Anti-parasitic drugs ( 抗寄生虫药 )

1. Anti-parasitic drugs(抗寄生虫药)

2. Anti-parasitic drugs 1. Anti-malarial drugs(抗疟药) 2. Anti-schistosomiasis and anti-filariasis drugs(抗血吸虫病和抗丝虫病药) 3. Anti-amebiasis and anti-trichomoniasis drugs(抗阿米巴病和抗滴虫病药) 4. Anthelmintic drugs(抗肠蠕虫药)

3. Youyou Tu Satoshi Ōmura William C. Campbell

4. Figure 1: The 2015 Nobel Prize in Physiology or Medicine awards discoveries regarding novel therapies for some of the most devastating parasitic diseases: River Blindness, Lymphatic Filariasis (Elephantiasis) and Malaria. The distribution of these diseases is quite similar and is collectively shown in blue on the world map. 淋巴丝虫病（象皮病） 河盲症 疟疾 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2015/press.html

5. Satoshi Ōmura searched for novel strains of Streptomyces bacteria （链霉菌）as a source for new bioactive compounds. He isolated microbes from soil samples in Japan, cultured them in the laboratory (inset to left) and characterized many thousands of Streptomyces cultures. From those, he selected around 50 cultures that appeared most promising, and one of these cultures later turned out to be Streptomyces avermitilis (阿维链霉菌), the source of Avermectin(阿维菌素).

6. William C. Campbell discovered that one of Ōmura’s Streptomyces cultures was very effective in killing off parasites and the active compound, Avermectin, was purified. Avermectin was further modified to Ivermectin(伊维菌素), which turned out to be highly effective in both animals and humans against a variety of parasites, including those that cause River Blindness and Lymphatic Filariasis. 阿维菌素 伊维菌素

7. Youyou Tu searched ancient literature on herbal medicine in her quest to develop novel malaria therapies. The plant Artemisia annua（青蒿） turned out to be an interesting candidate, and Tu developed a purification procedure, which rendered the active agent, Artemisinin（青蒿素）, a drug that is remarkably effective against Malaria. 青蒿素

8. Part1 1. Anti-malarial drugs(抗疟药)

9. Part1 Antimalarial drugs (抗疟药) • The malarial parasite(Plasmodium)(疟原虫), is a very small, single-cell blood organism. • It lives as a parasite in other organisms, namely man and mosquito. • The parasite is the cause of the tropical (热带)disease malaria(疟疾).

10. Anti-malarial drugs Anti-malarial drugs(抗疟药) 1. Biology of malarial parasite: (1)Classification of malaria: Human malaria is caused by 4 species of malarial parasite(plasmodium,疟原虫), include: P.falciparum(恶性疟原虫), P.vivax(间日疟原虫), P.malariae(三日疟原虫), P.ovale(卵形疟原虫). Common malaria in our country aresubtertian malaria(恶性疟) andtertianmalaria(间日疟). The conditions of tertian malariaare milder, therefore, itis calledbenign malaria(良性疟)too.

11. Anti-malarial drugs Parasite Life Cycle

12. Anti-malarial drugs (2)Life cycle of malarial parasite: Although malaria can be transmitted by transfusion of infected blood, human beings are infected more commonly by sporozoites(子孢子) injected by the bite of infected female mosquitoes. ①Asexual propagated stage in human body; ②Sexual propagated stage in female mosquitoes.

13. Anti-malarial drugs ①Asexualpropagatedstageinhuman body: ▲Exo-erythrocytic stage: There are two types of sporozoites of tertian malaria(间日疟), that is: Tackysporozoite(速发型子孢子),and Bradysporozoite(迟发型子孢子). The tackysporozoites leave the circula-tion and localized in liver cells, then they rapidly transform, multiply and develop into schizonts(裂殖体) and merozoites(裂殖子). There are no symptoms in this stage.

14. Anti-malarial drugs Thebradysporozoitesenter liver cells, then go into hypnozoite(休眠期), they become to dormancytes(休眠子), which is the source of tertian malaria relapse. • Pyrimethamine(乙胺嘧啶)can kill tacky-sporozoites in the exo-erythrocyticstage. • Primaquine(伯氨喹)can kill bradyspor-ozoites to radically treattertian malaria (间日疟), and prevent tertian malaria relapse.

