Plasmodium

氯胍在体外的抗疟功效主要依赖于其活性代谢物环胍，后者具有更强的抗疟活性（IC50=2.4-19 μM）。二氢叶酸还原酶 (DHFR) 的抑制剂是环胍。在体外，氯胍和阿托伐醌的组合可以很好地协同工作。这两种药物均能有效对抗红细胞前（肝）阶段的疟疾寄生虫以及配子细胞[1]。
为了增强阿托伐醌的作用，氯胍作为双胍而不是其代谢物环胍（一种抑制剂）发挥作用寄生虫二氢叶酸还原酶 [DHFR]。由于氯胍不会改变其他线粒体电子传递抑制剂（如粘噻唑和抗霉素）的作用，因此其对阿托伐醌的增强作用具有特异性[2]。
氯胍、4-氯苯基-1-双胍 (CPB) 和环胍 (CG) ），活性代谢物，均可逆地抑制 5-HT3 受体反应，IC50 值分别为 1.81、1.48 和 4.36 μM[3]。

氯胍（口服；2.9 mg/kg 体重；每天一次，分别持续 5 天和 6 周）会导致 Wistar 品系白化大鼠出现轻度退行性变化，持续 5 天，严重退行性变化，持续 6 周。接受氯胍治疗的大鼠显示，血清睾酮水平[4]。
当在两个慢性阶段和三个急性阶段给实验性感染吉布氏伯克虫的狗服用马拉隆（阿托伐醌和氯胍）时，寄生虫血症水平下降，临床症状得到改善[5]。

培养 16 至 18 天大的大鼠的支持细胞，并将其暴露于浓度为 0.3 μM 至 10 μM 的氯胍中五天。然后评估支持细胞细胞核的活力和完整性。此外，还评估了转铁蛋白和胶质细胞系源性神经营养因子的基因表达[4]。

Rats: Proguanil (2.9 mg/kg body weight) is given daily to groups of ten to twelve-week-old rats for five days and six weeks, respectively. Following that, weights of the body and reproductive organs are recorded, sperm parameters are examined, and testicular and epididymal histology is performed. Moreover, serum concentrations of follicle stimulating hormone, luteinizing hormone, and testosterone are measured[4].

Absorption, Distribution and Excretion
Rapidly and well absorbed in humans following oral doses ranging from 50 to 500 mg.

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Metabolism / Metabolites
Variably metabolized in the liver by cytochrome P450 isoenzymes to the active triazine metabolite, cycloguanil. This variable metabolism of proguanil may have profound clinical importance in poor metabolizers such as the Asian and African populations at risk for malaria infection. Prophylaxis with proguanil may not be effective in these persons because they may not achieve adequate therapeutic levels of the active compound, cycloguanil, even after multiple doses.
Proguanil has known human metabolites that include Cycloguanil and 4-Chlorophenylbiguanide.

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Biological Half-Life
Approximately 20 hours

Hepatotoxicity
The combination of atovaquone and proguanil has been associated with transient and minor serum aminotransferase elevations in a small proportion of patients. More importantly, there have been rare reports of idiosyncratic acute liver injury due in patients on atovaquone/ proguanil but the number of cases has been too few to define a typical clinical course. In one reported case, the onset of injury was after 3 weeks and presentation was with fatigue and jaundice and a cholestatic pattern of serum enzyme elevations. The injury resolved within 2 months of stopping the medication (Case 1). In another case report of chloroquine and proguanil, liver injury arose within days of starting the combination and the pattern of serum enzyme elevations was mixed. In both cases, allergic features were minimal and autoantibodies were not present. In both cases, combination therapy was used and either agent may have been the cause of the injury. Atovaquone and proguanil have also been linked to rare instances of Stevens Johnson syndrome which is often accompanied by mild liver injury or liver enzyme elevations.
Likelihood score: E* (unproven but sometimes suspected cause of clinically apparent liver injury).

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Protein Binding
Approximately 75%

[1]. Atovaquone and proguanil hydrochloride: a review of nonclinical studies. J Travel Med. 1999 May;6 Suppl 1:S8-12.

