1. What treats Rocky Mountain Spotted Fever (RMSF)?
2. What treats Bartonella sp?

1. Doxycylcine for adults; Chloramphenicol for Pregnant women
2. Azithromycin or erythromycin

What are the 4 blood-borne bacteria that are treated by Doxycyline?

Which ones can be treated with chloramphenicol?

Orientia Tsutsugamushi (D and C)

Coxiella Burnetti (D)

Ehrlichia Chafeensis (D)

RMSF (D and C)

Of these four, if it has a 'c' in the name, it is not treated by Chloramphenicol

If given as a child, will produce brown teeth.

If given to pregnant women, the child will have malformed, brown teeth

1. What is an example of a tetracycline?
2. What is its MOA?

1. Doxycycline (remember, they both have cycline in them)
2. The bind to the 30s subunit rRNA and and blocks tRNA from binding to the A site on the 50s

1. Decreased accumulation (efflux pump)
2. Ribosomal protection protein that displaces tetra.
3. Enzymatic inactivation

Toxicity of Tetracyclines?

When is the greatest period of risk for tooth malformation/coloration?

GI irritation, photosensitivity, nephrotoxicity (except for doxycycline - not excreted by kidney {by GI tract})

Mid preganancy-4-6mo may cause malformation of deciduous teeth. A few mos after birth up to age 5 for malformation of permanent teeth.

Permanent discoloration risk between 5-8yrs.

What is the MOA of Chloramphenicol?

Why wouldn't you give Chloramphenicol and a macrolide at the same time?

Similar to a macrolide(near the same site). Binds to the 50s at the peptidyltransferase site and prevents transpeptidation.

Their binding sites are so near that they can interfere with each other's binding. 

What causes the toxicity of Chloramphenicol?

What is the MOR to this drug?

It inhibits several mitochondrial enzymes.

Plasmid-encoded acetyltransferase, decreased permeability into the cell, ribosomal mutations that prevent drug binding.

1. A dose-dependent toxicity→leads to thrombocytopenia, anemia and leukopenia
2. An idiosyncratic toxicity (<.1%) in which aplastic anemia causes pancytopenia and is fatal.

Bacterial meningitis, typhoid fever and anaerobic infections.

These are generally infections that are more dangerous than the risk of taking the drug (always take a different drug if you can).

How do you distinguish malaria vs babesia?

Make sure to look at 7 for the life-cycle of malaria.

Babesia is much milder: flu-like

RBC have babesia tetrad rings in their cytoplasm.

Malaria: high fever, reddish limbs

P falciparum makes ring forms in RBCs

Treats the late hepatic stage of the plasmodium exoerythrocytic form of malaria.

Also treats the latent forms of all four plasmodial species: falciparum, vivax, malariae and ovale.

Also effective against the gametocytic forms of the malaria.

1. What is the MOA and MOR of Chloroquine?
2. On which stages of malaria is it active?
3. With what drug is it given for P. vivax and P. ovale?

1. Malaria will invade erythrocytes and feed on intracellular Hb. Chloroquine diffuses across the food vacuole membrane. Typically, Malaria will digest Hb, freeing heme. It will then convert heme into Hz (hemozoin), which is not harmful to the parasite. Chloroquine inhibits Heme→Hz. The buildup of free heme disrupts membranes, killing the parasite. The MOR is reduced diffusion of CQ into the vacuoles and the CRT gene.
2. The erythrocytic stages (makes sense because it targets malaria that is feeding on Hb)
3. Because P. vivax and P. ovale have latent liver phases, Primaquine is given with Chloroquine.

At frequent and high doses through paraenteral routes: hypotension, vasodilation, suppressed myocardiac function, cardiac arythmias and eventually cardiac arrest.

CNS: nightmares, confusion, convulsions and coma

Very important to monitor dosing.

What is the MOA, and against which forms of malaria are they effective against:

Mefloquine, Artesunate, Atovaquone and Primaquine.

MOA of and effective malaria stages for:

Pyrilmethamine-sulfadoxine and Proguanil

When is Mefloquine typically given?

What are the side effects?

In instances of Chlorquine resistance, and also to travelers prophylactically.

Dizziness, nightmares, ataxia, headaches, alterations of motor functions, visual and auditory disturbances.

What is the toxicity of Primaquine?

Abdominal distress, mild anemia, cyanosis, leukocytosis and acute hemolysis and hemolytic anemia in those with G6P dehydrogenase deficiency. (The RBCs aren't producing enough NADH to combat the ROS created by Primaquine)

Given orally, because if this is given parenterally, there can be hypertensive episodes (this makes sense b/c the drug has a tendency to form ROS which will NO→NO₃, causing vasoconstriction).

1. Against which stages of malaria is Artesunate effective?
2. What is the MOA for it?

1. The gametocytic and asexual erythrocytic stages of vivax and falciparum.
2. The heme ion in the RBC catalyzes cleavage of the endoperoxide in the molecule, creating a radical. The molecule then becomes an alkylating agent-damages the sarcoplasmic reticulum ATPase of the parasite.NOTE: It makes sense for this to be effective against the erythrocytic stage b/c it needs the heme ion to become activated

Artesunate and alkylate rhyme...

