Download Parasitic Diseases

CLASS: Fundamentals II
DATE: December 7, 2010
PROFESSOR: El Kouni
I.
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PARASITIC DISEASES
Scribe: Rachel Tucker
Proof: Ross Isbell
Page 1 of 7
Parasitic Diseases [S1]
a. Parasitic diseases are a very big problem in the world today
b. Global prevalence exceeds 50%: this means that 50% of the world is plagued with parasitic diseases today.
c. Most of these diseases are ignored because their symptoms are not very drastic as those seen with AIDS, for
example.
d. However, some of these diseases cannot be ignored because of their high mortality rate.
i. Malaria: 1.5 million people are killed by it every year
Table: The top ten human parasites (based on WHO estimates) [S2]
a. Ascaris: infects 900 million per year and kills 20,000
b. Hookworm
i. Prevalent in AL
ii. 800 million infections and 55,000 deaths per year
c. Malaria: 1.5 million are killed per year
d. Second to malaria is schistosomiasis: 750,000 killed per year
i. Biggest concern for GIs in WWII and in Asia in the war there
e. Although these are the most important parasitic diseases, they don’t occur often in the US
i. Some have been eradicated
ii. The intermediate hosts of some have been eliminated from the environment
f. Because these diseases aren’t prevalent in the US, they’ve been ignored for quite a bit of time
i. Drug companies must have a profit to make a drug
ii. These diseases are prevalent in third world countries, Africa, Asia
iii. These countries can’t afford the drugs
Chemotherapy of Parasitic Diseases [S3]
a. There was the advent of molecular biology and a growing interest in the interaction between host and
parasite.
i. This has led to more efficient study of the parasites
ii. This has also led to the search for ideal drugs
iii. However, you’ll see as you study this that it’s very difficult to develop drugs for these diseases
b. Chemotherapy is the only way to treat these diseases because there are no vaccines.
i. There were many unsuccessful attempts to make a malaria vaccine (1 st and 2nd generation)
c. There is work going on to develop new drugs
i. Reason: some of these diseases (e.g. trypanosomes or leischmania) are still being treated with heavy
metals which have strong side effects against the host
ii. Also need new drugs to overcome parasitic resistance (e.g. malaria); this is very much needed
iii. Richer countries have not dedicated much to this research.
d. Most drugs are found via empirical discovery
i. You have 10,000 compounds on the shelf. You take one down and try it against schistosomiasis, for
example. If it works, great; if it doesn’t, you try it against malaria, and so on
ii. This is not a drug rationally designed to kill a particular parasite
iii. In fact, some of these kill very well, like Project One Tab, which will be discussed later on, came from this
type of screening.
iv. This process is very laborious and time consuming.
e. Rational design of anti-parasitic drugs was lacking until recently when we really started putting our hands and
minds on how to treat these parasites by studying their biochemistry to search for targets which could be
used for chemotherapy
Antihelmintic Drugs [S4]
a. Antihelmintic = antiworm
Helminths can be divided into three groups [S5]
a. Trematodes: schistosomiasis
b. Nematodes: ascaris
c. Cestodes: flatworms
Targets for antihelmintic drugs [S6]
a. Why these are important in parasites
i. Parasites either divide very quickly, so you must have replication
ii. Or, they have to put a large number of eggs into the body. Schistosomiasis, for example, expels 10,000—
100,000 eggs per day.
iii. This means you need energy, DNA synthesis
CLASS: Fundamentals II
Scribe: Rachel Tucker
DATE: December 7, 2010
Proof: Ross Isbell
PROFESSOR: El Kouni
PARASITIC DISEASES
Page 2 of 7
iv. Also have microtubular function with DNA synthesis, so if you block that, you can’t make the spindle and
mitosis and meiosis cannot occur.
b. Energy metabolism: parasites need energy
c. Neuromuscular coordination
i. Most of time parasites are located in hostile environments and must keep a strong attachment to it.
ii. Schistosomes attach to mesenteric veins against the blood flow, so the parasite must have very strong
muscular function to keep itself in place.
