Plasmodium; antiarrhythmic; K+ channel blocker

Quinine causes apoptosis in MES-SA cells and is cytotoxic to them [4]. Multidrug resistance (MDR) is one of important issues to cause the chemotherapy failure against cancers including gynecological malignancies. Despite some MDR reversal evidences of natural compounds including quinidine and cinchonine, there are no reports on MDR reversal activity of hydrocinchonine with its analogues quinidine and cinchonine especially in uterine sarcoma cells. Thus, in the current study, we comparatively investigated the potent efficacy of hydrocinchonine and its analogues quinidine and cinchonine as MDR-reversal agents for combined therapy with antitumor agent paclitaxel (TAX). Hydrocinchonine, cinchonine, and quinidine significantly increased the cytotoxicity of TAX in P-glycoprotein (gp)-positive MES-SA/DX5, but not in the P-gp-negative MES-SA cells at nontoxic concentrations by 3-(4,5-dimethylthiazol-2-yl)-2,5--diphenyltetrazolium bromide (MTT) assay. Rhodamine assay also revealed that hydrocinchonine, cinchonine, and quinidine effectively enhanced the accumulation of a P-gp substrate, rhodamine in TAX-treated MES-SA/DX5 cells compared with TAX-treated control. In addition, hydrocinchonine, cinchonine, and quinidine effectively cleaved poly (ADP-ribose) polymerase (PARP), activated caspase-3, and downregulated P-gp expression as well as increased sub-G1 apoptotic portion in TAX-treated MES-SA/DX5 cells. Taken together, hydrocinchonine exerted MDR reversal activity and synergistic apoptotic effect with TAX in MES-SA/DX5 cells almost comparable with quinidine and cinchonine as a potent MDR-reversal and combined therapy agent with TAX.[4]

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1. The effect of quinidine on the fast-activating, fast-inactivating potassium current (IK(f] in acutely dissociated melanotrophs of the adult rat pituitary was examined. Macroscopic currents were measured by use of the whole-cell configuration of the patch clamp technique. 2. Bath application of quinidine caused a dose-dependent reduction of the peak amplitude of IK(f). The Kd for blockade of IK(f) at 0 mV was estimated to be 41 +/- 5.6 microM. 3. Quinidine elicited a dose-dependent increase of the rate of the decay of IK(f) and this effect was enhanced by membrane depolarization. The possibility that this phenomenon reflects an open channel blocking reaction is discussed. 4. Quinidine also caused a 5 mV hyperpolarizing shift of the steady-state inactivation curve and increased the half-time for recovery from inactivation. Quinidine did not affect the onset of inactivation measured at -30 mV. 5. Internal quinidine did not appear substantially to affect either the peak amplitude or kinetics of IK(f). 6. A study of some structural analogues showed that hydroquinidine and quinacrine had effects similar to those of quinidine. The effect of quinacrine on the amplitude and kinetics of IK(f) was also pH-dependent. Cinchonine, which bears a close structural resemblance to quinidine, was much less effective as a blocker of IK(f).[1]

Quinine has an influence on PTZ-induced epilepsy threshold [5]. DM/dextromethorphan (25 and 50 mg/kg) significantly increased PTZ- induced seizure threshold. dextromethorphan/quinidine (DM/Q) at doses of 10/20 and 25/20 mg/kg had anticonvulsant effect, while at a dose of 50/20 mg/kg attenuated anticonvulsant effect of DM 50 mg/kg. Ketamine (5 mg/kg) or WAY-100635 (1 mg/kg) potentiated, while BD-1047 (2.5 and 5 mg/kg) attenuated the anticonvulsant effect of DM/Q 10/20 mg/kg. Conclusion: The results of present study demonstrate that combination with quinidine potentiates the anticonvulsant effect of DM at lower doses, while attenuates it at higher dose. Meanwhile, the effects of DM/Q on seizure activity likely involve an interaction with NMDA, the sigma-1 or the 5-HT1A receptor which may be secondary to the elevation of DM levels. [5]