1. What is one of the main problems with Artesunate?
2. Toxicity? With which drug is this typically given?

1. It induces its own cyt p450, increasing its own clearance.

    

   1. Some patients have more of an effect than others, so it is very difficult to determine dosage.

    

   Also, when it is used alone, there is a high level of parasite recrudescence (get sick again).

2. Neural effects. Can be a teratogen. 
3. Mefloquine

1. What is the MOA of Atovaquone?
2. Which malaria is it effective against?
3. What is the MOR?

1. Interferes with electron transport in the mitochondria of malaria protazoa (Cyt BC1). This destroys the membrane potential. NOTE: Atovaquone affects cyt BC1
2. P. falciparum's liver stages. (Not P. vivax)
3. Mutations to the Cyt BC1 gene

1. What are the side effects of Atovaquone?
2. What drug is this typically given with?

1. Abdominal pain, vomiting, diarrhea, etc.
2. Works synergistically with proguanil.

P. vivax and P. ovale were/are both endemic to areas that had a winter. So, when there were no mosquitos around to transport the protozoa, these sp. would "hibernate" in the liver. Primoquine targets these forms.

P falciparum and P. malariae are both endemic to tropical regions.

All four forms, when they first enter the human, move first into the liver, multiply, then enter the blood.

1. What is the MOR to pyrimethamine-sulfadoxine and proguanil?
2. Toxicity?
3. What is the active form of proguanil?

1. Mutations to the DHF reductase/ thymidylate synthase enzyme.
2. Some rash, and small depression in hematopoiesis. Large doses - folate deficiency (you can counteract this with leukovorin).  The sulfadoxine has some renal toxicity and skin rash (mainly in immunocompromised patients).
3. Cyloguanil (closes the ring)

1. What is the toxicity of proguanil?

1. Large doses can cause diarrhea and blood in stool. - Think proguanil = guano = blood in stool

1. What would you prescribe prophylactically for Chlorquine-resistant P. falciparum?
2. What about for treatment of P. falciparum?
3. What do you give for prophylaxis/treatment of P. malariae?
4. Prophylaxis/treatment of vivax and ovale?

Clindamycin, quinine and quinidine.

Alternative therapy is azithromycin

1. What ribosomes do clindamycin, quinine, quinidine and azythromycin inhibit?
2. What is clindamycin given with?
3. Toxicity of clindamycin?

1. The apicoplast ribosomes found in certain protozoa.
2. quinine.
3. High incidence of diarrhea. Some patients develop pseudomembranous-colitis because it kills all endogenous flora except for C. dificil - toxin buildup (fatal)

Which is preferably given: quinine or quinidine?

What is the toxicity of quinidine?

MOR?

Quinidine is more potent, and given more often.

Cinchonism, hypotension and hypoglycemia. Quinidine has some cardiac toxicity.

PF1 multidrug resistance gene.

1. What are the Phase I drugs for ALL?
2. The Phase II drugs?

1. Vincristine, prednisone, daunorubicin and asparaginase.
2. Cyclophosphamide, cytarabine and 6-mercaptopurine.

1. MOA for prednisone.

1. Adrenocorticosteroid - induces the lysis of lymphocytes

1. What is the treatment for AML?
2. What is this drug typically given in combination with?

1. Cytarabine (Ara-C)
2. daunorubicin, idarubicin or mitoxanthrone

Treatment for APL?

Treatment for APL relapse?

APL has an aberrant retinoic acid receptor; give an all-trans retinoic acid (ATRA) with daunorunicin or idarubicin.

Arsenic trioxide.

MOA and MOR of cytarabine?

(Ignore picture on the right)

1. Treatment for CML?
2. MOA of the two drugs?

1. Imatinib mesylate (Gleevec) often in combination with hydroxyurea. Also, allogeneic stem cell transplantation (allo-SCT).
2. Imatinib - inhibits BCR-ABL. Hydroxyurea - inhibits ribonucleoside diphosphate reductase.

1. Toxicity for Hydroxyurea?

1. GI distress and hematopoietic depression.

MOPP: mechlorethamine, vincristine (Oncovin), procarbazine and prednisone. This is the classic treatment - not used much anymore.

ABDV: Doxorubicin (Adriamycin), bleomycin, dacarbazine and vinblastine. Newer method.

Hybrid MOPP/ABDV

Treatment depends on grade: Low vs Intermediate vs High.

Chlorambucil, fludarabine or rituximab.

High grade=CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone)+ Rituximab 

What is a Chimeric antibody?

What is an example?

It is a naked monoclonal antibody that is a fused mouse IgV regions with the human Fc.

Rituximab - treats B-Cell NHL.

What are Humanized MABs?

An example?

Not formed through cellular culture. The amino acids responsible for antigen-binding (hypervariable regions) of a mouse Ig and the rest is human Ig.

Alemtuzumab - Ab against CD52 (on both B and T cells). Used against B-Cll

ADCC: Ab-dependent cellular cytotoxicity

CDC: Complement-dependent cytotoxicity

1. Why is Rituximab synergistic with chemotherapy?
2. Toxicity of Rituximab?

1. It sensitizes lymphocytes to the apoptotic effects of chemotherapy.
2. Infusion reactions (the body will make Abs against the mouse Fab), neutropenia and severe skin toxicity (severe inflammation at the site of injection). NOTE: we do not see as much of the infusion reactions in the humanized MABs.

What is a Conjugated MAB?

What is an example?