VII.
Class of antihelmintic drugs [S7]
a. Miscellaneous drugs are those that don’t fit into the other two categories
VIII.
Mode of Action of Benzimidazoles [S8]
a. Inhibition of glucose transport will affect energy.
b. Inhibition of fumarate reductase will affect energy, as well as microtubular function, which will in turn inhibit
DNA synthesis.
IX.
Mebendazole [S9]
a. READ SLIDE
b. Not effective against strongyloids and hydatid disease
i. Strongyloids: historically it was not a problem, but currently is an opportunistic infection of AIDS patients
X.
Albendazole [S10]
a. READ SLIDE
b. tugument: skin surface of the worm
c. Remember that mebendazole was not effective against hydatide disease, while albendazole is.
d. Dubbed the “penicillin of antiparasitic diseases” because of its wide use in treatment of nematodes
XI.
Thiabendazole [S11]
a. Although you don’t need to delve into the chemistry, these are all derivatives of benzimidazole.
b. You really only need to know that these are benzimidazoles and what they do.
c. READ SLIDE
d. Ovicidal and lavicidal: kills both eggs and larvae of the parasite
e. It inhibits fumarase reductase, and that will affect energy
i. If you know that this affects energy, this will be enough for me to accept that as an answer
XII.
Ivermectin [S12]
a. There’s a very nice story behind this one
b. In the US, it’s used to treat heartworms in dogs.
i. It was originally developed for this purpose and a lot of money was made there
ii. By golly, when they treated human parasitic diseases with it, they found that it is really very effective.
iii. America now gives this drug to the WHO, which again gives it for free to countries affected by these
diseases.
c. Japanese has this “hobby” of taking samples from the ground and playing with the bacteria there.
i. This drug came from one of those bacteria: Streptomyces avermitilis
ii. This was found around Tokyo
d. READ SLIDE
e. Effective against endo and ectoparasites: effective against parasites that are on the skin or in the body.
f. River blindness
i. Used very often for this
ii. In Africa, there are villages where no one over the age of 16 can see.
iii. The parasite infects and destroys the eye.
iv. Children guide the blind with sticks; the child holds onto one end, and the blind person holds on to the
other.
g. Something you have to remember:
i. This is not effective against trematodes or cestodes, ONLY effective against nematodes
ii. However, it almost universally affects nematodes, thus, it is another one of the “penicillins” of parasites
iii. Reason for this: it deals with GABA junctions. Trematodes and cestodes don’t have a GABA system, while
nematodes do.
iv. Coordination of the muscle of trematodes and cestodes works by the acetyl choline esterase system.
XIII.
Niclosamide [S13]
a. We’re now discussing the miscellaneous drugs.
b. READ SLIDE
c. Again, because this inhibits glucose, it’s an energy inhibitor
d. Rapidly and quantitatively excreted in the urine
i. Not much is metabolized
CLASS: Fundamentals II
Scribe: Rachel Tucker
DATE: December 7, 2010
Proof: Ross Isbell
PROFESSOR: El Kouni
PARASITIC DISEASES
Page 3 of 7
ii. It is absorbed by contact within the body, and whatever is leftover is secreted as unchanged metabolites
XIV.
Schistosomiasis I [S14]
a. Now we’ll talk about one of the most important trematodes: schistosomes
XV.
Schistosomiasis II [S15]
a. READ SLIDE
XVI.