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Amphetamine is metabolized by cytochrome P-450 (P450) to p-hydroxyamphetamine and phenylacetone in mammalian species. P450 metabolism is affected by genetic polymorphisms and by xenobiotic interactions in an isozyme-specific fashion. Little is known concerning the isozyme selectivity of amphetamine metabolism. Quinidine selectively inhibits the debrisoquine-specific isozyme (P450db) which displays genetic polymorphism in humans and rats. We now report the effect of quinidine on the metabolism of amphetamine to p-hydroxyamphetamine in vivo. At 0 h male Lewis rats received (po): no treatment (I), 80 mg quinidine/kg in 50% ethanol (II), or 50% ethanol (III), followed at 2 h by 15 mg d-amphetamine sulfate/kg (po). Urine specimens were collected and pooled at 0, 24, and 48 h. Amphetamine and p-hydroxyamphetamine concentrations were determined using a new GC/MS method for simultaneous quantitation. The ethanol vehicle-control (III) had no significant effect on amphetamine metabolism. Quinidine pretreatment (II) resulted in a significant decrease in the excretion of p-hydroxyamphetamine at 24 and 48 h to 7.2 and 24.1% of the vehicle-control levels, respectively, accompanied by a significant increase in amphetamine excretion between 24 and 48 h to 542% of the control. These data show that quinidine inhibits in vivo metabolism of amphetamine in rats and suggest that amphetamine metabolism may, in part, be mediated by an isozyme of P450 which displays genetic polymorphism. The inhibition of amphetamine metabolism results in an increased ratio of parent drug to metabolite concentration (metabolic ratio) in the urine, which mimics the effect of genetic polymorphisms. [3]

Cytotoxicity assay [4]
Cell Types: MES-SA and MESSA/DX5 cells
Tested Concentrations: 10 μM
Incubation Duration: 24 hrs (hours)
Experimental Results: Concentration-dependent cytotoxicity to MES-SA cells.

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Apoptosis analysis [4]
Cell Types: MES-SA and MESSA/DX5 Cell
Tested Concentrations: 10 μM
Incubation Duration: 24 hrs (hours)
Experimental Results: The content of sub-G1 DNA in the apoptotic part induced by paclitaxel increased, while paclitaxel did not affect sub-G1 DNA Influence the contents to undergo apoptosis.

Animal/Disease Models: NMRI strain male mice (age 5-6 weeks, weight 25-30 grams) [5]
Doses: 10, 20 and 30 mg/kg
Route of Administration: intraperitoneal (ip) injection; intraperitoneal (ip) injection. 10, 20 and 30 mg/kg;
Experimental Results: The 30 mg/kg dose increased the threshold dose for tonic hindlimb extension attacks compared with saline-treated controls (p<0.05).

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NMRI male mice (25-30 g) received quinidine (10, 20, and 30 mg/kg), DM (5, 10, 25, and 50 mg/kg) or DM/Q (10/20, 25/20, and 50/20 mg/kg), 30 min before the infusion of PTZ. ketamine (1 and 5 mg/kg), BD-1047 (2.5 and 5 mg/kg) or WAY-100635 (0.5 and 1 mg/kg) were administrated as pre-treatment 30 min before the selected dose of DM/Q. Seizures were induced by intravenous PTZ infusion. All data were presented as means ± S.E.M. One-way ANOVA test was used to determine statistical significance (p < 0.05).[5]

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In experiment 1 (including 11 groups), animals received different doses of quinidine (10, 20, and 30 mg/kg, i.p.), DM (5, 10, 25, and 50 mg/kg, i.p.) or DM/Q (5/20, 10/20, 25/20, and 50/20 mg/kg, i.p.) 30 min before determining PTZ-induced seizure threshold. Based on our experiments, quinidine at a dose of 20 mg/kg and DM at a dose of 10 mg/kg were used in later experiments.[5]

94328 man TDLo oral 7609 mg/kg/78W SKIN AND APPENDAGES (SKIN): DERMATITIS, ALLERGIC: AFTER SYSTEMIC EXPOSURE Archives of Internal Medicine., 145(446), 1985 [PMID:3977514]
94328 women TDLo oral 337 mg/kg/17D- BLOOD: CHANGES IN CELL COUNT (UNSPECIFIED) American Journal of Medicine., 77(345), 1984 [PMID:6465180]
94328 mouse LDLo intraperitoneal 150 mg/kg Toxicology and Applied Pharmacology., 23(288), 1972 [PMID:5074577]

[1]. Quinidine-induced inhibition of the fast transient outward K+ current in rat melanotrophs. Br J Pharmacol. 1991 Jul;103(3):1807-13.

[2]. Class I antiarrhythmic agents: quinidine, procainamide and N-acetylprocainamide, disopyramide. Pharmacol Ther. 1983;23(2):179-91.

[3]. Quinidine inhibits in vivo metabolism of amphetamine in rats: impact upon correlation between GC/MS and immunoassay findings in rat urine. J Anal Toxicol. 1990 Sep-Oct;14(5):311-7.

[4]. Hydrocinchonine, cinchonine, and quinidine potentiate paclitaxel-induced cytotoxicity and apoptosis via multidrug resistance reversal in MES-SA/DX5 uterine sarcoma cells. Environ Toxicol. 2011 Aug;26(4):424-31.

