepatotoxicity of perhexiline. Toxicol In Vitro. 2020 Dec;69:104987.

[3]. Elimination of chronic lymphocytic leukemia cells in stromal microenvironment by targeting CPT with an antiangina drug perhexiline. Oncogene. 2016 Oct 27;35(43):5663-5673.

[4]. Enantioselectivity in the tissue distribution of perhexiline contributes to different effects on hepatic histology and peripheral neural function in rats. Pharmacol Res Perspect. 2018 Jun;6(3):e00406.

[5]. Perhexiline Demonstrates FYN-mediated Antitumor Activity in Glioblastoma. Mol Cancer Ther. 2020 Jul;19(7):1415-1422.

Piperacillin belongs to the piperidine class of drugs and is a cardiovascular medication. Piperacillin is a coronary vasodilator, especially used to treat exertional angina. It may cause neuropathy and hepatitis. Piperacillin is only detected in individuals who have taken the drug. It is a coronary vasodilator, especially used to treat exertional angina. It may cause neuropathy and hepatitis. [PubChem] Piperacillin binds to the mitochondrial enzymes carnitine palmitoyltransferase (CPT)-1 and CPT-2. It alters myocardial substrate utilization by inhibiting CPT-1 (and to a lesser extent, CPT-2), shifting myocardial substrate utilization from long-chain fatty acids to carbohydrates, thereby increasing the utilization of glucose and lactate. This leads to increased ATP production at the same oxygen consumption, thus improving myocardial efficiency. 2-(2,2-Dicyclohexylethyl)piperidine. A coronary vasodilator, especially used to treat exertional angina. It may cause neuropathy and hepatitis. Drug Indications For the treatment of severe angina. Mechanism of Action Piperacillin binds to mitochondrial enzymes carnitine palmitoyltransferase (CPT)-1 and CPT-2. It alters myocardial substrate utilization by inhibiting CPT-1 (and to a lesser extent, CPT-2), shifting it from long-chain fatty acids to carbohydrates, thereby increasing glucose and lactate utilization. This leads to increased ATP production at the same oxygen consumption, thus improving myocardial efficiency. Pharmacodynamics For the treatment of refractory or unresponsive angina. Piperacillin increases glucose metabolism by inhibiting free fatty acid metabolism, thereby improving oxygen utilization efficiency during myocardial ischemia. Piperacillin also enhances platelet responsiveness to nitric oxide in patients with angina and acute coronary syndrome. The main mechanism by which piperacillin exerts this specific effect is by increasing platelet responsiveness to cGMP. Piperacillin may also reduce the ability of neutrophil-derived oxygen to scavenge nitric oxide. When used as monotherapy, piperacillin can relieve angina symptoms, improve exercise tolerance, and increase the workload required to induce myocardial ischemia. The primary therapeutic applications of piperacillin are: short-term treatment (lasting less than 3 months) for patients with severe ischemia awaiting coronary revascularization, or long-term treatment for patients with ischemic symptoms unresponsive to other treatments.

C19H35N

277.49

277.277

6621-47-2

Perhexiline maleate;6724-53-4

4746

Typically exists as solid at room temperature

340ºC at 760 mmHg

164.5ºC

5.624

1

1

4

20

245

0

C1CCC(CC1)C(CC2CCCCN2)C3CCCCC3

CYXKNKQEMFBLER-UHFFFAOYSA-N

InChI=1S/C19H35N/c1-3-9-16(10-4-1)19(17-11-5-2-6-12-17)15-18-13-7-8-14-20-18/h16-20H,1-15H2

2-(2,2-dicyclohexylethyl)piperidine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

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.)