Figure: Geographic Distribution of Schistosomiasis [S16]
a. Mansoni is concentrated in South America
b. In Africa, it was mostly heamatobium and mansoni but now mansoni is taking over the heamatobium in some
areas, especially Egypt.
i. Reason: intermediate host is the snail. Mansoni’s host is overtaking the snails which harbor heamatobium
ii. Snail distribution is the main cause of this switch in distribution
c. Japonicum, as you can see from the name, occurs mostly in Asia
XVII. Pathogenesis of Schistosomiasis [S17]
a. This is one of the most important parasitic diseases
b. The symptoms come from the endless deposition of eggs
c. In the body you have 20-30 pairs of worms, which will stay in the body for about 40 years if you don’t treat for
them.
d. They produce 400-4000 eggs/day, so if you multiply this by 20, that’s 80,000 eggs/day laid.
i. Most are trapped in the liver  hepatic fibrosis with granulomas in them
ii. Portal hypertension
e. Experiments with mice show that the worm will clog the whole portal vein in the liver.
f. In people who suffer from heamatobium, bladder cancer occurs
i. This is the most common cancer in Egypt because of the prevalence of heamatobium
XVIII. Photo: two boys in Egypt with schistosomiasis [S18]
a. One is in the early stages and the other is very advanced
i. In the advanced case, see distended spleen and the liver is almost completely gone.
ii. This child cannot be saved because the liver is gone
XIX.
Photo: Filipino boy with schistosomiasis [S19]
a. Caused by japonicum
XX.
Praziquantel I [S20]
a. This is the third “penicillin” of the parasites
b. Made by Merck, and then Hoffman La Roche tested it and found it effective against schistosomes
c. Effective against the three species of schistosomes talked about before
i. Earlier drugs were effective against only one or two of those species.
d. Very effective against trematodes, and also has some effect against cestodes
e. Remember that Ivermectin is effective against nematodes, and this is effective against trematodes and
cestodes. Albendazole is effective against nematodes.
i. Thus, the WHO suggested about ten years ago to combine these three drugs and give them to every child
in Africa to get rid of all these diseases together.
ii. However, these are almost all social diseases. This means that even if you eliminate a parasite from the
body, you can become immediately reinfected if you enter the same contaminated water source.
iii. Lack of potable water is the real problem here.
iv. Most of these parasites have a cycle in the water. In dry places you don’t see incidence of this disease.
XXI.
Praziquantel II [S21]
a. What you have to know about this
i. Effective against all the schistosomiasis, however, we don’t know how it works
XXII. Proposed Mechanism of Praziquantel [S22]
a. Causes contraction of the muscles so that the parasite leaves its place in the body and gets shifted to the
liver or to the lungs (as in heamatobium)
b. It looks like a Ca ionophore. This is not the case, however.
c. It acts synergistically with the humoral immune response
i. The praziquantel destroys some of the tugument in the schistosomes and makes them more susceptible to
the immune response.
ii. In infected mice, the humoral immune response was suppressed and Praziquantel was given. It was found
that the tugument of the parasite was destroyed, but the parasite was able to recover
iii. When the same experiment was performed in mice that were not immunosuppressed, the parasites were
eliminated
iv. It seems that Praziquantel primes the immune response.
d. This is all you have to know here. You don’t have to go more than that.
CLASS: Fundamentals II
Scribe: Rachel Tucker
DATE: December 7, 2010
Proof: Ross Isbell
PROFESSOR: El Kouni
PARASITIC DISEASES
Page 4 of 7
XXIII. Metrifonate (Bilarcil) [S23]
a. One of the old ones
b. READ SLIDE
c. Dichlorvos is the active ingredient
d. This is another drug whose effects were discovered by surprise
i. Diptherix anti-fly sprayer: used to kill houseflies
ii. In Africa, it was noticed that in houses sprayed by this substance, the people there had fewer infections
with schistosomes.
e. Inhibits ACh esterase
i. Makes the worm unable to stay in its place and it can drift outside the body
ii. It phosphorylates the serine of the enzyme
iii. Has no effect on humans because the human enzyme is 10X more resistant than the parasite’s enzyme.
f. Don’t worry about what it kills in the lab, but know that it kills haematobium in vivo and that it’s an
organophosphate compound.