15. Anti-malarial drugs ▲Erythrocytic stage: The schizonts(裂殖体) then rupture, each releasing thousands of merozoites (裂殖子), then enter the circulation and invade erythrocytes, initiate the eryth-rocytic stage, and transform trophozoite (滋养体) and schizonts, then release many merozoites. There are a lot of symptoms in this stage. Chloroquine(氯喹), Quinine(奎宁), and Artemisinin(青蒿素)are effective to this stage, they can control the symptoms, and prevent attack of malaria.

16. Anti-malarial drugs ②Sexual propagated stage in female mosquitoes: Some erythrocytic malarial parasites differentiate into sexual forms known as gametocytes(配子体). The ♂ and ♀ gametocytes in the gut of the mosquito combine to thezygote(合子), which develops in the gut wall to infective sporozoites(子孢子), which invades salivary gland, become the source of infection. Pyrimethamine can inhibit the development of ♂ and ♀ gametocytes in mosquito to control transmission of malaria. Primaquine can kill various gametocytes of subtertian and tertian malaria.

17. Anti-malarial drugs Antimalarialdrugs-DrugClassification • Tissue schizonticides 组织裂殖体杀灭剂 • eliminate developing or dormant liver forms(红外期裂殖体); • ---For control the prevention(预防) and relapse (复发) • Blood schizonticides 血裂殖体杀灭剂 • act on erythrocytic parasites(红内期裂殖体); • ---For control the symptom (症状) • 3. Gametocides杀配子药kill sexual stages and prevent transmission to mosquitoes. • ---For control the communication(传播)

19. 氯喹 阿莫地喹 奎宁 奎尼丁 甲氟喹 伯氨喹 磺胺多辛-乙胺嘧啶 氯胍 多西环素 卤泛曲林 苯芴醇 青蒿素 阿托伐醌/氯胍(马拉隆)

20. 青蒿素 氯喹 甲氟喹 奎宁 乙胺嘧啶 磺胺多辛 四环素 阿托伐醌 /氯胍(马拉隆) 伯氨喹

21. 氯喹 甲氟喹 奎宁 伯氨喹 磺胺多辛-乙胺嘧啶 阿托伐醌/氯胍(马拉隆) 青蒿素

22. Anti-malarial drugs Chloroquine(氯喹) • Chloroquine is a synthetic 4-aminoquinoline derivate

23. Anti-malarial drugs Chloroquine Mechanism of actions • Accumulation in erythrocyte→PH↑ → malarial pigment sythesis↓ • Haemoglobinquinoline喹啉 compound → haemoglobin accumulate in plasmodium ↑ • Insert in the double stranded DNA helix → DNA replication and RNA transcription ↓

24. Anti-malarial drugs Chloroquine Pharmacological effects • 1. Antimalarial effects: erythrocytic stage • Rapid schizonticidal(裂殖体杀灭剂)activity against all infections of malaria species . • gametocytocidal(杀配子体)against P. vivax, P. malariae and P. ovale as well as immature gametocytes (stages 1-3) of P. falciparum. • The effects are fast and lasting. • The symptoms will vanish after oral administration of chloroquine in 24~48 h, blood malarial parasites disappear in 48 ~72 h, the recurrence rate in one month is low. • 2. Immune inhibition • Treatment of rheumatoid arthritis, lupus erythematosus • 3. Extraintestinal amebiasis • Amoeba trophozoite amebic liver abscess

25. Anti-malarial drugs ADME of chloroquine Chloroquine A: well absorbed after oral administration; Tmax = 3~5 hr, t½> 1 week; D: Widely distributed, the concentration in liver, lung, and kidney is higher 200 ~ 700 times than blood; The concentration in erythrocyte is higher 20 ~ 30 times than plasma; the concentration in infected erythrocyte by malarial parasite is higher 25 times than normal erythrocyte. M: 50% liver E: principally excreted in the urine with an initial half-life of 3–5 days but a much longer terminal elimination half-life of 1–2 months

26. Anti-malarial drugs Clinical uses: Chloroquine ①Malaria: ▲to control the symptoms of benign malaria(良性疟); ▲to cure subtertian malaria(恶性疟); ▲symptomatic prevention in epidemic area(疫区的症状性预防). ②Amebiasis(阿米巴病): It can kill amebic trophozoite(滋养体), to treat systemic amebiasis(肠外阿米巴病), such as amebic hepatitis(阿米巴肝炎) and amebic hepatic abscess(阿米巴肝脓肿). ③Immune disease(免疫性疾病).