[2]. A mechanism for the synergistic antimalarial action of atovaquone and proguanil. Antimicrob Agents Chemother. 1999 Jun;43(6):1334-9.

[3]. The antimalarial drug proguanil is an antagonist at 5-HT3 receptors. J Pharmacol Exp Ther. 2014 Dec;351(3):674-84.

[4]. Prolonged administration of proguanil induces reproductive toxicity in male rats. J Toxicol Sci. 2011 Oct;36(5):587-99.

[5]. The in vitro interactions and in vivo efficacy of atovaquone and proguanil against Babesia gibsoni infection in dogs. Vet Parasitol. 2013 Nov 8;197(3-4):527-33.

Proguanil is a biguanide compound which has isopropyl and p-chlorophenyl substituents on the terminal N atoms. A prophylactic antimalarial drug, it works by inhibiting the enzyme dihydrofolate reductase, which is involved in the reproduction of the malaria parasites Plasmodium falciparum and P. vivax within the red blood cells. It has a role as an antimalarial, an antiprotozoal drug and an EC 1.5.1.3 (dihydrofolate reductase) inhibitor. It is a member of biguanides and a member of monochlorobenzenes.
Proguanil is a prophylactic antimalarial drug, which works by stopping the malaria parasite, Plasmodium falciparum and Plasmodium vivax, from reproducing once it is in the red blood cells. It does this by inhibiting the enzyme, dihydrofolate reductase, which is involved in the reproduction of the parasite.
Proguanil is an Antimalarial. The mechanism of action of proguanil is as a Dihydrofolate Reductase Inhibitor.
Proguanil is a biguanide derivative which is active against several protozoal species and is used in combination with atovaquone and chloroquine for the prevention and therapy of malaria. Proguanil has not been evaluated extensively as a single agent, but the combinations of proguanil with atovaquone or chloroquine have been used to treat malaria and have been linked to serum enzyme elevations during therapy and rare instances of clinically apparent acute liver injury.
A biguanide compound which metabolizes in the body to form cycloguanil, an anti-malaria agent.

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Drug Indication
For the causal prevention and suppression of malaria caused by susceptible strains of P. falciparum and other species of Plasmodium found in some geographical areas of the world.

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Mechanism of Action
Proguanil inhibits the dihydrofolate reductase of plasmodia and thereby blocks the biosynthesis of purines and pyrimidines, which are essential for DNA synthesis and cell multiplication. This leads to failure of nuclear division at the time of schizont formation in erythrocytes and liver.

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Pharmacodynamics
Proguanil is a biguanide derivative that is converted to an active metabolite called cycloguanil. It exerts its antimalarial action by inhibiting parasitic dihydrofolate reductase enzyme. It has causal prophylactic and suppressive activity against P. falciparum and cures the acute infection. It is also effective in suppressing the clinical attacks of vivax malaria. However it is slower compared to 4-aminoquinolines.

C11H16CLN5

253.73

253.109

C, 52.07; H, 6.36; Cl, 13.97; N, 27.60

500-92-5

Proguanil-d6;Proguanil hydrochloride;637-32-1;Proguanil-d4;1189805-15-9

6178111

Solid powder

1.29g/cm3

402.7ºC at 760mmHg

129°

197.4ºC

1.6110 (estimate)

3.263

83.79

3

1

4

17

292

0

ClC1C([H])=C([H])C(=C([H])C=1[H])N([H])/C(/N([H])[H])=N/C(/N([H])[H])=N/C([H])(C([H])([H])[H])C([H])([H])[H]

SSOLNOMRVKKSON-UHFFFAOYSA-N

InChI=1S/C11H16ClN5/c1-7(2)15-10(13)17-11(14)16-9-5-3-8(12)4-6-9/h3-7H,1-2H3,(H5,13,14,15,16,17)

Biguanide, 1-(p-chlorophenyl)-5-isopropyl-

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)

DMSO : 51~130 mg/mL ( 201.0~512.36 mM )
Ethanol : ~51 mg/mL

配方 1 中的溶解度: ≥ 2.17 mg/mL (8.55 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 21.7 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.17 mg/mL (8.55 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 21.7 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.17 mg/mL (8.55 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 21.7 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.17 mg/mL (8.55 mM)

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。