XXIV. Oxamniquine (Vansil, Mansil) [S24]
a. One of the quinolines
b. READ SLIDE
XXV. Antiprotozoal Drugs [S25]
a. The problem with these: they’re very primitive
XXVI. Sodium Antimony Gluconate [S26]
a. This has been used since the pharaohs.
b. It’s a heavy metal: pentavalent salt of antimony
c. READ SLIDE
d. Realize that this is the first drug we’ve discussed that’s effective against leishmaniasis.
e. The mechanism is not known, but it could be inhibiting energy metabolism
f. Administered by slow IV injection because it becomes very painful if given quickly.
XXVII. Metronidazole [S27]
a. READ SLIDE
b. Giardia is in most prominent in Colorado in the US
c. Care must be taken when it’s administered to a patient because of CNS and neutropenia involvement.
XXVIII. Iodoquinol [S28]
a. One of the quinolines
b. READ SLIDE
c. Don’t worry about the chemical name of it (#1)
XXIX. Paromomycin [S29]
a. Forget about this
XXX. Table: The Top Ten Human Parasites (Based on WHO estimates) [S30]
a. Skipped because he talked about it at the beginning of the lecture.
XXXI. Malaria I [S31]
a. More on this because it’s the most prominent disease we’ll talk about it and most likely encountered.
b. Very widely spread. About 800 million are affected by it with 1.5 million dead.
c. Even though it’s been eradicated in some countries, it remains a big problem worldwide.
i. In the USA the intermediate host, Anopheles mosquito, does not live here, but you never know.
XXXII. Figure: Geographic Distribution of Malaria [S32]
a. Distribution up through Mexico
XXXIII. Malaria II [S33]
a. Four species of protozoa, Plasmodium, which cause malaria
i. Falciparum: most important because it’s the most lethal.
ii. Vivax and ovale: mostly in South America and Africa; also, the most drug resistant
b. The origin of the name Malaria
i. It translates to “bad air”
ii. When the seasons came around Rome, there was a bad smell accompanied by malaria outbreaks.
XXXIV. Malaria Transmission [S34]
a. READ SLIDE
XXXV. Figure: Lifecycle of Malaria (based on Plasmodium vivax) [S35]
a. This is not for memorization; it’s just to give you an idea of the logic behind prescribing a particular drug.
b. Process
i. You’re bitten by a mosquito and the mosquito inserts sporozoites into the bloodstream.
ii. The sporozoites go first to the liver
CLASS: Fundamentals II
Scribe: Rachel Tucker
DATE: December 7, 2010
Proof: Ross Isbell
PROFESSOR: El Kouni
PARASITIC DISEASES
Page 5 of 7
iii. They penetrate the hepatic cells of the liver and they stay there and divide and mature.
iv. The cell then ruptures, and merozoites are released
v. Merozoites attack RBC’s and enter the cycle of replication again and again
1. This causes sequential high temperature periods: it’s a consequence of division in the RBC’s.
vi. Sometimes merozoites are converted into macrogametes and microgametes: female and male species of
the merozoite
vii. When the blood is sucked by the mosquito, it takes up gametocytes which go to its intestines and develop
viii. From the mosquito’s intestines the cycle continues
c. It’s important to remember the liver stage
i. Also have insect stage, gametocyte stage, and blood stage
ii. In the case of the liver stage, malariae and farciparum get completely cleared from the liver at one time and
move to the blood together.
iii. In the case of ovale and vivax, some leave the liver for the blood, some stay behind as hepnozoides
(named as such because they act as if they’re dormant in the liver)
d. Of the drugs we’re going to talk about, there are some against the liver stage, the rbc stage, gametocyte
stage, or insect stage
XXXVI. Malaria Pathogenesis and Pathology [S36]
a. READ SLIDE
b. This is to give you an idea to understand the disease. You aren’t necessarily responsible for this.