27. Anti-malarial drugs Adverse reaction Chloroquine • Rare at the usual antimalarial dosage • Pruritus (搔痒症) common among dark-skinned people. • Transient headaches, nausea, vomiting, gastrointestinal symptoms and "blurred vision“. • Others: aplastic blood and neurological disorders, such as polyneuritis多发性神经炎, ototoxicity, seizures and neuromyopathy.

28. Anti-malarial drugs Otherangentskillerythrocyticparasites Quinine 奎宁 Mefloquine甲氟喹 Pyronaridine 咯萘啶 Artemisinin青蒿素 Artemether and artesunate 蒿甲醚和青蒿琥酯

29. Anti-malarial drugs Quinine(奎宁) quinine Quinineis the chief alkaloid of cincho-na(金鸡纳), the bark of the South Ameri-can cinchona tree. (1)Anti-malarial action and clinical uses: Quinineacts primarily as a blood schi-zontocide(杀裂殖体药) to control the clini-cal symptoms; It is a gametocide for gametocytes(配子体) of P. vivax(间日疟原虫) & P. malariae(三日疟原虫) also, but not effective for game-tocytes of P. falciparum(恶性疟原虫). Quinineis more toxic and less effective than chloroquine. but,it is especially valuable to treat: ①chloroquine-resistant and multidrug-resistant subtertian malaria(耐氯喹和多药耐受的恶性疟), ②severe cerebral malaria(严重的脑型疟).

30. Anti-malarial drugs quinine (2)Adverse reaction:more. ①Cinchonism(金鸡纳反应): ringing in the ears(耳鸣), headache, nausea, disturbed vision, etc. ②Myocardial depression(心肌抑制作用): to reduce myocardial contractility, and slow down conduction and prolong refra-ctory period,but weaker thanquinidine (奎尼丁, dextrogyre of quinine). ③Stimulating womb(兴奋子宫): can induce abortion, not to be take by pregnant woman. ④Idiosyncrasy(特异质反应): acute hemolytic reaction.

31. Anti-malarial drugs Mefloquine(甲氟喹) mefloquine (1)Anti-malarial action: It isan efficient schizontocide in erythrocytic stage, effective to chloroquine-resistant subtertian malaria. (2)Clinical uses: ①to treat chloroquine-resistant subter-tian malaria. ②to prevent and control the symptoms of benign malaria, once/two week. (3)Adverse reaction: GI reaction, nervous and pschic reaction.

32. Anti-malarial drugs Artemisinin(Qinghaosu, 青蒿素) • (1)Anti-malarial action: • It isa highly efficient malariacide of schizonts in erythrocytic stage. • The effects are faster than that of chloroquine, and effective to chloroquine-resistant subtertian malaria,especially effective to cerebral malaria. • (2)Clinical uses: • to treat chloroquine-resistant subter-tian malaria,and to treatbenign malaria also. but its recurrence rate is high. • (3)Adverse reaction: less, • GI reaction, occasionally serum GPT.

33. 蒿甲醚 - 本芴醇 青蒿琥酯，阿莫地喹 双氢青蒿素 - 哌喹

35. Anti-malarial drugs Primaquine(伯氨喹) primaquine Pharmacological effects (1)Anti-malarial action: target: dormancytes(休眠子) of tertian malaria various gametocytes(配子体) of subtertian malaria→dissemination(传播)↓ hypnozoites(迟发型子孢子)of the relapsing malarial parasites -The only drug currently used for the treatment of relapsing malaria Owing to elimination fast, the effects are not lasting.

36. Anti-malarial drugs primaquine Antimalarialdrugs-Primaquine (2)Mechanism of actions Inhibition of coenzyme Q Inhibition of reduction of NADP (3)Clinical uses: ①use it withchloroquineto radically treat benign malaria(良性疟); ②to prevent transmission ofsubterti-an malaria(恶性疟).