[5]. Effect of dextromethorphan/quinidine on pentylenetetrazole- induced clonic and tonic seizure thresholds in mice. Neurosci Lett. 2020 Jun 11;729:134988.

Quinidine D-gluconate is a D-gluconate adduct. It is functionally related to a quinidine.
Quinidine Gluconate is the gluconate salt form of quinidine, an alkaloid with antimalarial and antiarrhythmic (Class la) properties. Quinidine gluconate exerts its anti-malarial activity by acting primarily as an intra-erythrocytic schizonticide through association with the hemepolymer (hemozoin) in the acidic food vacuole of the parasite thereby preventing further polymerization by heme polymerase enzyme. This results in accumulation of toxic heme and death of the parasite. Quinidine gluconate exerts its antiarrhythmic effects by depressing the flow of sodium ions into cells during phase 0 of the cardiac action potential, thereby slowing the impulse conduction through the atrioventricular (AV) node, reducing the maximal rate of phase 0 depolarization and prolonging the refractory period. Quinidine gluconate also reduces the slope of phase 4 depolarization in Purkinje-fibres resulting in slowed conduction and reduced automaticity in the heart.
See also: Quinidine (has active moiety).

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In conclusion, the results of this study show that adding quinidine increases the anticonvulsant effect of low doses of DM, while attenuates the anticonvulsant effect of high dose of DM. Our results suggest that the effects of DM/Q on seizure activity is due to the elevation of DM concentration, based on the earlier reports that the FDA- approved DM/Q increases the ratio of DM to DX. Meanwhile, using ketamine, WAY-100635, or BD-1047 we showed that NMDA receptor, sigma-1 receptor, and 5-HT1A receptor are to some extent involved in the central effects of DM/Q on seizure activity. [5]

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Quinidine D-gluconate is a D-gluconate adduct. It is functionally related to a quinidine.
Quinidine Gluconate is the gluconate salt form of quinidine, an alkaloid with antimalarial and antiarrhythmic (Class la) properties. Quinidine gluconate exerts its anti-malarial activity by acting primarily as an intra-erythrocytic schizonticide through association with the hemepolymer (hemozoin) in the acidic food vacuole of the parasite thereby preventing further polymerization by heme polymerase enzyme. This results in accumulation of toxic heme and death of the parasite. Quinidine gluconate exerts its antiarrhythmic effects by depressing the flow of sodium ions into cells during phase 0 of the cardiac action potential, thereby slowing the impulse conduction through the atrioventricular (AV) node, reducing the maximal rate of phase 0 depolarization and prolonging the refractory period. Quinidine gluconate also reduces the slope of phase 4 depolarization in Purkinje-fibres resulting in slowed conduction and reduced automaticity in the heart.
QUINIDINE GLUCONATE is a small molecule drug with a maximum clinical trial phase of IV (across all indications) that was first approved in 1950 and is indicated for malaria and ventricular arrhythmia. This drug has a black box warning from the FDA.

C20H24N2O2.C6H12O7

520.57204

520.242

C, 59.99; H, 6.97; N, 5.38; O, 27.66

7054-25-3

Quinidine hydrochloride monohydrate;6151-40-2;Quinidine (15% dihydroquinidine);56-54-2;Quinidine sulfate;50-54-4;Quinidine sulfate dihydrate;6591-63-5;Quinidine polygalacturonate;27555-34-6;Quinidine-d3;1267657-68-0

94328

Typically exists as solid at room temperature

175-176ºC

7

11

9

37

627

8

COC1=CC2=C(C=CN=C2C=C1)C(C3CC4CCN3CC4C=C)O.C(C(C(C(C(C(=O)O)O)O)O)O)O

XHKUDCCTVQUHJQ-LCYSNFERSA-N

InChI=1S/C20H24N2O2.C6H12O7/c1-3-13-12-22-9-7-14(13)10-19(22)20(23)16-6-8-21-18-5-4-15(24-2)11-17(16)18;7-1-2(8)3(9)4(10)5(11)6(12)13/h3-6,8,11,13-14,19-20,23H,1,7,9-10,12H2,2H3;2-5,7-11H,1H2,(H,12,13)/t13-,14-,19+,20-;2-,3-,4+,5-/m01/s1

(S)-[(2R,4S,5R)-5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methanol;(2R,3S,4R,5R)-2,3,4,5,6-pentahydroxyhexanoic acid

Quinidine gluconate; Duraquin; Gluquinate; Quinalan; Quinatime; Dura-tab; Quinidine mono-d-gluconate; ...; 7054-25-3;

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

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.)