XXXVII. Plasmodium falciparum [S37]
a. READ SLIDE
b. Symptoms listed are especially linked to children
c. “…release 2.5-20 times more merozoites.” This is called high parasitemia.
i. If you take a slide with rbc, you see the incidence of infected rbc is much higher in falciparum than other
species.
d. Vivax and ovale only infect very young blood cells
e. Malariae only attacks old blood cells
f. Falciparum is dangerous because of the high parasitemia
XXXVIII.
Figure: Lifecycle of Malaria (based on Plasmodium vivax) [S38]
a. skipped
XXXIX. Recurrence of Malaria [S39]
a. In treating malaria, there are two kinds of recurrence
b. Relapse
i. Only in vivax and ovale because with these two, you still have some leftover in the liver.
ii. If you clear up the blood, you will have have malaria 3-4 yrs later without having been exposed in your
environment.
iii. Some of the dormant protozoa will become merozoites and enter the blood
iv. To get rid of it, you must use 2 kinds of drugs: one to kill the rbc stage, and one to kill the liver stage.
c. Recrudescence
i. Occurs with falciparum
ii. Occurs from bad disease management to begin with
iii. If you really give low amount of the drug for a short time over and over again and the protozoan will
become resistant to that treatment.
iv. A treatment will kill most of the organisms, but if two or three merozoites are left, there will be a long lag
before all rbc’s are infected. This is why you see the period of no symptomology before the disease returns.
XL.
Goals of Chemotherapy in Malaria [S40]
a. Two goals
i. Prophylaxis
ii. Cure
1. Suppressive: suppresses the symptoms of malaria
2. Radical: completely clear the body of the merozoites
3. For example, for viruses, very often suppressive therapy is used because you can’t completely get
rid of the virus (i.e. HIV or Herpes Simplex)
XLI.
Prophylaxis of Malaria [S41]
a. Clinical prophylaxis
i. READ SLIDE
ii. Take a drug that will prevent the malaria symptoms by killing merozoites
iii. Will destroy the blood stage, but will still have liver stage
b. Casual prophylaxis
CLASS: Fundamentals II
Scribe: Rachel Tucker
DATE: December 7, 2010
Proof: Ross Isbell
PROFESSOR: El Kouni
PARASITIC DISEASES
Page 6 of 7
i. Prevents it from going into the rbc stage
ii. If you prevent the tissue stage, you also prevent the rbc stage.
XLII.
Types of Anti-Malarial Drugs [S42]
a. Four types of antimalarial drugs in use.
XLIII. Anti-Malarial Drugs [S43]
a. Antimalarial drugs are divided into two classes based on how well defined their mechanism is.
b. Undefined: quinolines (although now we have a handle on how they work)
c. Well-defined: dihydrofolate reductase (DFHR) inhibitors and sulfhydrazine drugs
XLIV. What Determines the Choice of Drug? [S44]
a. You must know this
b. Purpose of chemotherapy: prophylaxis or cure?
c. Type of infection: vivax, ovale, malariae, or falciparum?
i. Falciparum and malariae are treated the same way.
ii. Vivax and ovale are treated almost the same way.
XLV. Quinolines [S45]
a. READ SLIDE
XLVI. Proposed Mechanism of Quinolines [S46]
a. This is a recent discovery
b. When RBC are digested, heme is released. This heme, if it stays in the cell, would kill the parasite.
i. The protozoa produce a heme polymerase which polymerizes iron in the cell so it isn’t available to kill the
parasite.
c. It is believed that heme polymerase is inhibited by quinolines. Thus, there is heme in the cell and it kills the
parasite.
XLVII. Figure: Quinoline Anti-Malarial Drugs [S47]
a. This is for your own use. These are the quinolines
b. Most important: chloroquine, mefloquine (newest), quinine (oldest)
XLVIII. Quinine [S48]
a. Major alkaloid from cinchona called guina guina, which is found in South America.
i. Known historically as Jesuit bark
ii. Jesuits had a monopoly on this, so if you weren’t on good terms with them you were in bad shape.
iii. Chewing on the bark gives relief. The Indians learned this.
b. During colonial times, the most common drink in Africa and India was gin and tonic
i. Tonic water contains quinine, so it was used as prophylaxis
ii. “Don’t always think about drugs. Think about something nice.”
c. READ SLIDE
d. This is still used as a good backup drug.