37. Anti-malarial drugs primaquine (3)Adverse reaction: Itstoxicity is large Nervous system :Transient dizziness , nausea, vomiting, gastrointestinal symptoms Blood system:Acute hemolytic anemia(急性溶血性贫血), methemoglobinemia高铁血红蛋白血症

38. Anti-malarial drugs Pyrimethamine(乙胺嘧啶) primethamine (1)Anti-malarial action: ①It can killschizonts(裂殖体) of subtertian malarial parasites and benign malarial parasites in exoerythrocytic stage; ②It can also killimmature schizonts of erythrocytic stage; ③It can not kill gametocytes(配子体), but can inhibit development of sporophytes(孢子体) in mosquito. Mechanism of actions Dihydrofolate reductase inhibitor

39. Anti-malarial drugs primethamine (2)Clinical uses: Itis mainly used to prevent malaria, the first chosen drug for malarial prevention. (3)Adverse reaction: Folate metabolism disturbtance Its toxicity is less. But long-term and larger dose admi-nistration, it can cause megaloblastic anemia(巨红细胞贫血). This adverse reaction can be treated by formyl tetrahydrofolic acid(甲酰四氢叶酸). In addition, once large dose can cause acute intoxication.

40. Anti-malarial drugs 3. Summarization: (1)Selection of antimalarial drugs: ①Symptom control: Chloroquine; ②Cerebral malaria: Artemisinin, im. Quinine dihydrochloride, iv gtt(静脉滴注); ③Chloroquine-resistant subtertian malaria: Artemisinin, Quinine, Mefloquine; ④Resting stage: Pyrimethamine + Primaquine; ⑤Prevent transmission: Pyrimethamine. (2)Combined administration: Chloroquine + Primaquine; Pyrimethamine + Primaquine(防止复发).

43. Atovaquone(阿托伐醌) • Atovaquone, a hydroxynaphthoquinone , was initially developed as an antimalarial agent • Atovaquone has also been approved by the FDA for the treatment of mild to moderate P jiroveci pneumonia. • Malarone= atovaquone (250 mg) + proguanil (100 mg) • highly effective for both the treatment and chemoprophylaxis of falciparum malaria（恶性疟疾）, and it is now approved for both indications in the USA. • For chemoprophylaxis, Malarone must be taken daily. It has an advantage over mefloquine and doxycycline in requiring shorter periods of treatment before and after the period at risk for malaria transmission, but it is more expensive than the other agents. It should be taken with food.

44. Part2 Anti-schistosomiasis drugs(抗血吸虫药)

46. Schistosomiasis(血吸虫病) is caused by Schistosoma(血吸虫, 裂体吸虫) infection. • There are five kinds of Schistosoma caused Schistosomiasis of human: • S. japonia(日本血吸虫), S. heamatobium (埃及血吸虫), S. mansoni(曼索血吸虫), S. intercalatum(间插血吸虫) and S. mekongi (湄公血吸虫). • In our country, the schistosomiasis is caused mainly by S. japonia.

48. 肝硬化主征 巨 脾 腹 水 门脉高压

49. Anti-schistosomiasis drugs • In the past, the drug treated schisto-somiasis was PAT(酒石酸锑钾, potassium antimony tartrate), its course of treat-ment was longer, the toxicity larger, need iv administration, and the ADRs were severe. • Since 1970’, praziquantel(吡喹酮) had bediscovered, because its ADRs is less, praziquantel became the main drug to treat schistosomiasis.

50. Anti-schistosomiasis drugs Praziquantel(吡喹酮) praziquantel (1)Anti-parasite effects: It is a highly effective and broad spectrum anti-parasite drug. It can kill schistosoma(血吸虫) directly; and it can kill other trematde(吸虫) too, e.g. clonorchis sinensis(华支睾吸虫, 即“肝吸虫”), lung fluke(肺吸虫), fasciolopsis(布氏姜片虫, 即“肠吸虫”); certain intestinal parasites(e.g. tapeworm(绦虫). Mechanism of anti-schistosoma effects: It can increase the membrane permeability to certain monovalent and divalent cation, particularly Ca2+, to cause schistosoma muscular contraction and spastic paralysis.