XLIX. Quinidine [49]
a. READ SLIDE
b. If you don’t have quinine, you can use this.
L.
Chloroquine and Amodiquine [S50]
a. Chloroquine is the drug of choice.
i. Enormous volume of distribution
ii. Elimination time is 2 months so it stays in the body for a long time
iii. Especially good against falciparum.
b. READ SLIDE
c. Dark urine is caused by the high concentrations of quinine in the body. This was common during colonial
times (Africa, India)
LI.
Meflaquine [S51]
a. Newest drug: 1984
b. Used to overcome resistance with chloroquine
i. Problem: since we’re an affluent country, we use this as prophylaxis for travelers so that it’ll get any type of
malaria they’ll come in contact with.
ii. This has the potential to nullify this benefit of the drug.
LII.
Primaquine [S52]
a. Different than the other quinolines: not used against the blood stage, mostly used to treat the tissue stage
b. READ SLIDE
c. Not used for prophylaxis because of side effects
i. Intravascular hemoglysis and anemia in G6PD deficiency as a result of oxidation stress
LIII.
Toxicity of Primaquine [S53]
CLASS: Fundamentals II
Scribe: Rachel Tucker
DATE: December 7, 2010
Proof: Ross Isbell
PROFESSOR: El Kouni
PARASITIC DISEASES
Page 7 of 7
a. Why this drug is not used as prophylaxis
b. It inhibits glutathione reduction
i. Thus, the enzyme cannot generate NADPH
ii. If you can’t regenerate NADPH in the absence of Glucose-6-phosphate dehydrogenase (G6PD), you
cannot reduce glutathione
iii. Thus, you will have destructive free radicals in the cell.
iv. This is why you must be careful in prescribing this drug to someone with a G6PD deficiency
LIV.
Figure: Synthesis of DNA from guanosine triphosphate by malaria parasites [S54]
a. Sulfadiazines
i. Inhibit dihydropteroate synthetase so dihydrofolate is not produced
b. Typically, treatment involves an inhibitor of both enzymes (pointed to by the arrows with circles on the end):
sulfa compounds and dihydrofolate reductase being administered together.
i. Less a chance of development of resistance.
ii. This drug combo is also effective against numerous other diseases
iii. If you don’t have these functioning enzymes, you have no DNA or RNA synthesis. This is especially true for
the dihydrofolate reductase because it’s involved in so many different reactions in nucleotide metabolism.
LV.
Table: !C50 (nM) for Inhibition of DHFR by Pyrimethamine and Trimethoprim [S55]
a. These two drugs are used to inhibit dihydrofolate reductase
b. The human enzyme is much more resistant to the drug as compared to the protozoal enzyme.
c. This is a big field of research: looking for compounds to inhibit this enzyme
i. This is important for cancer as well; however, this is more difficult because disease originates in the host.
LVI.
Figure: Mefloquine + Sulfadoxine/Pyrimethamine: The Triple Combination [S56]
a. All three of these drugs are attached in one tablet.
i. Have both inhibition of dihydrofolate reductase (quinoline compounds) and sulfabenozene
ii. This is called “fancy mef”
iii. Also used to prevent resistance
LVII.
Figure: Sesquiterpene Lactones [S57]
a. Found in China: Qinghaosu
b. Don’t have the same mechanism of any other anti-malarial drugs
c. Good prospect for future treatment
d. Additional notes:
i. 250,000 compounds have been screened for the treatment of malaria and none have worked.
ii. Remember you have quinolines, sulfadeozines, and inhibitors of dihydrofolate reductase, and finally the
Qinghaosu (pronounced “Shing-how”)
LVIII. Figure: Phenanthrenes [S58]
a. skipped
[End 52:33 mins]